Radionuclide therapy. Review article

Transcription

1 Volume 58 (3) 2011 Review article Radionuclide therapy Abstract This article follows the article An Introduction to Nuclear Medicine published in this issue of The Radiographer. Nuclear medicine is the injection, ingestion or inhalation of a radiopharmaceutical for the purpose of diagnosis or therapy. While the previous article focussed on the fundamental principles of diagnostic imaging, this paper focuses on the role of nuclear medicine in the treatment of disease. Radionuclide therapy differs from other forms of ionising radiation therapies, such as external beam radiation therapy and brachytherapy, in that photons are not the prime means damaging the target volume. Rather beta and sometimes alpha particles are used to deliver the dose to the target. Delivery methods and biodistribution of the radionuclides are important considerations for optimising the dose to the target volume and for minimising the radiation burden to non-target tissues. One of the benefits associated with some radionuclides used in therapy is that imaging can occur at the concurrently if the radiopharmaceuticals emits both a particle and a photon. This article provides an overview of the mechanisms of dose delivery, types of radionuclides that are used in therapy, clinical applications, recent advances and the future of radionuclides therapies. An understanding of the technical and clinical aspects of radionuclide therapies can provide an improved understanding for medical radiation scientists and in doing so benefit the patient. Keywords: nuclear medicine, radionuclide therapy. JM Wheat 1,2 BAppSci(RT), MMedRadSc(NM), MHlthSc(HM), DHlthSc GM Currie 1,2 MMedRadSc, MAppMngt, MBA, PhD Introduction Shortly after the discovery of radium by Marie and Pierre Curie in 1898, Alexander Graham Bell postulated its use to treat tumours (13) and by 1913 it had been used to treat various diseases. 1 While these activities represent the pioneering days of radiation therapy, it was also the birth of radionuclide therapy. Radionuclide therapy remains a central activity in nuclear medicine quite independent of the applications of radiation therapy today. Indeed, many of the radionuclides first employed for functional studies in nuclear medicine remain in use today as therapeutic agents. This article is designed to provide a broad introduction to the general principles and applications of radionuclide therapy. For the purposes of this article, brachytherapy and teletherapy will be excluded, both of which have synergies with radionuclide therapy. Principles of radionuclide therapy An in depth discussion of the mechanisms of cell damage associated with the formation of hydroxyl free radicals and subsequent reaction with DNA and RNA to produce molecular alterations is beyond the scope of this article. These principles are common to radiation therapy, radionuclide therapy and indeed the safe application of diagnostic procedures. While the general principles of radiation therapy and radionuclide therapy are the same, there are a number of significant differences that should be considered: 2 External beam and brachytherapy emissions are composed of photons, while radionuclide therapy employs particulate emissions (usually beta but some alpha). Radionuclide therapy (and brachytherapy) is associated with prolonged and contiguous exposures, many months in some cases while external beam therapy has very brief high exposures repeat typically daily for a number of weeks. Radionuclide therapy (and brachytherapy) has a declining dose over time due to radionuclide decay while external beam therapy can provide the same repeatable dose on a daily basis. Dose delivery relies on the biodistribution of the radionuclide which may be non-uniform and variable between patients while external beam therapy is externally planned and delivered to a defined field (typically), and brachytherapy is delivered directly to the target tumour. The following discussion will focus on the unique traits and challenges of radionuclide therapy. The principle of delivery of the radiation dose to the target site in radionuclide therapy is the same as that for diagnostic imaging in nuclear medicine (Figure 1). A biological compound of known biodistribution is labelled or tagged to a particulate emitting radionuclide. The therapeutic premise for its efficacy is that the radiopharmaceutical will be delivered to the intended tumour site, be retained indefinitely (for the full length of its radioactive life) and deliver a prolonged radiation dose to those tissues. There are a number of routes of dose administration employed to more efficiently deliver that dose; oral, intra-tumoural, intra-arterial, intra-portal, intravenous and intra-cavital. Each route of administration is aimed at maximising the dose delivery and retention (biodistribution) in the target site (tumour). Advances in dose delivery, like pre-targeting, will be discussed later in this article. In practice, a significant issue confronting R Davidson 1 BBus, MAppSc(MI), PhD H Kiat 1,2 MBBS, FRACP, FACP 1 School of Dentistry and Health Sciences, Faculty of Science, Charles Sturt University, Wagga Wagga, New South Wales 2650, Australia. 