Introduction Radionuclide therapy (or “targeted”, “metabolic” or “molecular” radiotherapy) may be defined as a radiation therapy that uses local, loco-regional or generally administered open (i.e. “unsealed”) radionuclides to achieve a transfer of radiation energy to a pathological target tissue and by this means to exert a destructive tissue effect. This “internal” radiation therapy has distinct similarities to, but also profound differences from the more commonly used external radiotherapy (EBRT). The tissue effect is expressed as the absorbed radiation dose in grays (Gy), i.e. the amount of transferred energy in joules per unit mass of target tissue. The fundamental use of this unit is similar to that in EBRT, and there is a similar relationship between radiation dose and response in terms of cell killing/survival. Therefore, calculation of the radiation absorbed dose to a targeted tissue makes sense at any point in treatment. In this respect, radionuclide therapy dosimetry may be considered an inherent part of radionuclide therapy in principle, as in EBRT. In the literature, there is considerable confusion over the proper use of the term “dose”, which actually refers to the “radiation dose” in the SI unit “grays”. However, dose in the context of radionuclide therapy is frequently used when actually the “administered activity” in GBq or mCi is meant. To avoid confusion, the terms “radiation dose” and “absorbed dose” are used when indicating Gy and the term “activity dose” when indicating GBq. 1 To establish individual minimum effective and maximum tolerated absorbed doses To establish a dose–response relation to predict tumour response and normal organ toxicity on the basis of pre-therapy dosimetry To objectively compare the dose–response results of different radionuclide therapies, either between different patients or between different radiopharmaceuticals, as well as to perform comparisons with the results routinely obtained with external radiotherapy To increase the knowledge of clinical radionuclide radiobiology, in part with the aim of developing new approaches and regimens 2 3 4 5 6 7 2 8 10 Radioiodine therapy in differentiated thyroid carcinoma 11 12 13 131 14 15 16 17 131 18 131 131 19 131 13 20 21 22 131 23 The treatment of DTC in childhood varies substantially from the standard approach in adults mainly owing to the different tumour biology in this age group. Usually activities of 50–100 MBq/kg are given, treatment data on children being scarce and non-systematic. 124 131 24 124 25 131 131 26 27 28 29 9 131 30 31 131 32 123 33 34 35 36 29 2 37 35 131 38 9 131 39 40 Radiopeptide therapy for neuro-endocrine tumours 41 44 111 0 42 90 0 3 41 43 90 45 90 111 86 46 47 48 51 1 Table 1 Absorbed doses to principal organs and to tumour (Gy/GBq ±SD), deriving from different radiopeptides   109 50 50 47 110 111 112 Therapy 111 0 3 177 0 3 90 0 3 90 0 3 90 0 3 90 0 3 Dosimetry 111 0 3 177 0 3 111 0 3 86 0 3 86 0 3 111 0 3 Patients 16 5 30 3 8 5 Kidneys 0.52 ± 0.24 1.65 ± 0.47 b 2.73 ± 1.41  2.84 ± 0.64 Kidneys + protection  0.88 ± 0.19   1.71 ± 0.89  Liver 0.065 ± 0.01 0.21 ± 0.07 0.72 ± 0.57 0.66 ± 0.15 0.72 ± 0.40 0.92 ± 0.35 Spleen 0.34 ± 0.16 2.15 ± 0.39 7.62 ± 6.30 2.32 ± 1.97 2.19 ± 1.11 6.57 ± 5.25 Red marrow 0.03 ± 0.01 0.07 ± 0.004 0.03 ± 0.01 0.49 ± 0.002 0.06 ± 0.02 0.17 ± 0.02 Tumour (range) a 3.9–37.9 1.4–31 3.21–19.58 2.1–29.5 2.4–41.7 a 50 b 44 90 0 3 111 0 3 52 43 111 0 53 90 0 3 111 0 86 0 3 54 177 0 3 177 max max 177 0 3 111 0 90 0 3 177 0 3 44 90 0 3 55 2 56 L L 57 43 90 0 3 177 0 3 58 90 0 3 59 111 60 41 43 90 0 3 61 62 1 63 111 0 45 177 90 90 177 177 90 64 90 177 Fig. 1 90 86 63  Treatment of solid tumours by radiolabelled antibodies 65 Although at later time points after injection of radiolabelled monoclonal antibodies, adequate to high uptake may serve to delineate deposits of solid tumours, the relatively unfavourable therapeutic window between the anti-tumour effect and toxicity hampers the introduction of these agents in the clinic. Solid tumours are generally more radioresistant than, for example, malignant lymphoma. The absorbed doses required to achieve a response of tumour deposits are higher than those needed to obtain a response in malignant lymphoma. Activity doses leading to adequate absorbed doses in tumour deposits therefore result in significant radiation-induced toxicity, primarily of the bone marrow, as the most radiation-sensitive organ; myeloablation may be the goal as well as the result of this. 66 67 68 66 131 69 131 70 131 71 72 90 73 90 74 90 90 177 75 76 77 78 79 Radioimmunotherapy of B-cell lymphoma 90 131 80 81 82 84 111 131 85 86 131 87 9 88 10 111 90 131 89 90 91 10 64 92 93 94 131 95 131 96 131 90 97 98 99 100 101 102 Discussion 103 Journal of Clinical Oncology 104 105 131 124 86 25 59 1 2 Table 2. Methodological issues in performing clinical dosimetry - Diagnostic tracer and/or therapeutic activity study - Planar and/or tomographic (SPECT and/or PET) quantification - Dynamic and/or multiple time point activity sampling - Linearity of detector response in low and/or high activity - Correction factors for attenuation, scatter and/or partial volume effects - Nuclear medicine and/or radiological volume and response - Standard (MIRD,...) and/or simulative (Monte Carlo,...) modelling - Tissue heterogeneity and/or spatial resolution limits - Treatment of minimal residual disease and/or partial volume effects - Disease-induced and/or therapy-induced changes in parameters - Macro- and/or microdosimetry techniques - Animal and/or human dosimetry data 106 2 107 59 86 108 In conclusion, recent developments in molecular medicine, PET/CT and SPECT/CT cameras and radiobiology offer major scientific and clinical opportunities in radionuclide therapy dosimetry. However, only prospective, randomised trials with adequate methodology can provide the evidence that applied clinical dosimetry results in better patient outcome than is achieved with fixed activity dosing methods.