Radiation Protection Dosimetry Advance Access published March 26, 2015 Radiation Protection Dosimetry (2015), pp. 1–8
doi:10.1093/rpd/ncv061
PATIENT DOSIMETRY IN NUCLEAR MEDICINE So¨ren Mattsson* Medical Radiation Physics, Department of Translational Medicine, Lund University, Ska˚ne University Hospital Malmo¨, SE-205 02 Malmo¨, Sweden *Corresponding author: [email protected]
INTRODUCTION In spite of considerable progress, many advances remain to be achieved in the estimation of organ absorbed doses and in the prediction of biological effects of ionising radiation from radiopharmaceuticals. For patients undergoing diagnostic procedures, the biokinetics of the radiopharmaceutical (actually of the radionuclide) is determined for a limited number of representative patients. It is not considered necessary and practically feasible to make dose estimates for each individual patient. Published biokinetic data for a number of radiopharmaceuticals are, however, still scarce, especially with regard to quantitative measurements(1). The main clinical interest is the distribution of the test substance during the first hours after administration, whereas for dosimetry, long-term retention is as important, sometimes even more important. When radiopharmaceuticals are used for therapy, it is essential to determine the biokinetics for the individual patient to be able to estimate the absorbed doses to critical normal organs/tissues and to the target volume with high accuracy. In practice, however, still many therapies are carried out without pre-therapy activity administration, measurements and individual dose planning. The aim of this paper was to describe current methods for patient dosimetry and to draw attention to some of the remaining problems in the radiation dosimetry for radiopharmaceuticals with reference both to diagnostic nuclear medicine and to therapy with radiopharmaceuticals.
ACTIVITY CONTENT IN ORGANS AND TISSUES AND ITS TIME VARIATION For pharmaceuticals labelled with radionuclides emitting single photons, the planar conjugate view method(2) has been the way to investigate the activity content in organs and tissues and its time variation. The accuracy of this technique is limited by the lack of knowledge of the source-organ thickness and the difficulties to correct for organ overlap(3). SPECT is a way to solve some of these problems, but to get acceptable statistics in the images very long acquisition times are needed. New more sensitive SPECT cameras may help. In SPECT/CT, the CT images are used, not only for identification of anatomical details but also as a basis for attenuation correction(4). In a similar way, PET/CT is used for patient-specific 3D image-based internal dosimetry using the patient’s own anatomy and spatial distribution of activity as a function of time. DESCRIPTIVE BIOKINETIC MODELS VERSUS DETAILED COMPARTMENT MODELS The ultimate goal is to construct detailed physiologically and metabolically correct compartment models(5) for each substance and situation. This is often not possible due to lack of data and understanding of the detailed behaviour of the substance in the body. Therefore, for dosimetry, the biokinetic information is usually presented in terms of fractional uptakes and
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In diagnostic nuclear medicine, the biokinetics of the radiopharmaceutical (actually of the radionuclide) is determined for a number of representative patients. At therapy, it is essential to determine the patient’s individual biokinetics of the radiopharmaceutical in order to calculate the absorbed doses to critical normal organs/tissues and to the target volume(s) with high accuracy. For the diagnostic situations, there is still a lack of quantitative determinations of the organ/tissue contents of radiopharmaceuticals and their variation with time. Planar gamma camera imaging using the conjugate view technique combined with a limited number of SPECT/CT images is the main method for such studies. In a similar way, PET/CT is used for 3D image-based internal dosimetry for PET substances. The transition from stylised reference phantoms to voxel phantoms will lead to improved dose estimates for diagnostic procedures. Examples of dose coefficients and effective doses for diagnostic substances are given. For the therapeutic situation, a pre-therapeutic low activity administration is used for quantitative measurements of organ/tissue distribution data by a gamma camera or a SPECT- or PET-unit. Together with CT and/or MR images this will be the base for individual dose calculations using Monte Carlo technique. Treatments based on administered activity should only be used if biological variations between patients are small or if a pre-therapeutic activity administration is impossible.
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HUMANLIKE PHANTOMS FOR ABSORBED DOSE CALCULATIONS The dosimetric MIRD system(7) for assessment of absorbed dose is based on knowledge of the cumulated activity in a source region, and the absorbed fraction of energy in a target region due to radiation emitted in the source region. Summing up contributions from all source regions will give an estimate of the absorbed dose to the target region. The ongoing transition from stylised reference computational phantoms to voxel phantoms (available for adult male and female(8) and planned for children) may lead to improved dose estimates. Alternative phantoms, e.g. the non-uniform rational B-spline(9) can be an alternative and represents a broader population of nuclear medicine patients. Still the dose estimates are valid only for the phantom and not for the individual patient. A real challenge for the therapeutic situation is to describe the individual patient by imaging (CT, MR) and then make individual dose calculations using Monte Carlo simulations(10, 11) based on a pre-therapeutic biokinetic investigation. To check the results of such calculations, in vivo measurements—when using photon and betaparticle-emitting radionuclides—can be done using small TLDs, OSL dosemeters, diodes and now also quantum dot dosemeters, the latter with physical dimensions of a few nanometres(12). DIAGNOSTIC NUCLEAR MEDICINE Biokinetic models designed for the purpose of dose calculations for specific radiopharmaceuticals are published in the open literature, often together with some type of dose estimates. Alternatively, biokinetic models can be constructed from various published data related to the uptake, turn-over and retention of the radiopharmaceutical. The ICRP has evaluated published biokinetic and dosimetric data related to radiopharmaceuticals in current diagnostic use during over 40 y and
initiated a number of additional biokinetic studies. Most of the substances used today are covered in the ICRP Publications 106(6), 80(13) and 53(14). These data refer with some exceptions to normal patients. For patients with various degrees of illnesses, there is still a need to estimate biokinetics and organ/tissue doses. Further studies of age-dependent biokinetics and dosimetry are also highly desirable. The work regarding radiopharmaceutical dosimetry is done in parallel to the work in ICRP regarding development of biokinetic and dosimetric models for the estimation of equivalent and effective dose coefficients for occupational and public exposures from internal emitters(15). 99m
Tc substances
Organ doses and effective doses for a number of 99mTclabelled substances have been published by ICRP(6, 13, 14). Organ doses may differ considerably between substances, but the effective dose is robust to such variations. As the physical half-life is short (6.01 h), variations in biokinetic behaviour will not influence the effective dose very much and for most substances the effective dose coefficient is 0.004–0.017 with a mean value of 0.009 mSv MBq21(17) (see some examples in Figure 1). PET substances Also for PET substances, the variations in effective dose coefficients for 18F (Tphys ¼ 1.8 h) and 11C (Tphys ¼ 20 min) labelled substances, respectively, are relatively small: for 18F 0.016–0.028 mSv MBq21 with a mean value of 0.02 mSv MBq21 and for 11C substances 0.0027–0.0084 with a mean value of 0.005 mSv MBq21 (see some examples in Figure 2). 123,124,125,131
I-iodide
Biokinetic models for iodide have been published by ICRP to be used both for occupational and environmental exposure(18) and for nuclear medicine investigations(14). For dose estimation in nuclear medicine, the MIRD model by Berman(19) has been widely used. ICRP(20) has also published a model for iodide in the pregnant woman and the fetus. In ICRP models intended for nuclear medicine patients, the uptake in stomach wall and salivary glands has to be included. This is not the case for the models intended for dosimetry of occupationally or environmentally exposed persons. On the other hand, models for patient dosimetry have been simplified in such a way that they are unsuitable for dosimetry of the long-lived isotope 129I; however, not used in nuclear medicine, but of interest in connection with environmental and occupational exposures. Owing to this discrepancy a more general compartment model, which can be used for different purposes, has been developed(21). A more elaborated physiological systems model for iodine has recently been proposed for use in radiation
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biological half-times for specific regions of the body, i.e. first-order kinetics are assumed for the transfer between regions(6). Thus, a sum of exponential functions is normally used to describe the retention. In addition to the radiopharmaceutical-specific models, a number of general models describing the kinetics of the excretion routes are used: a kidney–bladder model, a liver–gallbladder model and a gastro-intestinal tract model(6). Many radiopharmaceuticals are mainly and quickly excreted through the urine. In those cases, the assumption about the bladder voiding period may be critical for the dosimetry. ICRP(6) assumes a bladder voiding interval of 3.5 h for adults as well as for 15 and 10 y old, 3.0 h for 5 y old and 2.0 for 1 y old and newborn. The variations are, however, considerable and influence the absorbed dose to the bladder wall and a number of nearby organs.
