**2. Prostate cancer and skeletal metastases**

The incidence of malignancy in the Netherlands was 74.500 patients in 2005. This will increase to approximately 95.000 new cases in 2015. Because malignancy related death is decreasing and it is likely to decrease further the prevalence of cancer patients will increase to an estimated 692.000 patients in 2015, compared to 366.000 in 2000 (an estimated doubling time of 15 years) (Coebergh, van de Poll-Franse, and Alers 2004; Visser and van Noord 2005). One of the major causes of cancer related death in men is prostate cancer. These patients will be the focus of this chapter.

The incidence of prostate cancer is high worldwide. It is the most common malignancy in men in the Netherlands. Approximately 9000 men are being diagnosed with prostate cancer each year (Figure 1). The rising incidence may be attributed to the incremental use of screening methods using prostate specific antigen (PSA) to detect prostate cancer. This hypothesis is supported by the growing number of patients being diagnosed with early

Bone Seeking Radiopharmaceuticals for Metastatic Bone Pain 217

dimensions (pathophysiological, sensory, emotional, cognitive, and behavioural). These five dimensions together form a complex pattern of relations (Quirijnen et al. 1996). Stress is a well known stimulus for nociceptive pain. The impression that pain may be uncontrollable produces stress for patients, which may lead to increased suffering and despair, and decreases the patient's performance (Chapman and Gavrin 1999). An effective pain management strategy requires breaking off this cycle using all available means. An effective pain control strategy, however, requires patients to take large quantities of opioids, often as much as 60 – 200 mg/day. This large dose may cause considerable side effects, including nausea, vomiting, constipation, and central sedation, all of which combine to a decrease in quality of life. Patients will have to take large doses of anti-emetics and laxatives to counteract nausea and constipation, respectively. Central sedation increases drowsiness, resulting in frequent falls, bone fractures, and driving accidents (Etches 1999). Supplemental therapy with local radiation, wide-field radiation, bisphosphonates, or bone seeking radiopharmaceuticals can significantly reduce the dose of opioids for most patients or may even completely eliminate the need for the

Metastatic disease in prostate cancer may be treated first with hormonal therapy such as bilateral orchidectomy or medical first line hormone treatment (luteinizing hormone-releasing hormone agonist therapy). This androgen-deprivation therapy may be extended to maximal androgen blockade by adding anti-androgens (bicalutamide, flutamide, nilutamide). High risk prostate cancer patients may benefit from such a regimen even in the early stages of the disease (Klotz 2008). It is also recognized that discontinuation of an anti-androgen once hormone-refractory biochemical progression occurs is associated with a biochemical response in many patients. Anti-androgens may become agonistic due to a combination of androgen receptor over-expression and mutation (Kelly and Scher 1993; Small and Srinivas 1995). After a median of two years the prostate cancer cells generally become insensitive for hormonal treatment. In the case of hormone-refractory disease the patient may be treated by chemotherapy, local radiotherapy, systemic radiopharmaceuticals, bisphosphonates and

The clinical benefit of chemotherapy in hormone-refractory prostate cancer patients is limited. Some drugs showed potential as first-line treatment in hormone-refractory prostate carcinoma but were not sufficiently tested in clinical trials (Berthold, Sternberg, and Tannock 2005). Patients however may benefit from docetaxel chemotherapy in combination with prednisone. In a landmark study treatment with 75 mg/m2 docetaxel i.v. every three weeks with 5 mg prednisone twice daily p.o. was compared with mitoxantrone 12 mg/m2 every three weeks (Tannock et al. 2004). The median survival increased from 16.3 months in the mitoxantrone-group to 19.2 months in the docetaxel-group (Berthold et al. 2008). The group receiving docetaxel three weekly had a hazard ratio for death of 0.79 (95 percent confidence interval, 0.67 to 0.93; p=0.004) compared to the mitoxantrone-group (Berthold et al. 2008). Pain and quality of life improved significantly better in the docetaxel group and more patients (45% versus 32%; p<0.001) showed a 50% reduction of serum PSA levels (Tannock et al. 2004). However, docetaxel nor any other treatment will be curative in an

Patients with hormone-refractory prostate cancer who have progressive disease after firstline chemotherapy may still benefit from several treatment options. At this stage of disease, patients can expect only a short duration of survival, and most patients become

medications in a few patients (Krishnamurthy and Krishnamurthy 2000).

analgesics, depending on the clinical status (Auclerc et al. 2000).

advanced stage of prostate cancer.

stages of prostate cancer. The incidence also increases with age. Consequently, with a growing number of old men in our society the incidence of prostate cancer will further increase. Fortunately mortality from prostate cancer is decreasing due to better diagnostic methods and treatments (Dijkman and Debruyne 1996).