2 Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales 2109, Australia. Correspondence to jwheat@csu.edu.au The Radiographer

2 Figure 1: Schematic representation of the basic principles of dose delivery in radionuclide therapy. An exogenous version of a naturally occurring endogenous compound is produced to localise in a particular physiological manner (eg. phosphate metabolism into bone). A radionuclide with a particulate emission is tagged or labelled to the exogenous compound. The radiopharmaceutical is introduced to the biological compartment (eg. intravenous injection) and biodistribution follows. The particulate emission associated with the radiopharmaceutical delivers the dose burden to the tissues. radionuclide therapy is the non-specific localisation of tracers. While radiation therapy is more apt at minimising the radiation burden to non-target tissues, radionuclide therapy like chemotherapy perhaps, is more prone to systemic collateral damage. There is no golden bullet that sees radionuclide localise selectively in just the tumour. Indeed, the relative few radiopharmaceuticals used routinely for radionuclide therapy reflect those that are more specific in localisation. Another important consideration is the biological half-life. Even when localisation specificity is very high, rapid metabolism or excretion can change the biodistribution and this includes the use of intra-tumoural techniques. Furthermore, the time the radionuclide remains in circulation prior to tumour localisation or indeed following elimination from the tumour (including lymphatic drainage) has a bearing on collateral radiation dosage. Localisation and the radionuclide energy will also determine the extent of radiation damage (Figure 2). That is, radionuclide localisation in a small tumour with an energetic beta is likely to cause damage to surrounding normal tissues. Similarly, a larger tumour with localisation superficially on that tumour will damage surrounding normal tissues and perhaps not penetrate the entire tumour. Conversely, a larger tumour with internal localisation of the radionuclide will maximise tumour dose and minimise collateral damage to surrounding tissues. There are, however, significant advantages associated with the use of radionuclide therapy. For some tumour / radiopharmaceutical combinations there is a very high target to background ratio that results in significantly lower collateral damage than would be associated with radiation therapy. Research and development has focussed on highly specific radiopharmaceuticals; radiolabelled peptides and antibodies for example. This has emerged as a sub discipline of radionuclide therapy referred to as targeted radionuclide therapy and even targeted molecular therapy. Nonetheless, traditional radionuclide Figure 2: Collateral damage associated with radionuclide therapy. The blue zones present tumour targeted for therapy. The purple zones represent the area of localisation of the therapeutic agent. The red arrows define the maximum range of the particulate emissions. The schematic on the left highlights collateral damage in surrounding tissue due to the proximity of the therapeutic agent to the surface of the tumour. In the centre, an example of localisation in the centre of the tumour reduces (or eliminates) collateral damage but may not adequately irradiate the rapidly dividing growth tumours cells on the surface of a large tumour. The schematic on the right represents a small tumour which would be ineffectively treated with a medium or high energy beta emitter (low energy or alpha emitter might yield better outcomes). Strontium-89 ( 89 Sr) metastron palliation of bone metastases provides a good example of the effects of collateral damage with bone marrow irradiation causing myelosuppression. One approach developed to overcome these issues is the use of multiple radionuclides. Lutitium-177 ( 177 Lu) and Yittrium- ( Y) labelled somatostatin analogues (octreotide or octreotate) produce a medium energy beta and a high energy beta respectively to produce a better range of dose distribution. 