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protection(22) and is now also used in the most recent ICRP radiopharmaceutical dose compendium(17). Other substances Figure 3 gives dose coefficients (mSv MBq21) for some radioiodides and other substances labelled with 123 I and 131I as well as for some 201Tl-, 111In-, 75Se-, 67 Ga-, 51Cr-, 14C- and 3H-labelled substances. Dose per investigation To get the effective dose per investigation, the dose coefficients have been multiplied with the administered activities typically used. Figure 4 gives a rough classification of nuclear medicine investigations with respect to the effective dose to adult patients(6, 13, 16, 17). Challenges in dosimetry for diagnostic nuclear medicine For a number of radiopharmaceuticals, biokinetic data are more than 20 y old. Therefore there is a need to generate new data on biokinetics using state-of-the-art equipment. Other limitations are the few subjects per study and both genders are not always well represented.
Biokinetic data for children differs from those for adults and in general more age-specific biokinetic data, especially for children, are needed as well as biokinetic data for ill. To facilitate the collection of relevant data from different hospitals and facilitate exchange of data, more uniform dosimetry protocols should be used(23).
THERAPEUTIC NUCLEAR MEDICINE Therapeutic nuclear medicine is using radionuclides that are either conjugated to tumour-targeting agents (e.g. antibodies, peptides and small molecules) or concentrate in specific tissues through natural mechanisms that occur in cells with an abnormal growth rate or otherwise targeted cells (e.g. in benign thyroid disorders)(10). For most current cancer treatment options available today (e.g. conventional chemotherapy and external radiotherapy), the approach has been to destroy populations of cells that show uncontrolled growth. This focus on non-specific cell division implies that the treatment will often be non-selective, also damaging rapidly dividing non-tumour cells, such as those in the gut. Delivering targeted radiation to malignant cells with therapeutic radiopharmaceuticals has significant advantages. It allows one to seek out and destroy
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Figure 1. Effective dose coefficient (mSv MBq21) for 99mTc-labelled radiopharmaceuticals(6, 13, 17).
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13, 17)
for
18
F- and 11C-labelled radiopharmaceuticals and for 15 O-water.
diseased cells while protecting healthy cells in the vicinity. The selected antibody or peptide is preferentially one that itself can reduce or limit cellular proliferation by its action on a specific antigen or cell surface receptor. When combined with a radionuclide, it offers a synergistic effect in destroying malignant cells. At present, effective targeted radiopharmaceutical therapies have been developed and validated for a few tumour types, such as malignant lymphoma. For most other tumour types, the older non-specific types of cancer treatments are still the dominant form of therapy. Dose planning has to be carried out on an individual patient by patient basis and comprises the pre-treatment determination of the amount of activity to administer in order to maximise the effect on the tumour while managing the dose to normal tissue. This pre-treatment determination involves quantitative uptake and retention measurements in target volume and in normal tissues. In addition, knowledge of organ volumes is necessary for the calculation of the absorbed dose. Dose planning is however not always performed and the prescription is based on the results of earlier escalation trials(11). Such cohort-based treatment planning can lead to under- or over-treatment in individual patients due to different biodistribution among patients. Consequently, the cohort-based approach
82
Rb-chloride and
should only be used if biological variations between patients are small or if a pre-therapeutic activity administration is impossible. Benign thyroid disorders and thyroid cancer 131 I-iodide is used to treat benign thyroid disease since 1940s. It is still the dominating radiopharmaceutical therapy with respect to number of treated patients. Fixedactivity treatments are still used in many places. For treatment of hyperthyroidism, studies have shown that this results in too much activity to most patients(24, 25) and recent studies have shown that an absorbed dose-based criterion (requires knowledge of thyroid volume and 24 h uptake) gives a better outcome of the treatment(26 –28). It is important both for the individual patient and for the understanding of the radioiodine therapy and its future optimisation that the absorbed dose to the thyroid is quantified(29). 131 I-iodide is also used for treatment of differentiated thyroid cancer. After total thyroidectomy, thyroid cancer is treated with fixed administered activity with multiple re-administrations dependent on the patient response. Repeat administration continues until no iodide uptake is demonstrated. There are multiple reasons for this treatment: (1) to eradicate
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Figure 2. Effective dose coefficient (6,
PATIENT DOSIMETRY IN NUCLEAR MEDICINE
89
Figure 4. Overview of range of effective dose per investigation for radiopharmaceuticals with different radioactive markers(16, 17). Note the log-scale.
thyroid remnants, (2) to irradiate any neoplastic focus and (3) to perform total-body scanning for persistent carcinoma.
Sr-chloride, or they may emit a minor amount of gamma radiation, such as 153Sm-EDTMP (ethylene diamine tetramethylene phosphonate), which also allows visualising the distribution of the substance using a gamma camera. Another beta-emitting substances that have been used for bone palliation are 186,188 Re-EHDP (hydroxyethylidene diphosphonate). Alpha emitters have shown to be advantageous, due to the short-range and high energy of the alpha particles. A bone-seeking substance of special interest is 223Rachloride(30). A more careful dose planning, especially in relation to the red bone marrow dose, than has been done up to now is a prerequisite for the ongoing work on absorbed dose escalation (also using a mixture of short- and long-lived radionuclides) and the development of integrated therapies, combining chemotherapy or biphosphonate therapy with radiopharmaceutical therapy or combining external and radiopharmaceutical therapy.
Bone palliation Bone pain arising from skeletal metastases from prostate or breast tumours are treated with bone-seeking radiopharmaceuticals when other therapeutic measures fail. The substances are preferentially taken up in the metastases since the proliferation rate is higher there. For this purpose, pure beta-emitters are used, such as
Monoclonal antibodies for treatment of lymphoma, micrometastases and disseminated tumours By labelling tumour specific monoclonal antibodies with radionuclides a potential tool for a treatment, and hopefully an eradication of micrometastases and disseminated tumours, is obtained. Such substances have
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Figure 3. Effective dose coefficient (mSv MBq21) for 201Tl-, 131,123I-, 111In-, 75Se-, 67Ga-, 51Cr-, 14C- and 3H-labelled substances(6, 13, 17). Mean values for 11C-, 99mTc- and 18F-labelled substances are indicated on the x-axis. Note the log-scale.
