Molecular Radiotherapy

CME Nuclear medicine Clinical Medicine 2012, Vol 12, No 4: 381–6

demanding specialist skills. A recent review in haemophilia-related post-haemorrhage Molecular radiotherapy of molecular radiotherapy across the UK synovitis of the knees and ankles.8 showed that whilst the administration of I-131 is fairly widespread, the use of new From pain relief to extending life therapeutic radiopharmaceuticals is lim- John Buscombe, consultant in nuclear ited primarily to a few centres in the South- Radiotherapy is an important treatment medicine, Department of Nuclear Medicine, East and North-West of England.1 Access to option for metastatic bone pain palliation. Addenbrooke’s Hospital, Cambridge treatment is, therefore, constrained both by Local field external beam radiotherapy is Shaunak Navalkissoor, consultant in drug availability and by the small number highly effective in patients with relatively nuclear medicine, Department of Nuclear of specialists with the appropriate knowl- limited skeletal metastases. Disseminated, Medicine, Royal Free Hospital, London edge and experience to undertake this type painful bone metastases following hor- of therapy. mone or chemotherapy failure can be better managed using hemibody radiation or sys- Over the past 10 years the term ‘molecular temic bone-seeking radionuclides. The imaging’ has become increasing familiar, Benign disease treatment advantages of the radionuclide approach and often (mis)used as a code for positron Radioiodine are excellent, with selective bone targeting emission tomography (PET). In some and low incidence of side effects. senses this is correct as PET exploits Although often considered as a treatment Patients are selected on the basis of bone increased uptake of a molecule designed to for cancer, radionuclide therapies are fre- scintigraphy demonstrating increased target a specific tissue whether by a physi- quently used to manage benign disease. uptake at sites of accelerated bone turnover ological process or secondary to pathology. The most common therapeutic application in the bone surrounding the metastases. Nuclear medicine was originally con- in the UK is radioiodine (I-131) treatment The target cell is not the tumour cell itself ceived as a therapeutic specialty, not prima- of hyperthyroidism and non-toxic goitre. but the surrounding fibroblasts and oste- rily for imaging. The role of molecular I-131 is highly effective, safe and probably oblasts which produce the pain mediators radiotherapy has changed since the first the most cost-efficient available treatment such as substance P and slow releasing patients were exposed to therapeutic for hyperthyroidism.2-4 Some patients and substance.9 unsealed sources of radioisotopes referrers may be concerned about potential 70–80 years ago, using simple isotopes such adverse effects of radioactivity, but these Radionuclides for pain relief as radiophosphorous (P-32) or radioiodine reservations can usually be dealt with by (I-131). Since then, complex treatments appropriate discussion and education. A The different radionuclides used for bone have been developed such as radioimmu- lack of knowledge and inertia from refer- pain palliation offer distinct physical prop- notherapy for non-Hodgkin’s lymphoma rers would seem to present the more serious erties such as half-life duration and emitted (NHL) or Y-90 selective internal radio- impediments to increasing the number of radioactivity path length, which in turn therapy (SIRT) for liver metastasis. patients treated. influence clinical response. Treatment with P-32 and I-131 are still Samarium-153 (Sm-153) lexidronate, for available, although the use of the former Radiation synovectomy example, has a relatively short half-life and for polycythaemia is now limited. I-131 less penetrating beta particle emission than remains widely used to treat both benign Radiation synovectomy is commonly per- the major alternative, the calcium analogue and malignant thyroid disease and has formed in Germany, but offered by only a strontium-89 (Sr-89). Sm-153 lexidronate become routine for the former. They have few centres in the UK. It can provide treatment relieves pain rapidly and rarely the advantage of being inexpensive, require important, durable benefit in patients with leads to significant myelosuppression, a relatively straightforward infrastructure significant mono-arthropathies. Treatment although repeated injections at three or four for safe delivery and are administered regu- is administered by intra-articular radiop- month intervals may be required for sus- larly in many UK centres. Other treatments harmaceutical injection, usually under tained benefit. By comparison, pain relief such as radiation synovectomy or radi- radiological or ultrasonographic guid- may be delayed for two to four weeks after opeptide therapy of neuroendocrine ance.5–7 Several different radionuclide Sr-89 administration. Bone marrow recovery tumours (NETs) require specific expertise agents are available, the choice governed by may be slow, but symptom response dura- and are less widely available. the size of the joint being treated. Low- tion is prolonged and may exceed six months There is good evidence that molecular energy beta particle-emitting agents are following a single injection.10–12 radiotherapies are well tolerated, associated used for the small joints of the hands and These treatments can be co-administered with limited side effects and can improve feet, for example, whereas high-energy, with other systemic treatments for bone both quality of life and survival. long range beta-emitting isotopes are better pain such as bisphosphonates or chemo- The recent development of other radio- suited to large joints such as the knee. therapy,13,14 although the latter is associ- nuclide therapies has led to increased cost, Radiosynovectomy is particularly effective ated with a higher incidence of bone requiring dedicated inpatient facilities and in reducing pain and increasing movement marrow suppression.