3 therapy administered in a systemic fashion (e.g. oral or intravenous) can deliver therapeutic doses to both a primary tumour and distant (including widespread) metastases concurrently. The use of intra-cavital administration (e.g. synovial, pleural, peritoneal) have been successful for many decades for a localised dose delivery. Perhaps the most important tool in the armamentarium of radionuclide therapy is the tracer principle. That is, a small quantity of the radiopharmaceutical can be used to predict both the spatial distribution and temporal distribution of the larger therapeutic dose. Indeed, even pure beta emitters have had Bremsstrahlung imaging performed to map biodistribution of the radiopharmaceutical. Bremsstrahlung radiation are emissions that are produced when particles are slowed rapidly. 4 Some radionuclides like Iodine- ( I) and Samarium-153 ( 153 Sm) have both beta emitters for therapeutic effects and a gamma emitter for external imaging of the biodistribution. Historically, small doses (diagnostic dose) of I sodium iodide were administered to patients to both detect residual thyroid cancer or distant metastases, predict biodistribution of the therapeutic dose and to monitor response to therapy. An alternative approach would be to use the gamma emitting (non beta) Iodine-123 ( 123 I) for this purpose. As an alternative to Bremsstrahlung imaging for pure beta emitters, similar radiopharmaceuticals might be employed to predict biodistribution of the therapeutic dose. As one example the standard technetium-99m ( 99m Tc) bone scan can be used to predict biodistribution of 89 Sr metastron palliation of painful bone metastases. Arterial infusion therapeutic approaches (eg. Y SIR spheres therapy of liver tumours) 54 The Radiographer 2011

3 Table 1: Summary of a variety of radionuclides available for common use in radionuclide therapy. 2,4,5 Nuclide Particle Gamma suitable for imaging (MeV) Half-life Maximum particle energy (MeV) Maximum range in tissue (mm) Yttrium Y Beta 64.1 hours Rhenium 188 Re Beta hours Phosphorus 32 P Beta 14.3 days Strontium 89 Sr Beta 50.5 days Rhenium Re Beta days Gold 198 Au Beta 0.412** 2.7 days Samarium 153 Sm Beta days Iodine I Beta 0.364* 8.0 days Copper 64 Cu Beta and Positron 1.35** 12.9 hours Copper 67 Cu Beta hours Tin 117 msn Internal conversion / Auger electron days 0.16 electron capture - Lutetium 177 Lu Beta & days Phosphorus 33 P Beta 25.4 days Dysprosium 165 Dy Beta hours Holmium 166 Ho Beta hours Erbium 169 Er Beta 9.5 days Radium 223 Ra Alpha days Bismuth 212 Bi Alpha 60.5 min Astatine 211 At Alpha 7.2 hours Bismuth 213 Bi Alpha 46 min Actinium 225 Ac Alpha 10 days Terbium 149 Tb Alpha 4.2 hours * Energy at the upper limit for imaging** Energy beyond the limits of imaging might be first evaluated with 99m Tc macro aggregated albumin (MAA), macro aggregates that will be trapped in the first capillary beds they encounter (used intravenously for lung perfusion imaging) and, thus, can be used to quantitate the target localisation of the therapeutic dose and predict organs of potential collateral damage. In this example, systemic leakage from the arterial infusion system can be detected before the therapy dose is administered. Recently other approaches have emerged with pairing of a pharmaceutical labelled to both a gamma emitter and a particulate emitter. Perhaps the most notable example in clinical use is the use of Indium-111 ( 111 In) octreotide or Gallium-68 ( 68 Ga) octreotate to provide the imaging of neuroendocrine tumours and then the labelling of the same somatostatin analogues to 177 Lu (medium energy beta emission) and/or Y (high energy beta emission) for the therapeutic effect. This not only predicts biodistribution but it also predicts tumour response to therapy and can be used to monitor response to therapy. The ideal characteristics of a radiopharmaceutical for diagnostic imaging include: Readily available, easily produced and cheap. Short effective half-life (no longer than the time necessary to complete the study). Suitable half-life in consideration of transport times (overcome by generators for general nuclear medicine but remains an issue in PET) in accordance to the ALARA (As Low As Reasonably Achievable) principle. No particle emissions (alpha or beta) due to their high linear energy transfer (LET) and radiation dose. The radionuclide emission should be a gamma between 30 kev and 300 kev (ideally about 150 kev and monochromatic for most efficient detection by the gamma camera). Photon