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Neuroendocrine tumours Inoperable, advanced, recurrent and metastatic neuroendocrine tumours may be treated with 131I-mIBG (meta-iodobenzylguanidine). It is a noradrenaline analogue—taken up in neuroectodermal tumours including adulthood phaeochromocytoma, carcinoid, paraganglioma, medullary thyroid cancer and neuroblastoma in infancy and childhood. Information on whole-body kinetics and absorbed doses is available from several authors. Neuroendocrine tumours also express somatostatin receptors. There are several analogues developed for radiolabelling with 90Yor 177Lu. 90 Y DOTATATE ([DOTA0, D-Phe1, Tyr3]-octreotate) and 177Lu DOTATATE are currently the most used. Treatment with 177Lu-octreotate has increased significantly in frequency during the last years. At these
treatments, the kidneys are critical organs. Therefore, good kidney dosimetry is necessary(33, 34). Treatment of liver tumours with microspheres For inoperable primary liver cancers and liver metastases, selective internal radiation treatment is a treatment modality that is rapidly growing(35). Inert microspheres labelled with 90Y are injected into the intrahepatic artery via a catheter and under fluoroscopy. The planned dose in the liver is 4 Gy to normal liver tissues and four times more is expected to the tumours, but without individual dosimetry, the resulting doses can vary very much (at least a factor of four). A methodology for a more accurate dosimetry has therefore been described(36). Polycytemia Today there remains a distinct sub-group of elderly patients with polycythaemia vera and essential thrombocythaemia for whom 32P-orthophosphate is the most optimal treatment option. The phosphate ion is a bone-seeker and this makes the radiopharmaceutical suitable for radiotherapy of the bone marrow. The radiopharmaceutical is used to suppress hyperproliferative cell lines rather than to eradicate them. 32P is, however, also distributed into proliferating and proteinsynthesising cells, resulting in an enhanced absorbed dose, besides in bone tissue, also in liver and spleen(37). Usually, the substance is administered orally, but may also be given intravenously. The activity is generally given as a fixed activity per unit body surface alternatively a fixed activity per unit body weight. Typical activity and absorbed dose per administration for some common therapy agents are given in Table 1. NON-UNIFORM DISTRIBUTION OF ACTIVITY Data on sub-organ activity distributions are especially important in radionuclide therapy as ‘cold spots,’ or regions receiving inadequate absorbed dose, can lead to reduced tumour control probabilities and failure to cure or control disease. In such cases, the evaluation of the absorbed doses to tissue regions with sub-millimetre dimensions ranging up to dimensions of only a few centimetres is of interest. A number of the gamma (photon)-emitting radionuclides used in diagnostic nuclear medicine (e.g. 99m Tc, 123I, 111In, 67Ga, 201Tl) also emit Auger electrons or low-energy beta-particles(38 – 40). Their very short-range in biological tissues may lead to dose heterogeneity at the cellular level with radiobiological consequences. Experiments show that the biological effects of Auger emitters incorporated into DNA can be severe, with relative biological effectiveness .1
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been subject for research for a long period, and presently two commercially available labelled antibodies are ibritumomab tiuxetan labelled with 90Y (Zevalinw) and tositumomab labelled with 131I (Bexxarw) for the treatment of non-Hodgkins lymphoma(31). The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells, allowing radiation from the attached radionuclide to kill them and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells. As an example, the ibritumomab regimen takes 7–9 d, with two administrations of ibritumomab. The first uses 111 In-ibritumomab for imaging and assessment of the biodistribution of the compound. This test activity is also used to determine that no excess amounts go to the bone marrow, liver etc. Then, 90Y-ibritumomab is administered by i.v. infusion. For clinical research, various other antibodies are labelled with a number of radionuclides emitting beta-radiation, 90Y, 131I, 177Lu etc., and also alpha emitters, such as 211At (32), which show advantageous properties, since they will deliver a highly localised radiation dose to micro metastases. Often today in clinical routine, the dosage of the radionuclide in these cases is based on clinical studies of therapeutic effect and effect on normal tissues, such as red bone marrow or kidneys. As a result of these studies, a fixed activity per unit body weight has been established, which spares normal tissues from acute effects of the irradiation, but still has a therapeutic effect on the tumour. This is a simple but suboptimised way of treatment. In reality since a large margin is needed to the threshold for severe damage of the critical organ, the tumour dose may be too low to reach curative effect. An accurate dosimetry will therefore increase the probability for a successful treatment.
PATIENT DOSIMETRY IN NUCLEAR MEDICINE Table 1. Typical activity and absorbed dose per administration for some common therapy agents (excluding 131I-iodide) (7). Substance
32
P-phosphate Sr-chloride 153 Sm-EDTMP 90 Y-Zevalinw 131 I-Bexxarw 177 Lu-octreotate 89
Typical adm. activity (MBq) 185 150 2500 1000 3000 7400
Tumour dose (Gy)
Critical organ 1 (Gy)
Critical organ 2 (Gy)
Bone surfaces: 2.0 Red bone marrow: 1.7 Red bone marrow: 3.8 Red bone marrow: 2.7 Kidneys: 5.9
200
Red bone marrow: 2.0 Bone surfaces: 2.6 Bone surfaces: 17 Kidneys: 2.4 Thyroid: 8.1 Kidneys: 23
SUMMARY AND CONCLUSIONS There is continuously a need to collect biokinetic data from patients/volunteers related to the clinically used radiopharmaceuticals for diagnostic purposes. When radiopharmaceuticals are used for therapy, it is essential to try to determine the individual kinetics to be able to calculate the absorbed doses to critical normal organs/tissues with high accuracy. It is a challenge to develop a dosimetry that predicts the biological effects of short-range alpha particles, low-energy betaparticles and Auger electrons. There is currently not enough knowledge to fully understand what scale of dosimetry is needed to understand and predict radiation effects; absorbed
dose to whole organs, sub-organ regions, voxel regions, single cells. This research to use radiobiological modelling to convert the temporal and spatial distribution of absorbed dose to a BED for tumour tissue and for normal tissues might be a way forward.
FUNDING This work was partly supported by the Swedish Radiation Safety Authority [grant number SSM20141570]. REFERENCES 1. Eberlein, U., Bro¨er, J. H., Vandevoorde, C., Santos, P., Bardie`s, M., Bacher, K., Nosske, D. and Lassmann, M. Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine – a review. Eur. J. Nucl. Med. Mol. Imaging 38, 2269– 2281 (2011). 2. Fleming, J. S. A technique for the absolute measurement of activity using a gamma camera and computer. Phys. Med. Biol. 24, 176– 180 (1978). 3. Norrgren, K., Leide-Svegborn, S., Areberg, J. and Mattsson, S. Accuracy of the quantification of organ activity from planar gamma camera images. Cancer Biother. Radiopharm. 18, 125–131 (2003). 4. Mattsson, S. and Skretting, A. Sealed radionuclide and X-ray sources in nuclear medicine. In: Physics in Nuclear Medicine. Cantone, M. C. and Hoeschen, Ch., Eds. Springer, pp. 61–69 (2011). 5. Giussani, A. and Uusija¨rvi, H. Biokinetic models for radiopharmaceuticals. In: Physics in Nuclear Medicine. Cantone, M. C. and Hoeschen, Ch. Eds. Springer, pp. 233–255 (2011). 6. ICRP. Radiation dose to patients from radiopharmaceuticals. A third amendment to ICTP Publication 53. ICRP Publication 106. Ann. ICRP 38(1– 2) (2008). 7. Nosske, D., Mattsson, S. and Johansson, L. Dosimetry in nuclear medicine diagnosis and therapy. In: Medical Radiological Physics. (Landolt-Bo¨rnstein New Series, Group VIII: advanced Materials and Technologies), Vol. 7, Subvol. A, Kaul, A., Ed. Springer-Verlag, pp. 4: 1–62 (2012). 8. ICRP. Adult reference computational phantoms. ICRP Publication 110. Ann. ICRP 39(2) (2009). 9. Lee, C., Lee, C., Lodwik, D. and Bolch, W. E. NURBSbased 3-D anthropomorphic computational phantoms for
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compared with external X-rays. These findings clearly show that the assessment of biological risks associated with internal administration of diagnostic radiopharmaceuticals must focus not only on target organs as a whole, but also on the cellular level. MIRD has given detailed advice and presented S-values for the cellular level(41). It is still, however, difficult to establish the intracellular distribution of the radionuclides of interest so that such detailed S-values can be used effectively. For therapy, there is an increasing interest to combine targeting substances (antibodies, peptides etc.) with alpha particle or Auger electron emitters. Uptake non-uniformity and associated absorbed dose non-uniformity may significantly affect the outcome. Another factor is that the time of tumour volume changes is comparable with the time of maximal uptake and radiopharmaceutical effective half-time, affecting the dose estimates because of volume changes during dose delivery. The efficacy of targeted radionuclide therapy is thus dependent on the uniformity of the radionuclide uptake distribution, volume changes during treatment and also on radiosensitivity of the tissues. The biologically effective dose (BED) might be a relevant quantity in terms of establishing response or toxicity relationships(42). It also normalises differing dose rates of multiple modalities so that various treatment modalities can be combined.
