**9. Usefulness of radiopharmaceuticals for the palliation of painful bone metastases**

The development of bone metastases is commonly related to a serious reduction in quality of patient life because of pain occurrence and side effects of analgesics intake, especially

Internal Radiation Dosimetry: Models and Applications 39

leaves the blood quickly after an intravenous injection. The kidneys are the main route of excretion, but the gut has been seen in scintillation camera images and IRCP report assumes

Tin-117m labelled DTPA is investigated for the treatment of bone pain from metastases. Tin-117m can be imaged via the 156 keV gamma photons and the main energy deposition is performed by the corresponding conversion electrons. The conclusion from a phase I/II clinical study was that 117mSn-DTPA is an effective and safe radiopharmaceutical for the

153Sm-EDTMP is a therapeutic agent consisting of radioactive samarium and a tetraphosphonate chelator, ethylenediaminetetramethylenephosphonic acid (EDTMP). It is formulated as a sterile, non-pyrogenic, clear, colorless to light amber isotonic solution of samarium-153 lexidronam for intravenous administration (37 MBq/kg body weight) (Bodei, 2008). Onset of pain relief comes within one week, lasting from four weeks up to four months. The highest absorbed dose is received by bone marrow and bone surfaces. Imaging is commonly performed three hours after injection to verify the activity uptake. All activity not taken up in bone is excreted via urine and no further activity is excreted 24 hours after the injection. Dosimetry can therefore be performed from one scintillation camera imaging acquired 24h after injection or from one single probe measurement. The activity uptake in bone has been reported to increase with an increase in number of bone tumors (Farhangi,

Renium-186 is a beta minus emitter with a maximum beta energy of 1.07 MeV. The physical half-life is 89 hours. The radiopharmaceutical is taken up in bone via the phosphor complex HEDP (hydroxyethylidene diphosphonate). Quantitative imaging for pharmacokinetics and dosimetry is possible via the emission of 137 keV photons with a 9.47% probability.

Radium-223-chloride is taken up in bone by natural affinity. It decays in six steps into stable 207Pb. The injected activity has been reported as 46-250 kBq per kg of whole body weight (Nilsson, 2005, 2007). A clinical phase II study showed an improved survival without severe toxicity after four weekly injections of 50 kBq per kg of whole body weight compared to placebo injections (Nilsson, 2007). The photon emissions at 81.1 keV and 83.8 keV show the highest emission probabilities and offer the best opportunity to perform quantitative imaging during the treatment, which enables pharmacokinetic and dosimetric studies to be

Contraindications for radionuclide therapy are a life expectancy shorter than four weeks, severe renal insufficiency, and low blood counts due to a compromised bone marrow function. The absorbed dose to the tumour is the factor that determines the effectiveness of the therapy while the absorbed dose to the bone marrow correlates to the toxic effects received. The bone marrow is the dose limiting organ when bone-seeking radiopharmaceuticals are used (Lewington, 1993). Radionuclide therapy for pain palliation from bone metastases is currently performed based on a pre-set injected activity. The patients will, therefore, receive a range of absorbed doses due to individual differences in the pharmacokinetics. Voxel based, patient specific dosimetry automatically takes into account individual differences in pharmacokinetics and macroscopic anatomy. Furthermore, Monte Carlo simulations also take into account different cross sectional interaction data for all materials present in the body, which is, therefore, more accurate than convolution with a dose point kernel as this is based on an assumption of infinite, uniform medium.

treatment of bone metastases (Krishnamurthy, 1997; Srivastava, 1998).

4:1 ratio for urinary to faecal excretion.

1992; Brenner, 2001).