abundance should be high for shorter imaging times. To optimise image quality, high target-to-background ratio via preferential accumulation and retention of the radiopharmaceutical in the target organ combined with rapid clearance from non-target organs. There are a wide variety of radionuclides available for radionuclide therapy (Table 1). When considering therapeutic radiopharmaceuticals, the ideal properties have similarities and difference which include, without being limited to: Readily available, easily produced and cheap. While this is ideal it is rarely possible. The nature of therapeutic agents demands more rigour (and cost) in production. Many of the radionuclides are produced by neutron activation in high neutron fields in a reactor core. Removing radiochemical The Radiographer

4 impurities for these and fission produced radionuclides is costly. The effective half-life should be suitable for the type of therapy. A long half-life (supported by prolonged retention in the tumour) is preferred when a sustained dose is planned, for example the 50 day half-life of 89 Sr for use in palliation of painful bone metastases. For more acute exposures, a shorter half-life is desired. Nonetheless, the half-life needs to sufficiently long to allow the majority of the dose to be delivered once localisation at the tumour site has occurred but short enough to eliminate radiation hazards after elimination (from tumour) or excretion (from body). The radionuclide emission should be a particulate emission. The energy of the emission will depend on the purpose. Low energy beta emissions might be suitable for small tumours while higher energy beta emissions are needed for penetration of tissues up to 1 cm. An alpha emission might be preferred if high LET over a very short distance is preferred. Generally, an absence of photon emissions is preferred to eliminate any external radiation hazards. For example, very large doses of 89 Sr can be administered and the patient sent home because the pure beta emission poses no external radiation hazard. Conversely, a large I dose is accompanied by a 360 kev gamma emission which poses external hazards and requires hospitalisation and isolation of the patient. As previously discussed, the presence of a photon affords the luxury of imaging biodistribution, however, this attribute is generally be default rather than design. That is, it is not ideal for a therapeutic radiopharmaceutical to have a photon emission, but if it cannot be avoided then potential advantages for imaging need to be exploited. High target-to-background ratio via preferential accumulation and retention of the radiopharmaceutical in the target tumour combined with rapid clearance from non-target structures. Rapid clearance from normal tissues plays a crucial role in minimising collateral damage but does increase the radiation burden on the excreting organ (kidneys and bladder usually). While rapid washout from normal tissues is desired, prolonged retention in the target tumour is preferred. To use 89 Sr metastron once again as an example, it rapidly washes out of normal bone to be excreted by the kidneys but has prolonged retention (months) in metastatic bone. The kidney dose is reduced because virtually all excretion occurs in the first two days but the dose is tailored to be delivered over several months. Clinical applications of radionuclide therapy The following discussion provides a snapshot of currently available radionuclide therapy approaches. Some of these techniques have remained unchanged for many decades ( I therapy in thyroid disease), others have only undergone radiopharmaceutical refinement over many decades (bone pain palliation) and some have only recently emerged. Utilisation of these procedures often exhibit ebbs and flows reflecting medical populous at any given time (not always dependent on efficacy or safety considerations). While there are many applications of radionuclide therapy, the following discussion represents the principle clinical applications commonly employed over recent decades. Thyroid cancer Thyroid cancer typically accumulates less I than normal thyroid tissue. Thus, thyroid cancer therapy is complex. Generally, patients will have thyroidectomy which may leave residual thyroid tissue either unintentionally or by design (in order to spare posterior tissue and preserve parathyroid function). I ablation with doses up to MBq (more than 550MBq requires hospitalisation as a regulatory requirement) are used to destroy residual thyroid tissue. Once preferential accumulation of I in normal thyroid tissue has been