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10. 11. 12.
13.
15. 16.
17.
18. 19. 20. 21.
22. 23.
24. 25. 26.
27.
28. Stabin, M. G., Sharkey, R. M. and Siegel, J. A. RADAR Commentary: Evolution and current status of dosimetry in nuclear medicine. J. Nucl. Med. 52(7), 1156–1161 (2011). 29. Jo¨nsson, H. Radioiodine therapy of hyperthyroidism. Simplified patient specific absorbed dose planning. PhD thesis. Departments of Radiation Physics, Lund University, Malmo¨ University Hospital, Malmo¨, Sweden (2003); ISBN 91-628-5753-3. 30. Lassmann, M. and Nosske, D. Dosimetry of 223Ra-chloride: dose to normal organs and tissues. Eur. J. Nucl. Med. Mol. Imaging 40, 207–212 (2013). 31. DeNardo, G. L. Treatment of non-Hodgkin’s lymphoma (NHL) with radiolabeled antibodies (mAbs). Sem. Nucl. Med. 35(3), 202– 211 (2005). 32. Andersson, H. et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of 211At-MX35 F8ab’)2—a phase 1 study. J. Nucl. Med. 50, 1153–1160 (2009). 33. Garkavij, M. G., Nickel, M., Sjo¨green-Gleisner, K., Ljungberg, M., Ohlsson, T., Winga˚rdh, K., Strand, S. E. and Tennvall, J. 177Lu-[DOTA0, Tyr3] ocreotate therapy in patients with disseminated neuroendocrine tumors: Analysis of dosimetry with impact on future therapeutic strategy. Cancer 116, 1084– 1092 (2010). 34. Swa¨rd, C., Bernhardt, P., Ahlman, H., Wa¨ngberg, B., Forssell-Aronsson, E., Larsson, M., Svensson, J., RossiNorrlund, R. and Ko¨lby, L. [177Lu-DOTA 0-Tyr 3]octreotate treatment in patients with disseminated gastroenteropancreatic neuroendocrine tumors: the value of measuring absorbed dose to the kidney. World J. Surg. 34(6), 1368– 1372 (2010). 35. Ahmadzadehfar, H., Biersack, H. J. and Ezziddin, S. Radioembolization of liver tumors with yttrium-90 microspheres. Semin. Nucl. Med. 40, 105 –121 (2010). 36. Gulec, S. A., Sztejberg, M. L., Siege, J. A., Jevremovic, T. and Stabin, M. Hepatic structural dosimetry in 90Y microsphere treatment: A Monte Carlo modeling approach based on lobular microanatomy. J. Nucl. Med. 51, 301– 310 (2010). 37. Thomas, S. R. Options for radionuclide therapy: from fixed activity to patient-specific treatment planning. Cancer Biother. Radiopharm. 17, 71– 82 (2002). 38. Paquet, F., Barbey, P., Bardie`s, M., Biau, A., Blanchardon, E., Chetioui, A., Lebaron-Jacobs, L. and Pasquier, J. L. The assessment and management of risks associated with exposures to short-range Auger- and betaemitting radionuclides. State of the art and proposals for lines of research. J. Radiol. Prot. 33, R1–R16 (2013). 39. Bingham, D., Gardin, I. and Hoyes, K. P. The problem of Auger emitters for radiological protection. Radiat. Prot. Dosim. 92(1– 3), 219–228 (2000). 40. Hofer, K. G. Dosimetry and biological effects of incorporated Auger emitters. Radiat. Prot. Dosim. 79(1– 4), 405– 410 (1998). 41. Goddu, S. M., Howell, R. W., Bouchet, L. G., Bolch, W. E. and Rao, D. MIRD cellular S-values. Society of nuclear medicine, Inc. (1997). 42. Prideaux, A. R., Song, H., Hobbs, R. F., He, B., Frey, E. C., Ladenson, P. W., Wahl, R. L. and Sgouros, G. Three-dimensional radiobiologic dosimetry: Application of radiobiologic modeling to patient-specific 3-dimensional imaging-based internal dosimetry. J. Nucl. Med. 48, 1008–1016 (2007).
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14.
radiation dosimetry applications. Radiat. Prot. Dosim. 127(1– 4), 227–232 (2007). Sgouros, G. and Hobbs, R. F. Dosimetry for radiopharmaceutical therapy. Sem. Nucl. Med. 44, 172–178 (2014). Glatting, G., Bardie`s, M. and Lassmann, M. Treatment planning in molecular radiotherapy. Z. Med. Phys. 23, 262– 269 (2013). Stodilka, R. Z., Carson, J. J. L., Yu, K., Zaman, M. B., Li, C. and Wilkinson, D. Optical degradation of CdSe/ ZnS quantum dots upon gamma-ray irradiation. J. Phys. Chem. C, 113(6), 2580– 2585 (2009). ICRP. Radiation dose to patients from radiopharmaceuticals. Addendum 2 to ICRP Publication 53, ICRP Publication 80. Ann. ICRP 28(3) (1998). ICRP. Radiation dose to patients from radiopharmaceuticals. ICRP Publication 53. Ann. ICRP 18(1– 4) (1987). Harrison, J. Biokinetic and dosimetric modelling in the estimation of radiation risks from internal emitters. J. Radiol. Prot. 29, A81– A105 (2009). Mattsson, S. and Andersson, M. Rules of the thumb and practical hints for radiation protection in nuclear medicine. In: Radiation Protection in Nuclear Medicine. Mattsson, S. and Hoeschen, C. Eds. Springer-Verlag, pp. 151 –159 (2013). ICRP. Radiation dose to patients from radiopharmaceuticals: a compendium of current information related to frequently used substances. ICRP Publication 128 (2015) (in press). ICRP. Age-dependent doses to members of the public from intake of radionuclides. ICRP Publication 56. Part 1. Ann. ICRP 20(2) (1989). Berman, M. Iodine kinetics. In: Methods in Investigative and Diagnostic Endocrinology. Vol. 1. Berson, S. A. Ed. North Holland, pp. 172–203 (1972). ICRP. Doses to the embryo and fetus from intakes of radionuclides by the mother. ICRP Publication 88. Ann. ICRP 31(1–3) (corrected version, May 2002) (2001). Johansson, L., Leide-Svegborn, S., Mattsson, S. and Nosslin, B. Biokinetics of iodide in man: refinement of current ICRP dosimetry models. Cancer Biother. Radiopharm. 18, 445–450 (2003). Leggett, R. W. A physiological systems model for iodine for use in radiation protection. Radiat. Res. 174, 496– 516 (2010). Lassmann, M., Chiesa, C., Flux, G. and Bardie`s, M. Dosimetry committee guidance document: good practice of clinical dosimetry reporting. Eur. J. Nucl. Med. Mol. Imaging 38, 192–200 (2011). Jo¨nsson, H. and Mattsson, S. Excess radiation absorbed doses from non-optimised radioiodine treatment of hyperthyroidism. Radiat. Prot. Dosim. 108, 107–114 (2004). Stabin, M. G. Update: the case for patient-specific dosimetry in radionuclide therapy. Cancer Biother. Radiopharm. 23(3), 273–284 (2008). Kobe, C., Eschner, W., Sudbrock, F., Weber, I., Marx, K., Dietlein, M. and Schia, H. Graves’ disease and radioiodine therapy; is success of ablation dependent on the achieved dose above 200Gy? Nuklearmedizin 47, 13–17 (2008). Flux, G. D., Haq, M., Chittenden, S. J., Buckley, S., Hindorf, C., Newbold, K., Newbold, K. and Harmer, C. L. A dose-effect correlation for radioiodine ablation in differentiated thyroid cancer. Eur. J. Nucl. Med. Mol. Imaging 37, 270–275 (2010).