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Radium-223 somatostatin analogues which attach to the radiotherapy. The chimeric monoclonal type 2 receptor subtype (Fig 1). antibody rituximab has antitumour activity A new approach involves the use of low via targeting of the CD20 antigen expressed activity, bone-seeking alpha-emitting radi- Octreotide derivatives on mature lymphocytes and B cell tumours. onuclides given repeatedly at four-week This epitope is not present on precursor intervals to allow bone marrow recovery. In Many academic institutions have developed cells in the bone marrow so, after clearance phase II clinical trials, radium-223 (Ra- therapeutic radiopeptides using modified of CD20 cells (including tumour sites) 223) improved symptoms, reduced bone octreotide derivatives. The most promising, immunocompetent lymphocytes repopu- alkaline phosphatase and increased overall octreotate, can be linked via a chelator to late rapidly.39–40 15 survival compared with placebo. A phase beta particle-emitting isotopes such as lute- Anti-CD20 antibodies have been labelled III trial of Ra-223 versus placebo in over tium-177 (Lu-177) or yttrium-90 (Y-90) for with I-131 (I-131 tositumomab) and Y-90 900 men with prostate cancer reported a use in metastatic NETs. The results in over (ibritumomab tiuxetan). The latter is avail- 14-month median overall survival in the 1,500 patients, reported by a number of able in Europe and has been shown to Ra-223 treated group compared with centres around Europe, consistently show double the response rate to rituximab. 16 11 months on placebo. disease stability/overall response in about Treatment is administered by intravenous 70% of patients23–38 (Table 1). Disease stabi- infusion on an outpatient basis and is well 41,42 Networks to treat lisation appears to translate to prolonged tolerated. Y-90 ibritumomab tiuxetan neuroendocrine tumours median overall survival which may extend consolidation treatment following induc- beyond five years. Most centres observed tion chemotherapy prolonged progression- An expanding role of molecular radio- that patients who fail to show significant free survival by a factor of three in patients therapy has involved the palliative treat- radiological response immediately after with advanced follicular NHL.43 It has been ment of patients with disseminated NETs. therapy may demonstrate a late response, included safely in conditioning regimens Despite their low incidence, these tumours with tumour shrinkage up to one year after for autologous bone marrow transplanta- progress slowly such that the prevalence of the last treatment.35 tion in aggressive NHL, in combination NETs among patients attending a gastroin- To date, the promise of this treatment with myeloablative BEAM (BCNU, etopo- testinal tumour clinic approaches 10%.17 approach has been restricted by the paucity side, cytarabine and melphalan) chemo- Many of these tumours are hypersecretory, of RCT data. A multicentre phase III study therapy.44 leading to intractable symptoms such as of Lu-177-labelled DOTATATE is planned the carcinoid syndrome. Despite this slow in 2012–2013 which, it is hoped, will pro- The double whammy in liver growth NETs paradoxically often present vide the infrastructure and evidence base to tumours late with disseminated disease that cannot support future use. be managed surgically and are typically There is increasing use of Y-90 labelled chemotherapy resistant.17 Lymphoma particulates such as Y-90 resin beads (Y-90 SIR-Spheres®) or glass balls (Y-90 Follicular NHL is a radiosensitive disease TheraSpheres®). This approach, sometimes I-131 mIBG and presents an ideal target for molecular called SIRT, combines selective partial The first radiopharmaceutical agent used to treat NETs was I-131 metaiodobenzyl- Table 1. Some results of treating disseminated neuroendocrine tumours with guanidine (I-131mIBG), a catecholamine radiopeptides.23-38 analogue with similar properties to Response noradrenaline. It has been most success- Ref. No. Isotope Symptomatic Radiological Median survival fully used in neuroblastoma, malignant (%) (%) (months) phaeochromocytoma18,19 and NETs.20,21 25 87 Y-90 NR 20 NR There are no randomised control trials (RCTs) using I-131mIBG but case control 26 1,109 Y-90 30 34 24 studies show reduced symptoms and sur- 27 58 Y-90 58 9 37 vival improved by at least two years in 28 116 Y-90 83 27 NR patients treated with I-131mIBG compared 33 90 Y-90 88 5 27 with untreated patients.22 35 57 Y-90 72 23 22 One of the advantages of molecular radiotherapy in NETs is that the rate of success can 37 310 Lu-177 NR 30 46 be predicted by pre-imaging. There is posi- 38 51 Lu-177 NR 33 40

tive uptake on diagnostic I-123 or I-131mIBG Radiological response means complete or partial response, as defined by approved criteria such as World scans in 50–80% of patients with NET and Health Organization or Response Evaluation Criteria in Solid Tumors. No. = number of patients treated; NR = nearly 90% have uptake of radiolabelled not recorded.