overcome, subsequent treatments focus on ablating thyroid cancer and metastases. Indeed, imaging with diagnostic doses of I or 123 I tend not to show thyroid cancer or metastases while residual normal thyroid is present. The extent of disease, including metastases, may not be apparent until several courses of ablative therapy have been completed. Hyperthyroidism I radionuclide therapy has been used effectively for many decades for the treatment of hyperthyroidism; Graves and Plummer s disease in the main. In essence, the I therapy is used to decrease thyroid bulk (volume) and thus decrease thyroid function without necessarily removing function altogether. This is important in goitres and in autonomous functioning nodules. In the latter, the nodule operates outside the negative feedback mechanism and, thus, I dosing spares the normal thyroid tissue. There are a number of contraindications; pregnancy and breastfeeding are intuitive given the potential deleterious effects of high energy gamma radiation to the foetus and because of radionuclide excretion in breast milk. Severe thyrotoxicosis is also a contraindication because the I therapy can cause release of thyroid hormones resulting in thyroid storm and potential fatality. It is also worth considering that I can radio-sensitise the thyroid and, thus, it is more important to overdose the patient and render them hypothyroid than to leave them in a hyperthyroid state requiring additional doses; although euthyroid is the target. The required dose can be determined using the thyroid uptake calculation associated with the diagnostic thyroid scan, however, doses are typically less than 550 MBq which means hospitalisation is not required despite the associated gamma emission. Palliation of bone metastases Palliation of painful bone metastases has been an important role for radionuclide therapy for more than three decades. 6 Patients generally present with widespread skeletal metastases mapped on a bone scan with pain originating from evident metastatic deposits. Radionuclide palliation is indicated in patients not responding to opioid analgesic medication in whom haemodynamic and biochemical stability has been established. 6 Bone marrow suppression is the major concern in these patients and an acute side effect can be the flare phenomenon; a transient increase in pain. The duration of pain relief will depend on the radiopharmaceutical used, its half-life and the dose administered (Table 2). Shorter half-lives permit higher doses with more immediate pain relief that tends not to last as long. Longer half-lives require lower doses resulting in slower onset of peak pain relief but can result in protracted relief of pain. The goal of palliation is to improve the quality of life but is probably not indicated in patients with an expected survival of less than 3 months. There are a number of options: 6,7 32 P sodium phosphate has been used historically and has shown greatest success in breast cancer metastases. 89 Sr chloride or metastron is useful due to its longer half-life (50 days), has greater success in prostate cancer metastases and is associated with rapid washout from normal bone and prolonged retention in diseased bone. Re HEDP is a short lived beta emitter with an associated gamma 56 The Radiographer 2011

5 Table 2: Summary of a variety of radiopharmaceuticals available for common use in palliation of painful skeletal metastases. 6,7 Nuclide Half-life (days) Maximum range in tissue (mm) Dose (MBq) Response time (days) Response duration (weeks) Retreat interval (months) 32 P phosphate > 3 89 Sr chloride > 3 Re HEDP > Sm EDTMP / Kg (> 2500) > 2 Table 3: Summary of a variety of radiopharmaceuticals available for common use in radiosynovectomy. 8 Nuclide Half-life (days) Mean penetration (mm) Y silicate Er citrate Re colloid Au colloid emission at 137 kev that allows imaging of biodistribution. It has had greater success in prostate cancer metastases. 153 Sm EDTMP or quadramet is another short lived beta emitter with an associated gamma emission (103 kev) capable of producing imaging of the biodistribution. 117m Sn DTPA (pentetate) has also been reported for use in skeletal metastases palliation. In Australia, 89 Sr metastron and 153 Sm quadramet are principally employed. Radiosynovectomy Y silicate has been used for radiation synovectomy (also referred to as radiosynoviorthesis) for nearly 60 years. 8 It is principally used to relieve pain and inflammation in patients with resistant synovitis due to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and osteoarthritis. 