doi:10.1093/rpd/ncv061
PATIENT DOSIMETRY IN NUCLEAR MEDICINE So¨ren Mattsson* Medical Radiation Physics, Department of Translational Medicine, Lund University, Ska˚ne University Hospital Malmo¨, SE-205 02 Malmo¨, Sweden *Corresponding author: [email protected]
INTRODUCTION In spite of considerable progress, many advances remain to be achieved in the estimation of organ absorbed doses and in the prediction of biological effects of ionising radiation from radiopharmaceuticals. For patients undergoing diagnostic procedures, the biokinetics of the radiopharmaceutical (actually of the radionuclide) is determined for a limited number of representative patients. It is not considered necessary and practically feasible to make dose estimates for each individual patient. Published biokinetic data for a number of radiopharmaceuticals are, however, still scarce, especially with regard to quantitative measurements(1). The main clinical interest is the distribution of the test substance during the first hours after administration, whereas for dosimetry, long-term retention is as important, sometimes even more important. When radiopharmaceuticals are used for therapy, it is essential to determine the biokinetics for the individual patient to be able to estimate the absorbed doses to critical normal organs/tissues and to the target volume with high accuracy. In practice, however, still many therapies are carried out without pre-therapy activity administration, measurements and individual dose planning. The aim of this paper was to describe current methods for patient dosimetry and to draw attention to some of the remaining problems in the radiation dosimetry for radiopharmaceuticals with reference both to diagnostic nuclear medicine and to therapy with radiopharmaceuticals.
ACTIVITY CONTENT IN ORGANS AND TISSUES AND ITS TIME VARIATION For pharmaceuticals labelled with radionuclides emitting single photons, the planar conjugate view method(2) has been the way to investigate the activity content in organs and tissues and its time variation. The accuracy of this technique is limited by the lack of knowledge of the source-organ thickness and the difficulties to correct for organ overlap(3). SPECT is a way to solve some of these problems, but to get acceptable statistics in the images very long acquisition times are needed. New more sensitive SPECT cameras may help. In SPECT/CT, the CT images are used, not only for identification of anatomical details but also as a basis for attenuation correction(4). In a similar way, PET/CT is used for patient-specific 3D image-based internal dosimetry using the patient’s own anatomy and spatial distribution of activity as a function of time. DESCRIPTIVE BIOKINETIC MODELS VERSUS DETAILED COMPARTMENT MODELS The ultimate goal is to construct detailed physiologically and metabolically correct compartment models(5) for each substance and situation. This is often not possible due to lack of data and understanding of the detailed behaviour of the substance in the body. Therefore, for dosimetry, the biokinetic information is usually presented in terms of fractional uptakes and
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In diagnostic nuclear medicine, the biokinetics of the radiopharmaceutical (actually of the radionuclide) is determined for a number of representative patients. At therapy, it is essential to determine the patient’s individual biokinetics of the radiopharmaceutical in order to calculate the absorbed doses to critical normal organs/tissues and to the target volume(s) with high accuracy. For the diagnostic situations, there is still a lack of quantitative determinations of the organ/tissue contents of radiopharmaceuticals and their variation with time. Planar gamma camera imaging using the conjugate view technique combined with a limited number of SPECT/CT images is the main method for such studies. In a similar way, PET/CT is used for 3D image-based internal dosimetry for PET substances. The transition from stylised reference phantoms to voxel phantoms will lead to improved dose estimates for diagnostic procedures. Examples of dose coefficients and effective doses for diagnostic substances are given. For the therapeutic situation, a pre-therapeutic low activity administration is used for quantitative measurements of organ/tissue distribution data by a gamma camera or a SPECT- or PET-unit. Together with CT and/or MR images this will be the base for individual dose calculations using Monte Carlo technique. Treatments based on administered activity should only be used if biological variations between patients are small or if a pre-therapeutic activity administration is impossible.
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HUMANLIKE PHANTOMS FOR ABSORBED DOSE CALCULATIONS The dosimetric MIRD system(7) for assessment of absorbed dose is based on knowledge of the cumulated activity in a source region, and the absorbed fraction of energy in a target region due to radiation emitted in the source region. Summing up contributions from all source regions will give an estimate of the absorbed dose to the target region. The ongoing transition from stylised reference computational phantoms to voxel phantoms (available for adult male and female(8) and planned for children) may lead to improved dose estimates. Alternative phantoms, e.g. the non-uniform rational B-spline(9) can be an alternative and represents a broader population of nuclear medicine patients. Still the dose estimates are valid only for the phantom and not for the individual patient. A real challenge for the therapeutic situation is to describe the individual patient by imaging (CT, MR) and then make individual dose calculations using Monte Carlo simulations(10, 11) based on a pre-therapeutic biokinetic investigation. To check the results of such calculations, in vivo measurements—when using photon and betaparticle-emitting radionuclides—can be done using small TLDs, OSL dosemeters, diodes and now also quantum dot dosemeters, the latter with physical dimensions of a few nanometres(12). DIAGNOSTIC NUCLEAR MEDICINE Biokinetic models designed for the purpose of dose calculations for specific radiopharmaceuticals are published in the open literature, often together with some type of dose estimates. Alternatively, biokinetic models can be constructed from various published data related to the uptake, turn-over and retention of the radiopharmaceutical. The ICRP has evaluated published biokinetic and dosimetric data related to radiopharmaceuticals in current diagnostic use during over 40 y and
initiated a number of additional biokinetic studies. Most of the substances used today are covered in the ICRP Publications 106(6), 80(13) and 53(14). These data refer with some exceptions to normal patients. For patients with various degrees of illnesses, there is still a need to estimate biokinetics and organ/tissue doses. Further studies of age-dependent biokinetics and dosimetry are also highly desirable. The work regarding radiopharmaceutical dosimetry is done in parallel to the work in ICRP regarding development of biokinetic and dosimetric models for the estimation of equivalent and effective dose coefficients for occupational and public exposures from internal emitters(15). 99m
Tc substances
Organ doses and effective doses for a number of 99mTclabelled substances have been published by ICRP(6, 13, 14). Organ doses may differ considerably between substances, but the effective dose is robust to such variations. As the physical half-life is short (6.01 h), variations in biokinetic behaviour will not influence the effective dose very much and for most substances the effective dose coefficient is 0.004–0.017 with a mean value of 0.009 mSv MBq21(17) (see some examples in Figure 1). PET substances Also for PET substances, the variations in effective dose coefficients for 18F (Tphys ¼ 1.8 h) and 11C (Tphys ¼ 20 min) labelled substances, respectively, are relatively small: for 18F 0.016–0.028 mSv MBq21 with a mean value of 0.02 mSv MBq21 and for 11C substances 0.0027–0.0084 with a mean value of 0.005 mSv MBq21 (see some examples in Figure 2). 123,124,125,131
I-iodide
Biokinetic models for iodide have been published by ICRP to be used both for occupational and environmental exposure(18) and for nuclear medicine investigations(14). For dose estimation in nuclear medicine, the MIRD model by Berman(19) has been widely used. ICRP(20) has also published a model for iodide in the pregnant woman and the fetus. In ICRP models intended for nuclear medicine patients, the uptake in stomach wall and salivary glands has to be included. This is not the case for the models intended for dosimetry of occupationally or environmentally exposed persons. On the other hand, models for patient dosimetry have been simplified in such a way that they are unsuitable for dosimetry of the long-lived isotope 129I; however, not used in nuclear medicine, but of interest in connection with environmental and occupational exposures. Owing to this discrepancy a more general compartment model, which can be used for different purposes, has been developed(21). A more elaborated physiological systems model for iodine has recently been proposed for use in radiation
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biological half-times for specific regions of the body, i.e. first-order kinetics are assumed for the transfer between regions(6). Thus, a sum of exponential functions is normally used to describe the retention. In addition to the radiopharmaceutical-specific models, a number of general models describing the kinetics of the excretion routes are used: a kidney–bladder model, a liver–gallbladder model and a gastro-intestinal tract model(6). Many radiopharmaceuticals are mainly and quickly excreted through the urine. In those cases, the assumption about the bladder voiding period may be critical for the dosimetry. ICRP(6) assumes a bladder voiding interval of 3.5 h for adults as well as for 15 and 10 y old, 3.0 h for 5 y old and 2.0 for 1 y old and newborn. The variations are, however, considerable and influence the absorbed dose to the bladder wall and a number of nearby organs.