Excretion is predominantly through the kidneys.

performed. The main route of excretion is via faeces (Hindorf, 2008).

opiates (Silberstein, 2001). Therapeutic options for pain palliation include systemic therapy with cytotoxic agents, diphosphonate therapy, external beam radiotherapy and radionuclide therapy. Diphosphonate therapy has become a possible option for the treatment of patients affected by bone metastases since a new generation of diphosphonate has been developed; using zoledronic acid, indeed, the clinical benefits of diphosphonate (skeletal complications reduction and analgesic effects on bone pain), previously limited to patients with bone metastases from breast cancer or lesions due to multiple myeloma, have been extended to patients with bone metastases secondary to a broad range of solid tumors (Berenson, 2005). However, diphosphonates achieve only a modest analgesic effect and are associated with some non-renal adverse effects (Hillner, 2003; Lewington, 1996). External beam radiotherapy is the therapy of choice in cases of a single site of pain. However, when multiple painful metastases have been developed, local field radiotherapy is less effective and hemibody radiotherapy is associated with a significant morbidity (Lewington, 1996). Furthermore, external beam radiotherapy is often not suitable for repeated treatments. On the other hand, bone-seeking beta-emitting radiopharmaceuticals represent an effective tool for pain palliation in patients with multifocal bone disease, and make it possible to perform multiple administrations (Lam, 2004; Daformou, 2001; Englaro, 1992; Maini, 2003). Pain arises from both umoral and mechanical effects, including bone invasion, micro-fractures, increased intramedullary pressure and periosteal stretching (Lewington, 2005). Unlike opiates, which affect the entire nervous system, radionuclides exert their action mainly on cells at the peripheral nerve endings, where inflammatory, immune and malignant cells accumulate and release chemicals that modulate pain at the site of malignant invasion (Krishnamurthy, 2000). Furthermore, early response gene induction and a psychological-placebo component could account for the pain alleviation effect (Lewington, 1996; Leondi, 2004; Roche, 1994; Hellmann, 1994).

The goals of therapy are to alleviate pain, improve quality of life and mobility, reduce dependence on narcotic and non-narcotic analgesics, and improve performance status and possibly survival (Minutoli, 2006; Hindorf, 2011).

Bone tumours can be divided into osteolytic and sclerotic tumours. Sclerotic tumours are more suitable for targeted radionuclide therapy because of higher uptake of the radiopharmaceutical within the lesions. The majority of bone metastases from prostate cancer are sclerotic whilst metastases of breast cancer generally are mixed osteolytic/sclerotic. Also patients with bone metastases from tumours other than prostate and breast cancer and increased 99mTc-MDP uptake on bone scan can benefit from targeted radionuclide therapy (Leondi, 2004; Minutoli, 2006).

Two radiopharmaceuticals for the treatment of bone tumours are currently approved by the European Medicines Agency (EMEA): 153Sm-EDTMP (Quadramet®) and 89Sr-Cl2 (Metastron®). Other radiopharmaceuticals are at different stages of research, or are approved in some European Countries. These include 186Re-HEDP, 117mSn-DTPA and 223Ra-Cl2 (Alpharadin®). The use of 32P is now considered to be obsolete.

Strontium-89 was suggested for the treatment of bone tumours during the 1940s. It is naturally taken up in bone and is a pure β emitter with a long half-life (50.53 days). Pharmacokinetic and dosimetry studies have been based on imaging of 85Sr-Cl (Blake, 1986, 1987, 1998; Breen, 1992), although imaging based on bremsstrahlung photons from 89Sr has also been performed (ICRP, 1997). Tumour dosimetry is generally performed under the assumption that the activity uptake is five times higher than for normal bone. Strontium