8 The therapy is best suited for a small number of joints not responding to anti-inflammatory medications. There are a number of approaches (Table 3), however, Y silicate is the most common. Given the high energy and range in soft tissue of Y, this agent is best suited to larger joints (eg. knee) to prevent radiation damage to the articular surface. Smaller joints (eg. fingers) are more likely to benefit from the lower energy and range of 169 Er citrate. Re colloid provides an intermediate energy and range for medium size joints. The goal of therapy is to deliver a radiation dose to the layer of synovial cells in the joint capsule and as such, the therapeutic dose is administered into the joint itself. The major risks, other than sepsis, is leakage of the dose from the joint to infiltrate the lymphatics for subsequent systemic biodistribution and the radiation effects of a local leak. Malignant effusion Colloidal 32 P chromate can be used to prevent recurrent malignant effusions. The colloid has particle sizes in the order of microns and doses are administered intracavitally; intraperitoneal, intrapleural, and pericardial. Prior to administration of the therapeutic radiopharmaceutical, a small diagnostic dose of 99m Tc sulphur colloid can be used to eliminate loculated fluid; a contraindication. After injection, a Bremsstrahlung image should be produced to ensure uniform distribution within the cavity; the patient can be moved about for mixing if necessary. This therapy is aimed at preventing recurrence of the effusion by ablating the serosal surfaces and lymphatic deposits. This procedure is not common today and might be seen in rare cases for difficult patients with malignant ascites. Myeloproliferative disorders Polycythaemia vera is an overproduction of red cells with a poor survival. Patients are generally managed with medication, phlebotomy and chemotherapy. 32 P sodium phosphate is used on occasion in older patients (70+ years) not responding to other treatments. The goal of therapy is to increase survival through prolonged remission. Advances in radionuclide therapy There have been considerable developments in radionuclide therapy in recent years. Indeed, a number of new terms have been developed to better describe the more innovative approach taken to more effective treatment of tumours that otherwise confound treatment; radioimmunotherapy, targeted radionuclide therapy, peptide receptor radionuclide therapy, targeted gene therapy, targeted molecular therapy. Therapeutic molecular targeting, which nuclear medicine is uniquely positioned to map, is specific localisation of the therapeutic agent due to distinct interactions characterised by presence (or absence) in a given tumour. 9 The presence (or absence) of a tracer in tumour is relative to that of normal or surrounding tissue. There are a number of models used in molecular targeting: 9 Antigen-antibody Receptor-ligand Transporter-substrate Enzyme-substrate Hybrid models. While those radionuclide therapy approaches discussed above are in widespread use, advanced approaches tend to more sparsely adopted with key oncology referral centres with a high concentration of specialised expertise tending to be the service providers. Current advances that have emerged in clinical practice and which are also attracting ongoing research fit under a number of headings: Radioimmunotherapy (RIT); antibody-antigen model Peptide receptor radionuclide therapy (PRRT); receptor-ligand model Alpha particles Pre-targeting. The Radiographer

6 Figure 3: Schematic representation of the basic principles of pre-targeting in radionuclide therapy. The image on the top represents the traditional approach of invitro conjugation of the radionuclide to the pharmaceutical carrier, administration to the patient and subsequent localisation and tumour irradiation. Clearly the time required for the localisation in the tumour causes collateral radiation exposure and, indeed, there can be non-specific accumulation in non-target organs. The bottom schematic represents pre-targeting. The pharmaceutical carrier is administered and localised independently of the radionuclide. Once a suitable time has elapsed to allow highly specific accumulation on the tumour and elimination of unbound carrier, the radionuclide can be administered which subsequently rapidly labels to the carrier and delivers the radiation dose to the tumour. RIT relates primarily to the work being undertaken with monoclonal antibodies. While monoclonal antibodies are not a new approach (available since the 1950s) to either diagnosis or therapy, recent advances have largely overcome prohibitive limitations of