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Fig 1. 60-year-old man with metastatic medullary thyroid cancer shown on a recent CT scan to have progressive disease. He was referred for peptide receptor radionuclide therapy (PRRT) having had a positive In-111-pentetretotide study, and was treated with four cycles of 7.4 GBq of Lu-177 DOTATATE. Post-therapeutic imaging was performed the day after treatment with images demonstrating the biodistribution after the first cycle of treatment: (a) whole body study, (b) SPECT/ CT demonstrating good uptake in the liver metastases and (c) SPECT/CT demonstrating good uptake in the thyroid, left hilar mass and bone metastases in the sternum.

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embolisation with radiation to treat pri- fatigue for a week post-treatment and tran- treatments such as I-131 for thyroid disease mary liver tumours or organ-confined sient myelosuppression. are inexpensive whereas costs continue to metastases. Treatment delivery requires a Molecular radiotherapy is generally well escalate for more recently developed radi- team approach involving nuclear medicine, tolerated. Common reported side effects opharmaceuticals. Some of the latter may interventional radiology and oncology. In such as nausea and myelosuppression are be provided in the UK via the Cancer New early studies SIRT was shown to lengthen typically less severe and of shorter duration Drugs Fund, but significant regional dis- progression-free survival from seven than would be expected following systemic parities persist and limit access to high months to 12 months compared with chemotherapy. When formally tested as quality treatment. chemotherapy alone in patients with meta- part of a trial, patients gave much higher static colorectal cancer and liver predomi- scores for tolerability of molecular radio- Conclusions nant metastases.45 Cirrhosis does not pre- therapy than of the alterna- clude treatment, and Y-90 TheraSpheres in tives.12,15,16,41,42,51 A detailed review of current research is particular may be used safely in patients beyond the scope of this review. However, who have partial portal vein thrombosis. Cost it has been possible to show that molec- Early side effects include hepatic pain, typi- ular radiotherapy has multiple applica- cally occurring within 24–48 hours. There is a broad spectrum of cost for tions to treat benign and malignant dis- Several trials using radioembolisation to molecular radiotherapy. Long established eases (Table 2). The field is expanding treat primary hepatocellular carcinoma (HCC)46,47 report that it appears superior to transarterial chemoembolisation in Table 2. Current available radionuclide therapies. 48,49 downstaging patients with HCC. SIRT Radiopharmaceutical Clinical indication is increasingly used to treat patients with I-131 Hyperthyroidism hepatic metastases secondary to colorectal Thyroid cancer and NETs.45,50 Further randomised trials are investigating a multimodality approach P-32 Polycythaemia rubra vera combining newer chemotherapy regimens Sr-89 Pain relief of bone metastases with and without SIRT in metastatic colon Sm-153 lexidronate Pain relief of bone metastases cancer and HCC. Ra-223 Improved survival in patients with bone metastases Patient tolerability Y-90, Re-186, Er-169 colloids Radiation synovectomy I-131 mIBG Neuroblastoma Molecular radiotherapy such as I-131, Y-90 Phaeochromocytoma anti-CD 20 antibodies or SIRT is generally NETs given as a once only treatment. Some therapies like I-131 mIBG and Lu-177 DOTATATE Y-90 ibritumomab tiuxetan Non-Hodgkin’s lymphoma are fractionated at approximately 12-week Y-90 particulates Primary and secondary tumours in liver time intervals both to reduce the likelihood Y-90/Lu-177 PRRT NET of significant bone marrow toxicity and to mIBG = metaiodobenzylguanidine; NET = neuroendocrine tumour; PRRT = peptide receptor radionuclide deliver sustained benefit. For radiation pro- therapy. tection reasons, high activity I-131-based treatments usually necessitate admission to hospital for one to five days (due to the high Key points energy gamma rays) but many of the newer Molecular radiotherapy can be used in benign and malignant disease treatments using pure beta and alpha emit- ters can be administered safely as outpatient Access to molecular radiotherapy varies across the UK procedures. I-131 treatment for benign thyroid dis- The treatment methods used involve simple molecules such as 131I sodium iodide to radiolabelled antibodies. ease may cause a transient sore throat but is otherwise well tolerated in patients ren- Neuroendocrine tumours respond to molecular radiotherapy when chemotherapy and dered biochemically euthyroid prior to biotherapy fail treatment. The likelihood of post-treat- With the arrival of radium treatment in metastatic prostate cancer molecular ment hypothyroidism reflects both the radiotherapy moves from palliating pain to improving survival underlying aetiology and administered activity. I-131 mIBG or Lu-177 DOTATATE KEYWORDS: radionuclide, therapy, thyroid, lymphoma, neuroendocrine tumours, may cause nausea for 24–48 hours and prostate cancer

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