opiates (Silberstein, 2001). Therapeutic options for pain palliation include systemic therapy with cytotoxic agents, diphosphonate therapy, external beam radiotherapy and radionuclide therapy. Diphosphonate therapy has become a possible option for the treatment of patients affected by bone metastases since a new generation of diphosphonate has been developed; using zoledronic acid, indeed, the clinical benefits of diphosphonate (skeletal complications reduction and analgesic effects on bone pain), previously limited to patients with bone metastases from breast cancer or lesions due to multiple myeloma, have been extended to patients with bone metastases secondary to a broad range of solid tumors (Berenson, 2005). However, diphosphonates achieve only a modest analgesic effect and are associated with some non-renal adverse effects (Hillner, 2003; Lewington, 1996). External beam radiotherapy is the therapy of choice in cases of a single site of pain. However, when multiple painful metastases have been developed, local field radiotherapy is less effective and hemibody radiotherapy is associated with a significant morbidity (Lewington, 1996). Furthermore, external beam radiotherapy is often not suitable for repeated treatments. On the other hand, bone-seeking beta-emitting radiopharmaceuticals represent an effective tool for pain palliation in patients with multifocal bone disease, and make it possible to perform multiple administrations (Lam, 2004; Daformou, 2001; Englaro, 1992; Maini, 2003). Pain arises from both umoral and mechanical effects, including bone invasion, micro-fractures, increased intramedullary pressure and periosteal stretching (Lewington, 2005). Unlike opiates, which affect the entire nervous system, radionuclides exert their action mainly on cells at the peripheral nerve endings, where inflammatory, immune and malignant cells accumulate and release chemicals that modulate pain at the site of malignant invasion (Krishnamurthy, 2000). Furthermore, early response gene induction and a psychological-placebo component could account for the pain alleviation effect (Lewington, 1996; Leondi, 2004; Roche, 1994;

The goals of therapy are to alleviate pain, improve quality of life and mobility, reduce dependence on narcotic and non-narcotic analgesics, and improve performance status and

Bone tumours can be divided into osteolytic and sclerotic tumours. Sclerotic tumours are more suitable for targeted radionuclide therapy because of higher uptake of the radiopharmaceutical within the lesions. The majority of bone metastases from prostate cancer are sclerotic whilst metastases of breast cancer generally are mixed osteolytic/sclerotic. Also patients with bone metastases from tumours other than prostate and breast cancer and increased 99mTc-MDP uptake on bone scan can benefit from targeted

Two radiopharmaceuticals for the treatment of bone tumours are currently approved by the European Medicines Agency (EMEA): 153Sm-EDTMP (Quadramet®) and 89Sr-Cl2 (Metastron®). Other radiopharmaceuticals are at different stages of research, or are approved in some European Countries. These include 186Re-HEDP, 117mSn-DTPA and 223Ra-Cl2 (Alpharadin®).

Strontium-89 was suggested for the treatment of bone tumours during the 1940s. It is

Pharmacokinetic and dosimetry studies have been based on imaging of 85Sr-Cl (Blake, 1986, 1987, 1998; Breen, 1992), although imaging based on bremsstrahlung photons from 89Sr has also been performed (ICRP, 1997). Tumour dosimetry is generally performed under the assumption that the activity uptake is five times higher than for normal bone. Strontium

emitter with a long half-life (50.53 days).

Hellmann, 1994).

possibly survival (Minutoli, 2006; Hindorf, 2011).

radionuclide therapy (Leondi, 2004; Minutoli, 2006).

The use of 32P is now considered to be obsolete.

naturally taken up in bone and is a pure β-

leaves the blood quickly after an intravenous injection. The kidneys are the main route of excretion, but the gut has been seen in scintillation camera images and IRCP report assumes 4:1 ratio for urinary to faecal excretion.

Tin-117m labelled DTPA is investigated for the treatment of bone pain from metastases. Tin-117m can be imaged via the 156 keV gamma photons and the main energy deposition is performed by the corresponding conversion electrons. The conclusion from a phase I/II clinical study was that 117mSn-DTPA is an effective and safe radiopharmaceutical for the treatment of bone metastases (Krishnamurthy, 1997; Srivastava, 1998).