the past (discussed below). In essence, a tumour is recognised by the body as a foreign substance and this elicits an immune response. That is, unique antigens associated with the tumour will cause the production of unique antibodies designed to destroy them. Most immune responses are polyclonal and as a result the antibodies produced are not specific which means the antibody targets the foreign substance and other normal tissues; causing collateral damage. The production of monoclonal antibodies is a process that essentially identifies the single antibody of interest, reproduces that antibody and targets the antibody (and associated radionuclide) for a very specific antigen on the tumour. There have been a number of limitations: Variable penetration and tumour dose rate for different types of tumours None specific accumulation resulting in high bone marrow doses and subsequent myelosuppression. Radiolabeling to suitable nuclides The reproduction of the antibodies needs a suitable host and murine (mouse) monoclonal antibodies can themselves elicit an immune response. The immune response against a familiar antigen (in this case the murine monoclonal antibody) is more immediate and severe which limits re-treatment. These limitations have been overcome with the development of production methods that use fragments of the monoclonal antibody and by humanising the murine antibody. Nonetheless, there remain few monoclonal antibodies in use for therapy. Y Ibritumomab tiuxetan and I tositumomab have been used for non-hodgkin s lymphoma therapy. 10,11 I anti-carcinoembryonic antigen (CEA) is humanised polyclonal antibody has been used for metastatic colorectal cancer therapy. 12,13 Others include: 12,13 I or 177 Lu CC49 for colorectal cancer I A33 for colon cancer I cg250 for primary renal cell carcinoma Y pemtumomab for ovarian cancer I anti-tenascin for glioblastoma. PRRT is sometimes referred to as hormone delivered radiotherapy because therapeutic radionuclides are labelled (or conjugated) with hormones (peptides). The hormones provide a delivery system into the tumour cells to allow the radiation dose to be more specifically delivered. This approach to tumour therapy is possible due to the overexpression of peptide receptors by the tumour cell compared to normal tissues. No doubt the most documented PRRT is the use of somatostatin analogues (octreotide and octreotate) labelled to Y or 177 Lu to target neuroendocrine tumours (discussed below). Cholecystokinene-2 (CCK-2) and Substance P expressing tumours have also be targeted with labelling to Y for therapeutic use. 14 The advantages of beta emissions in delivering a high radiation dose to tissue without presenting external radiation hazards has been discussed above. The high LET of the beta particle is associated with its large mass (compared to a photon) and short range in tissue. 15 An alpha particle (Helium-4 [ 4 He]) by comparison has an enormous mass which results in very short ranges in tissue; in the order of 100 micrometres (or less). 15 Accompanying this short range are very high energies (5-8 MeV). 15 In combination, these two properties minimise collateral damage and maximise cell destruction due to comparably massive local radiation doses. Clearly, without uniform penetration of the alpha based radiopharmaceutical throughout the tumour, irradiation of an entire mass is limited. Nonetheless, for specific purposes, alpha emitters play an important role and there is considerable potential for development. 213 Bi anti-cd33 has been used for myeloid leukaemia and 211 At 81C6 (tenascin-c) has been used in glioblastoma as an advance of I labelling. 15 Pre-targeting is an approach aimed at enhancing radionuclide therapy. There are two strategies that can be employed; the first aimed at improving the delivery and distribution of the therapeutic tracer, and the second aimed at increasing its efficacy using combination therapies (e.g. chemotherapy). 13 The distribution can be enhanced in several ways. One common approach is to use an intervention (eg. interferon) that causes up-regulation of the target receptor or antigen, exacerbating the overexpression already being targeted. 13 This clearly increases the proportion of the dose that localises in the target tumour but some consideration needs to be given to the selectively of the up-regulation. That is, the relative expression reserve may be lower in the tumour than normal tissues and, thus, the relative up-regulation in normal tissues might be greater than tumours. A different approach is localised conjugation. In short, the tradition conjugation of the radionuclide and the pharmaceutical occurs invivo rather than invitro (Figure 3). In theory, pre-targeting should reduce the radiation dose to non-target cells through 58 The Radiographer 2011