PATIENT DOSIMETRY IN NUCLEAR MEDICINE
protection(22) and is now also used in the most recent ICRP radiopharmaceutical dose compendium(17). Other substances Figure 3 gives dose coefficients (mSv MBq21) for some radioiodides and other substances labelled with 123 I and 131I as well as for some 201Tl-, 111In-, 75Se-, 67 Ga-, 51Cr-, 14C- and 3H-labelled substances. Dose per investigation To get the effective dose per investigation, the dose coefficients have been multiplied with the administered activities typically used. Figure 4 gives a rough classification of nuclear medicine investigations with respect to the effective dose to adult patients(6, 13, 16, 17). Challenges in dosimetry for diagnostic nuclear medicine For a number of radiopharmaceuticals, biokinetic data are more than 20 y old. Therefore there is a need to generate new data on biokinetics using state-of-the-art equipment. Other limitations are the few subjects per study and both genders are not always well represented.
Biokinetic data for children differs from those for adults and in general more age-specific biokinetic data, especially for children, are needed as well as biokinetic data for ill. To facilitate the collection of relevant data from different hospitals and facilitate exchange of data, more uniform dosimetry protocols should be used(23).
THERAPEUTIC NUCLEAR MEDICINE Therapeutic nuclear medicine is using radionuclides that are either conjugated to tumour-targeting agents (e.g. antibodies, peptides and small molecules) or concentrate in specific tissues through natural mechanisms that occur in cells with an abnormal growth rate or otherwise targeted cells (e.g. in benign thyroid disorders)(10). For most current cancer treatment options available today (e.g. conventional chemotherapy and external radiotherapy), the approach has been to destroy populations of cells that show uncontrolled growth. This focus on non-specific cell division implies that the treatment will often be non-selective, also damaging rapidly dividing non-tumour cells, such as those in the gut. Delivering targeted radiation to malignant cells with therapeutic radiopharmaceuticals has significant advantages. It allows one to seek out and destroy
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Figure 1. Effective dose coefficient (mSv MBq21) for 99mTc-labelled radiopharmaceuticals(6, 13, 17).
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13, 17)
for
18
F- and 11C-labelled radiopharmaceuticals and for 15 O-water.
diseased cells while protecting healthy cells in the vicinity. The selected antibody or peptide is preferentially one that itself can reduce or limit cellular proliferation by its action on a specific antigen or cell surface receptor. When combined with a radionuclide, it offers a synergistic effect in destroying malignant cells. At present, effective targeted radiopharmaceutical therapies have been developed and validated for a few tumour types, such as malignant lymphoma. For most other tumour types, the older non-specific types of cancer treatments are still the dominant form of therapy. Dose planning has to be carried out on an individual patient by patient basis and comprises the pre-treatment determination of the amount of activity to administer in order to maximise the effect on the tumour while managing the dose to normal tissue. This pre-treatment determination involves quantitative uptake and retention measurements in target volume and in normal tissues. In addition, knowledge of organ volumes is necessary for the calculation of the absorbed dose. Dose planning is however not always performed and the prescription is based on the results of earlier escalation trials(11). Such cohort-based treatment planning can lead to under- or over-treatment in individual patients due to different biodistribution among patients. Consequently, the cohort-based approach
82
Rb-chloride and
should only be used if biological variations between patients are small or if a pre-therapeutic activity administration is impossible. Benign thyroid disorders and thyroid cancer 131 I-iodide is used to treat benign thyroid disease since 1940s. It is still the dominating radiopharmaceutical therapy with respect to number of treated patients. Fixedactivity treatments are still used in many places. For treatment of hyperthyroidism, studies have shown that this results in too much activity to most patients(24, 25) and recent studies have shown that an absorbed dose-based criterion (requires knowledge of thyroid volume and 24 h uptake) gives a better outcome of the treatment(26 –28). It is important both for the individual patient and for the understanding of the radioiodine therapy and its future optimisation that the absorbed dose to the thyroid is quantified(29). 131 I-iodide is also used for treatment of differentiated thyroid cancer. After total thyroidectomy, thyroid cancer is treated with fixed administered activity with multiple re-administrations dependent on the patient response. Repeat administration continues until no iodide uptake is demonstrated. There are multiple reasons for this treatment: (1) to eradicate
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Figure 2. Effective dose coefficient (6,
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89
Figure 4. Overview of range of effective dose per investigation for radiopharmaceuticals with different radioactive markers(16, 17). Note the log-scale.
thyroid remnants, (2) to irradiate any neoplastic focus and (3) to perform total-body scanning for persistent carcinoma.
Sr-chloride, or they may emit a minor amount of gamma radiation, such as 153Sm-EDTMP (ethylene diamine tetramethylene phosphonate), which also allows visualising the distribution of the substance using a gamma camera. Another beta-emitting substances that have been used for bone palliation are 186,188 Re-EHDP (hydroxyethylidene diphosphonate). Alpha emitters have shown to be advantageous, due to the short-range and high energy of the alpha particles. A bone-seeking substance of special interest is 223Rachloride(30). A more careful dose planning, especially in relation to the red bone marrow dose, than has been done up to now is a prerequisite for the ongoing work on absorbed dose escalation (also using a mixture of short- and long-lived radionuclides) and the development of integrated therapies, combining chemotherapy or biphosphonate therapy with radiopharmaceutical therapy or combining external and radiopharmaceutical therapy.
Bone palliation Bone pain arising from skeletal metastases from prostate or breast tumours are treated with bone-seeking radiopharmaceuticals when other therapeutic measures fail. The substances are preferentially taken up in the metastases since the proliferation rate is higher there. For this purpose, pure beta-emitters are used, such as
Monoclonal antibodies for treatment of lymphoma, micrometastases and disseminated tumours By labelling tumour specific monoclonal antibodies with radionuclides a potential tool for a treatment, and hopefully an eradication of micrometastases and disseminated tumours, is obtained. Such substances have
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Figure 3. Effective dose coefficient (mSv MBq21) for 201Tl-, 131,123I-, 111In-, 75Se-, 67Ga-, 51Cr-, 14C- and 3H-labelled substances(6, 13, 17). Mean values for 11C-, 99mTc- and 18F-labelled substances are indicated on the x-axis. Note the log-scale.