153Sm-EDTMP is a therapeutic agent consisting of radioactive samarium and a tetraphosphonate chelator, ethylenediaminetetramethylenephosphonic acid (EDTMP). It is formulated as a sterile, non-pyrogenic, clear, colorless to light amber isotonic solution of samarium-153 lexidronam for intravenous administration (37 MBq/kg body weight) (Bodei, 2008). Onset of pain relief comes within one week, lasting from four weeks up to four months. The highest absorbed dose is received by bone marrow and bone surfaces. Imaging is commonly performed three hours after injection to verify the activity uptake. All activity not taken up in bone is excreted via urine and no further activity is excreted 24 hours after the injection. Dosimetry can therefore be performed from one scintillation camera imaging acquired 24h after injection or from one single probe measurement. The activity uptake in bone has been reported to increase with an increase in number of bone tumors (Farhangi, 1992; Brenner, 2001).

Renium-186 is a beta minus emitter with a maximum beta energy of 1.07 MeV. The physical half-life is 89 hours. The radiopharmaceutical is taken up in bone via the phosphor complex HEDP (hydroxyethylidene diphosphonate). Quantitative imaging for pharmacokinetics and dosimetry is possible via the emission of 137 keV photons with a 9.47% probability. Excretion is predominantly through the kidneys.

Radium-223-chloride is taken up in bone by natural affinity. It decays in six steps into stable 207Pb. The injected activity has been reported as 46-250 kBq per kg of whole body weight (Nilsson, 2005, 2007). A clinical phase II study showed an improved survival without severe toxicity after four weekly injections of 50 kBq per kg of whole body weight compared to placebo injections (Nilsson, 2007). The photon emissions at 81.1 keV and 83.8 keV show the highest emission probabilities and offer the best opportunity to perform quantitative imaging during the treatment, which enables pharmacokinetic and dosimetric studies to be performed. The main route of excretion is via faeces (Hindorf, 2008).

Contraindications for radionuclide therapy are a life expectancy shorter than four weeks, severe renal insufficiency, and low blood counts due to a compromised bone marrow function. The absorbed dose to the tumour is the factor that determines the effectiveness of the therapy while the absorbed dose to the bone marrow correlates to the toxic effects received. The bone marrow is the dose limiting organ when bone-seeking radiopharmaceuticals are used (Lewington, 1993). Radionuclide therapy for pain palliation from bone metastases is currently performed based on a pre-set injected activity. The patients will, therefore, receive a range of absorbed doses due to individual differences in the pharmacokinetics. Voxel based, patient specific dosimetry automatically takes into account individual differences in pharmacokinetics and macroscopic anatomy. Furthermore, Monte Carlo simulations also take into account different cross sectional interaction data for all materials present in the body, which is, therefore, more accurate than convolution with a dose point kernel as this is based on an assumption of infinite, uniform medium.

Internal Radiation Dosimetry: Models and Applications 41

preferred especially for the treatment of larger and inhomogeneous lesions. In figure 5, the comparison between electron paths within small and large inhomogeneous lesions is represented through a Monte Carlo simulation in Geant4, in which radiations emitted from

177Lu has a longer half-life (6.7 days) and lower energy beta-emission (Emax = 0.497 MeV; Rmax = 2 mm) that allows to concentrate all the energy inside smaller tumours; moreover the gamma-emission of 177Lu (113 keV and 208 keV) is suitable for scintigraphy and dosimetry

Fig. 5. Comparison between the high-energy electron tracks (red) of 90Y and the ones of the lower-energy electrons from 177Lu. Photons originating from gamma ray emission or

Dext =2 cm Dint =2 mm

Concerning peptides, several new somatostatin analogues have been introduced for therapeutic and diagnostic purposes, including the agonists DOTA-(1-NaI3)octreotide

bremsstrahlung are represented in green.

Lu-177

(DOTANOC) and DOTA-(BzThi3)octreotide (DOTABOC).

D =2 mm

177Lu and 90Y are compared.

Y-90

during PRRT.

Radionuclide therapy as a palliative treatment of bone pain is efficient, although improved dosimetry methods could help to improve the treatment further.