7 reduced radionuclide residence time in circulation and more specific tumour uptake. 13 Neuroendocrine tumours Traditionally, I metaiodobenzylguanidine (MIBG) has been used with limited success for the treatment of pheochromocytomas and neuroblastoma. I MIBG has been used for palliation of neuroblastoma. Greater success has been reported recently employing somatostatin analogues like Y octreotide and 177 Lu octreotate to treat neuroendocrine tumours. 3 Peptide therapy is an important development in radionuclide therapy and represents what is referred to as targeted radionuclide therapy. Somatostatin receptor are found in numerous normal tissues, however, in some tumours like neuroendocrine and malignant lymphomas, they are up-regulated (over expression). 16,17 While the body has five main somatostatin receptors, there are three key ones on neuroendocrine tumours and octreotide has affinity for these three. 16,17 Nonetheless and as evidenced by 111 In octreotide imaging, the affinity to these three receptors results in some non-specific localisation. This may be tolerable for imaging but is less than optimal for therapy due to collateral damage. The key receptor for neuroendocrine tumours is receptor 2 and fortunately octreotate has predominant affinity for this receptor. Octreotate, however, has specific affinity for the number 2 somatostatin receptor and this produces higher quality imaging with 68 Ga octreotate. 16,17 More importantly, labelling octreotate with 177 Lu has allowed a more specific and effective treatment for neuroendocrine tumours. Liver metastases Liver metastases are a difficult challenge for the oncologist. One successful approach has been selective hepatic artery embolisation using microsphere occlusion of the arteries supplying the tumour(s). Similarly, chemotherapy agents can be selectively administered into the hepatic artery servicing the tumour to minimise the systemic effects of the therapy. The radionuclide approach is to selectively administer radiolabelled microspheres into the hepatic artery to deliver a localised radiation dose. Selective internal radiation therapy (SIRT) was pioneered in Australia to spare collateral damage typical of other therapeutic approaches. SIRT employs Y labelled microspheres and the biodistribution can be predicted in advance of therapy using a diagnostic dose of the gamma emitting 99m Tc MAA. This approach not only identifies the targets of therapy but can also quantitate both the dose fraction delivered to individual tumours and calculate leakage back to the body system. The future of radionuclide therapy The efficacy of the more traditional approaches to radionuclide therapy (e.g. palliation, thyroid therapy) have weathered decades of scrutiny and development. They will continue to stagnate and surge in terms of their clinical use but will remain a solid foundation on which to build more innovative approaches to radionuclide therapy. While RIT, PRRT, alpha particles and pre-targeting approaches show considerable promise in terms of improving available therapeutic strategies, there are a number of key areas where there is concentrated research and development efforts. These include, without being limited to: 9 Hypoxia Proliferation Apoptosis Angiogenesis Metabolism. Conclusion Radionuclide therapy remains an important strategy in therapeutic management of patients. Traditional radionuclide therapy protocols have been refined to maintain or extend efficacy in key pathologies. Emerging targeted approaches to cancer therapy provide an optimistic outlook for the future of radionuclide therapy and the synergies enjoyed with advanced diagnostic imaging (PET/CT and MRI) and with radiation therapy. References 1 Graham LS, Kereiakes JG, Harris C, Cohen MB. Nuclear medicine from Becquerel to the present. RadioGraphics 1989; 9: Kassis AI, Adelstein SJ. Radiobiologic Principles in radionuclide therapy. J Nucl Med 2005; 46: 4S 12S. 3 de Jong M, Breeman WAP, Valkema R, Bernard BF, Krenning EP. Combination radionuclide therapy using 177Lu and Y-labeled somatostatin analogs. J Nucl Med 2005; 46: 13S 17S. 4 Christian PE, Waterstram-Rich KM, editors. Nuclear medicine and PET/CT: technology and techniques (7th edition). Philadelphia: Elsevier Mosby; Theobald T (ed.). Sampson s textbook of radiopharmacy (4th edition). London: Pharmaceutcial Press; Lewington VJ. 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