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Neuroendocrine tumours Inoperable, advanced, recurrent and metastatic neuroendocrine tumours may be treated with 131I-mIBG (meta-iodobenzylguanidine). It is a noradrenaline analogue—taken up in neuroectodermal tumours including adulthood phaeochromocytoma, carcinoid, paraganglioma, medullary thyroid cancer and neuroblastoma in infancy and childhood. Information on whole-body kinetics and absorbed doses is available from several authors. Neuroendocrine tumours also express somatostatin receptors. There are several analogues developed for radiolabelling with 90Yor 177Lu. 90 Y DOTATATE ([DOTA0, D-Phe1, Tyr3]-octreotate) and 177Lu DOTATATE are currently the most used. Treatment with 177Lu-octreotate has increased significantly in frequency during the last years. At these
treatments, the kidneys are critical organs. Therefore, good kidney dosimetry is necessary(33, 34). Treatment of liver tumours with microspheres For inoperable primary liver cancers and liver metastases, selective internal radiation treatment is a treatment modality that is rapidly growing(35). Inert microspheres labelled with 90Y are injected into the intrahepatic artery via a catheter and under fluoroscopy. The planned dose in the liver is 4 Gy to normal liver tissues and four times more is expected to the tumours, but without individual dosimetry, the resulting doses can vary very much (at least a factor of four). A methodology for a more accurate dosimetry has therefore been described(36). Polycytemia Today there remains a distinct sub-group of elderly patients with polycythaemia vera and essential thrombocythaemia for whom 32P-orthophosphate is the most optimal treatment option. The phosphate ion is a bone-seeker and this makes the radiopharmaceutical suitable for radiotherapy of the bone marrow. The radiopharmaceutical is used to suppress hyperproliferative cell lines rather than to eradicate them. 32P is, however, also distributed into proliferating and proteinsynthesising cells, resulting in an enhanced absorbed dose, besides in bone tissue, also in liver and spleen(37). Usually, the substance is administered orally, but may also be given intravenously. The activity is generally given as a fixed activity per unit body surface alternatively a fixed activity per unit body weight. Typical activity and absorbed dose per administration for some common therapy agents are given in Table 1. NON-UNIFORM DISTRIBUTION OF ACTIVITY Data on sub-organ activity distributions are especially important in radionuclide therapy as ‘cold spots,’ or regions receiving inadequate absorbed dose, can lead to reduced tumour control probabilities and failure to cure or control disease. In such cases, the evaluation of the absorbed doses to tissue regions with sub-millimetre dimensions ranging up to dimensions of only a few centimetres is of interest. A number of the gamma (photon)-emitting radionuclides used in diagnostic nuclear medicine (e.g. 99m Tc, 123I, 111In, 67Ga, 201Tl) also emit Auger electrons or low-energy beta-particles(38 – 40). Their very short-range in biological tissues may lead to dose heterogeneity at the cellular level with radiobiological consequences. Experiments show that the biological effects of Auger emitters incorporated into DNA can be severe, with relative biological effectiveness .1
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been subject for research for a long period, and presently two commercially available labelled antibodies are ibritumomab tiuxetan labelled with 90Y (Zevalinw) and tositumomab labelled with 131I (Bexxarw) for the treatment of non-Hodgkins lymphoma(31). The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells, allowing radiation from the attached radionuclide to kill them and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells. As an example, the ibritumomab regimen takes 7–9 d, with two administrations of ibritumomab. The first uses 111 In-ibritumomab for imaging and assessment of the biodistribution of the compound. This test activity is also used to determine that no excess amounts go to the bone marrow, liver etc. Then, 90Y-ibritumomab is administered by i.v. infusion. For clinical research, various other antibodies are labelled with a number of radionuclides emitting beta-radiation, 90Y, 131I, 177Lu etc., and also alpha emitters, such as 211At (32), which show advantageous properties, since they will deliver a highly localised radiation dose to micro metastases. Often today in clinical routine, the dosage of the radionuclide in these cases is based on clinical studies of therapeutic effect and effect on normal tissues, such as red bone marrow or kidneys. As a result of these studies, a fixed activity per unit body weight has been established, which spares normal tissues from acute effects of the irradiation, but still has a therapeutic effect on the tumour. This is a simple but suboptimised way of treatment. In reality since a large margin is needed to the threshold for severe damage of the critical organ, the tumour dose may be too low to reach curative effect. An accurate dosimetry will therefore increase the probability for a successful treatment.
PATIENT DOSIMETRY IN NUCLEAR MEDICINE Table 1. Typical activity and absorbed dose per administration for some common therapy agents (excluding 131I-iodide) (7). Substance
32
P-phosphate Sr-chloride 153 Sm-EDTMP 90 Y-Zevalinw 131 I-Bexxarw 177 Lu-octreotate 89
Typical adm. activity (MBq) 185 150 2500 1000 3000 7400
Tumour dose (Gy)
Critical organ 1 (Gy)
Critical organ 2 (Gy)
Bone surfaces: 2.0 Red bone marrow: 1.7 Red bone marrow: 3.8 Red bone marrow: 2.7 Kidneys: 5.9
200
Red bone marrow: 2.0 Bone surfaces: 2.6 Bone surfaces: 17 Kidneys: 2.4 Thyroid: 8.1 Kidneys: 23
SUMMARY AND CONCLUSIONS There is continuously a need to collect biokinetic data from patients/volunteers related to the clinically used radiopharmaceuticals for diagnostic purposes. When radiopharmaceuticals are used for therapy, it is essential to try to determine the individual kinetics to be able to calculate the absorbed doses to critical normal organs/tissues with high accuracy. It is a challenge to develop a dosimetry that predicts the biological effects of short-range alpha particles, low-energy betaparticles and Auger electrons. There is currently not enough knowledge to fully understand what scale of dosimetry is needed to understand and predict radiation effects; absorbed
dose to whole organs, sub-organ regions, voxel regions, single cells. This research to use radiobiological modelling to convert the temporal and spatial distribution of absorbed dose to a BED for tumour tissue and for normal tissues might be a way forward.
FUNDING This work was partly supported by the Swedish Radiation Safety Authority [grant number SSM20141570]. REFERENCES 1. Eberlein, U., Bro¨er, J. H., Vandevoorde, C., Santos, P., Bardie`s, M., Bacher, K., Nosske, D. and Lassmann, M. Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine – a review. Eur. J. Nucl. Med. Mol. Imaging 38, 2269– 2281 (2011). 2. Fleming, J. S. A technique for the absolute measurement of activity using a gamma camera and computer. Phys. Med. Biol. 24, 176– 180 (1978). 3. Norrgren, K., Leide-Svegborn, S., Areberg, J. and Mattsson, S. Accuracy of the quantification of organ activity from planar gamma camera images. Cancer Biother. Radiopharm. 18, 125–131 (2003). 4. Mattsson, S. and Skretting, A. Sealed radionuclide and X-ray sources in nuclear medicine. In: Physics in Nuclear Medicine. Cantone, M. C. and Hoeschen, Ch., Eds. Springer, pp. 61–69 (2011). 5. Giussani, A. and Uusija¨rvi, H. Biokinetic models for radiopharmaceuticals. In: Physics in Nuclear Medicine. Cantone, M. C. and Hoeschen, Ch. Eds. Springer, pp. 233–255 (2011). 6. ICRP. Radiation dose to patients from radiopharmaceuticals. A third amendment to ICTP Publication 53. ICRP Publication 106. Ann. ICRP 38(1– 2) (2008). 7. Nosske, D., Mattsson, S. and Johansson, L. Dosimetry in nuclear medicine diagnosis and therapy. In: Medical Radiological Physics. (Landolt-Bo¨rnstein New Series, Group VIII: advanced Materials and Technologies), Vol. 7, Subvol. A, Kaul, A., Ed. Springer-Verlag, pp. 4: 1–62 (2012). 8. ICRP. Adult reference computational phantoms. ICRP Publication 110. Ann. ICRP 39(2) (2009). 9. Lee, C., Lee, C., Lodwik, D. and Bolch, W. E. NURBSbased 3-D anthropomorphic computational phantoms for
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compared with external X-rays. These findings clearly show that the assessment of biological risks associated with internal administration of diagnostic radiopharmaceuticals must focus not only on target organs as a whole, but also on the cellular level. MIRD has given detailed advice and presented S-values for the cellular level(41). It is still, however, difficult to establish the intracellular distribution of the radionuclides of interest so that such detailed S-values can be used effectively. For therapy, there is an increasing interest to combine targeting substances (antibodies, peptides etc.) with alpha particle or Auger electron emitters. Uptake non-uniformity and associated absorbed dose non-uniformity may significantly affect the outcome. Another factor is that the time of tumour volume changes is comparable with the time of maximal uptake and radiopharmaceutical effective half-time, affecting the dose estimates because of volume changes during dose delivery. The efficacy of targeted radionuclide therapy is thus dependent on the uniformity of the radionuclide uptake distribution, volume changes during treatment and also on radiosensitivity of the tissues. The biologically effective dose (BED) might be a relevant quantity in terms of establishing response or toxicity relationships(42). It also normalises differing dose rates of multiple modalities so that various treatment modalities can be combined.
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10. 11. 12.
13.
15. 16.
17.
18. 19. 20. 21.
22. 23.
24. 25. 26.
27.
28. Stabin, M. G., Sharkey, R. M. and Siegel, J. A. RADAR Commentary: Evolution and current status of dosimetry in nuclear medicine. J. Nucl. Med. 52(7), 1156–1161 (2011). 29. Jo¨nsson, H. Radioiodine therapy of hyperthyroidism. Simplified patient specific absorbed dose planning. PhD thesis. Departments of Radiation Physics, Lund University, Malmo¨ University Hospital, Malmo¨, Sweden (2003); ISBN 91-628-5753-3. 30. Lassmann, M. and Nosske, D. Dosimetry of 223Ra-chloride: dose to normal organs and tissues. Eur. J. Nucl. Med. Mol. Imaging 40, 207–212 (2013). 31. DeNardo, G. L. Treatment of non-Hodgkin’s lymphoma (NHL) with radiolabeled antibodies (mAbs). Sem. Nucl. Med. 35(3), 202– 211 (2005). 32. Andersson, H. et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of 211At-MX35 F8ab’)2—a phase 1 study. J. Nucl. Med. 50, 1153–1160 (2009). 33. Garkavij, M. G., Nickel, M., Sjo¨green-Gleisner, K., Ljungberg, M., Ohlsson, T., Winga˚rdh, K., Strand, S. E. and Tennvall, J. 177Lu-[DOTA0, Tyr3] ocreotate therapy in patients with disseminated neuroendocrine tumors: Analysis of dosimetry with impact on future therapeutic strategy. Cancer 116, 1084– 1092 (2010). 34. Swa¨rd, C., Bernhardt, P., Ahlman, H., Wa¨ngberg, B., Forssell-Aronsson, E., Larsson, M., Svensson, J., RossiNorrlund, R. and Ko¨lby, L. [177Lu-DOTA 0-Tyr 3]octreotate treatment in patients with disseminated gastroenteropancreatic neuroendocrine tumors: the value of measuring absorbed dose to the kidney. World J. Surg. 34(6), 1368– 1372 (2010). 35. Ahmadzadehfar, H., Biersack, H. J. and Ezziddin, S. Radioembolization of liver tumors with yttrium-90 microspheres. Semin. Nucl. Med. 40, 105 –121 (2010). 36. Gulec, S. A., Sztejberg, M. L., Siege, J. A., Jevremovic, T. and Stabin, M. Hepatic structural dosimetry in 90Y microsphere treatment: A Monte Carlo modeling approach based on lobular microanatomy. J. Nucl. Med. 51, 301– 310 (2010). 37. Thomas, S. R. Options for radionuclide therapy: from fixed activity to patient-specific treatment planning. Cancer Biother. Radiopharm. 17, 71– 82 (2002). 38. Paquet, F., Barbey, P., Bardie`s, M., Biau, A., Blanchardon, E., Chetioui, A., Lebaron-Jacobs, L. and Pasquier, J. L. The assessment and management of risks associated with exposures to short-range Auger- and betaemitting radionuclides. State of the art and proposals for lines of research. J. Radiol. Prot. 33, R1–R16 (2013). 39. Bingham, D., Gardin, I. and Hoyes, K. P. The problem of Auger emitters for radiological protection. Radiat. Prot. Dosim. 92(1– 3), 219–228 (2000). 40. Hofer, K. G. Dosimetry and biological effects of incorporated Auger emitters. Radiat. Prot. Dosim. 79(1– 4), 405– 410 (1998). 41. Goddu, S. M., Howell, R. W., Bouchet, L. G., Bolch, W. E. and Rao, D. MIRD cellular S-values. Society of nuclear medicine, Inc. (1997). 42. Prideaux, A. R., Song, H., Hobbs, R. F., He, B., Frey, E. C., Ladenson, P. W., Wahl, R. L. and Sgouros, G. Three-dimensional radiobiologic dosimetry: Application of radiobiologic modeling to patient-specific 3-dimensional imaging-based internal dosimetry. J. Nucl. Med. 48, 1008–1016 (2007).
Page 8 of 8
Downloaded from http://rpd.oxfordjournals.org/ at University of Pennsylvania Library on May 13, 2015
14.
radiation dosimetry applications. Radiat. Prot. Dosim. 127(1– 4), 227–232 (2007). Sgouros, G. and Hobbs, R. F. Dosimetry for radiopharmaceutical therapy. Sem. Nucl. Med. 44, 172–178 (2014). Glatting, G., Bardie`s, M. and Lassmann, M. Treatment planning in molecular radiotherapy. Z. Med. Phys. 23, 262– 269 (2013). Stodilka, R. Z., Carson, J. J. L., Yu, K., Zaman, M. B., Li, C. and Wilkinson, D. Optical degradation of CdSe/ ZnS quantum dots upon gamma-ray irradiation. J. Phys. Chem. C, 113(6), 2580– 2585 (2009). ICRP. Radiation dose to patients from radiopharmaceuticals. Addendum 2 to ICRP Publication 53, ICRP Publication 80. Ann. ICRP 28(3) (1998). ICRP. Radiation dose to patients from radiopharmaceuticals. ICRP Publication 53. Ann. ICRP 18(1– 4) (1987). Harrison, J. Biokinetic and dosimetric modelling in the estimation of radiation risks from internal emitters. J. Radiol. Prot. 29, A81– A105 (2009). Mattsson, S. and Andersson, M. Rules of the thumb and practical hints for radiation protection in nuclear medicine. In: Radiation Protection in Nuclear Medicine. Mattsson, S. and Hoeschen, C. Eds. Springer-Verlag, pp. 151 –159 (2013). ICRP. Radiation dose to patients from radiopharmaceuticals: a compendium of current information related to frequently used substances. ICRP Publication 128 (2015) (in press). ICRP. Age-dependent doses to members of the public from intake of radionuclides. ICRP Publication 56. Part 1. Ann. ICRP 20(2) (1989). Berman, M. Iodine kinetics. In: Methods in Investigative and Diagnostic Endocrinology. Vol. 1. Berson, S. A. Ed. North Holland, pp. 172–203 (1972). ICRP. Doses to the embryo and fetus from intakes of radionuclides by the mother. ICRP Publication 88. Ann. ICRP 31(1–3) (corrected version, May 2002) (2001). Johansson, L., Leide-Svegborn, S., Mattsson, S. and Nosslin, B. Biokinetics of iodide in man: refinement of current ICRP dosimetry models. Cancer Biother. Radiopharm. 18, 445–450 (2003). Leggett, R. W. A physiological systems model for iodine for use in radiation protection. Radiat. Res. 174, 496– 516 (2010). Lassmann, M., Chiesa, C., Flux, G. and Bardie`s, M. Dosimetry committee guidance document: good practice of clinical dosimetry reporting. Eur. J. Nucl. Med. Mol. Imaging 38, 192–200 (2011). Jo¨nsson, H. and Mattsson, S. Excess radiation absorbed doses from non-optimised radioiodine treatment of hyperthyroidism. Radiat. Prot. Dosim. 108, 107–114 (2004). Stabin, M. G. Update: the case for patient-specific dosimetry in radionuclide therapy. Cancer Biother. Radiopharm. 23(3), 273–284 (2008). Kobe, C., Eschner, W., Sudbrock, F., Weber, I., Marx, K., Dietlein, M. and Schia, H. Graves’ disease and radioiodine therapy; is success of ablation dependent on the achieved dose above 200Gy? Nuklearmedizin 47, 13–17 (2008). Flux, G. D., Haq, M., Chittenden, S. J., Buckley, S., Hindorf, C., Newbold, K., Newbold, K. and Harmer, C. L. A dose-effect correlation for radioiodine ablation in differentiated thyroid cancer. Eur. J. Nucl. Med. Mol. Imaging 37, 270–275 (2010).