Fig. 1. Prostate cancer incidence between 1989 – 2005 derived from data on www.ikcnet.nl

A hallmark of metastatic prostate cancer is the development of osteoblastic bone metastases. Almost all patients with advanced prostate cancer eventually develop osseous metastases. In a majority of patients with prostate cancer, bone is the only site of clinical metastases. Many of the established prognostic factors for advanced prostate cancer (eg, performance status, alkaline phosphatase level, and haemoglobin level) reflect the clinical consequences of bone metastases. Hence, patients who develop widespread, progressive, or early bone metastases tend to suffer more from their symptoms and fare worse. Conversely, patients who develop limited, stable, or delayed bone metastases tend to experience less morbidity and have a less dismal clinical outcome. Conceivably, targeting the relevant bone metastases–associated factors may improve therapeutic results (Tu and Lin 2008). These factors consist of the main cells involved in bone metastasis (cancer cells, osteoblasts, osteoclasts, endothelial cells and stromal cells) and the numerous communicating substances (eg, interleukins, VEGF, RANKL, TNF-alfa, endothelins). They form a complex interaction and a microenvironment in which cancer cells may flourish (Tu and Lin 2008).

Frequently these skeletal metastases cause pain. Less common complications include myelum compression and pathological fractures (Dijkman and Debruyne 1996). Besides hormonal treatment most other treatment modalities in advanced prostate cancer patients are intended to palliate bone pain. Metastatic bone pain is a nociceptive somatic pain, initiated and maintained through local tissue injury. It is well recognized that chronic pain (including cancer pain) is a multidimensional phenomenon consisting of five

stages of prostate cancer. The incidence also increases with age. Consequently, with a growing number of old men in our society the incidence of prostate cancer will further increase. Fortunately mortality from prostate cancer is decreasing due to better diagnostic

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 **Years**

Fig. 1. Prostate cancer incidence between 1989 – 2005 derived from data on www.ikcnet.nl A hallmark of metastatic prostate cancer is the development of osteoblastic bone metastases. Almost all patients with advanced prostate cancer eventually develop osseous metastases. In a majority of patients with prostate cancer, bone is the only site of clinical metastases. Many of the established prognostic factors for advanced prostate cancer (eg, performance status, alkaline phosphatase level, and haemoglobin level) reflect the clinical consequences of bone metastases. Hence, patients who develop widespread, progressive, or early bone metastases tend to suffer more from their symptoms and fare worse. Conversely, patients who develop limited, stable, or delayed bone metastases tend to experience less morbidity and have a less dismal clinical outcome. Conceivably, targeting the relevant bone metastases–associated factors may improve therapeutic results (Tu and Lin 2008). These factors consist of the main cells involved in bone metastasis (cancer cells, osteoblasts, osteoclasts, endothelial cells and stromal cells) and the numerous communicating substances (eg, interleukins, VEGF, RANKL, TNF-alfa, endothelins). They form a complex interaction and a microenvironment in which cancer cells may flourish

Frequently these skeletal metastases cause pain. Less common complications include myelum compression and pathological fractures (Dijkman and Debruyne 1996). Besides hormonal treatment most other treatment modalities in advanced prostate cancer patients are intended to palliate bone pain. Metastatic bone pain is a nociceptive somatic pain, initiated and maintained through local tissue injury. It is well recognized that chronic pain (including cancer pain) is a multidimensional phenomenon consisting of five

**Incidence absolute**

methods and treatments (Dijkman and Debruyne 1996).

(Tu and Lin 2008).

dimensions (pathophysiological, sensory, emotional, cognitive, and behavioural). These five dimensions together form a complex pattern of relations (Quirijnen et al. 1996). Stress is a well known stimulus for nociceptive pain. The impression that pain may be uncontrollable produces stress for patients, which may lead to increased suffering and despair, and decreases the patient's performance (Chapman and Gavrin 1999). An effective pain management strategy requires breaking off this cycle using all available means. An effective pain control strategy, however, requires patients to take large quantities of opioids, often as much as 60 – 200 mg/day. This large dose may cause considerable side effects, including nausea, vomiting, constipation, and central sedation, all of which combine to a decrease in quality of life. Patients will have to take large doses of anti-emetics and laxatives to counteract nausea and constipation, respectively. Central sedation increases drowsiness, resulting in frequent falls, bone fractures, and driving accidents (Etches 1999). Supplemental therapy with local radiation, wide-field radiation, bisphosphonates, or bone seeking radiopharmaceuticals can significantly reduce the dose of opioids for most patients or may even completely eliminate the need for the medications in a few patients (Krishnamurthy and Krishnamurthy 2000).

Metastatic disease in prostate cancer may be treated first with hormonal therapy such as bilateral orchidectomy or medical first line hormone treatment (luteinizing hormone-releasing hormone agonist therapy). This androgen-deprivation therapy may be extended to maximal androgen blockade by adding anti-androgens (bicalutamide, flutamide, nilutamide). High risk prostate cancer patients may benefit from such a regimen even in the early stages of the disease (Klotz 2008). It is also recognized that discontinuation of an anti-androgen once hormone-refractory biochemical progression occurs is associated with a biochemical response in many patients. Anti-androgens may become agonistic due to a combination of androgen receptor over-expression and mutation (Kelly and Scher 1993; Small and Srinivas 1995). After a median of two years the prostate cancer cells generally become insensitive for hormonal treatment. In the case of hormone-refractory disease the patient may be treated by chemotherapy, local radiotherapy, systemic radiopharmaceuticals, bisphosphonates and analgesics, depending on the clinical status (Auclerc et al. 2000).

The clinical benefit of chemotherapy in hormone-refractory prostate cancer patients is limited. Some drugs showed potential as first-line treatment in hormone-refractory prostate carcinoma but were not sufficiently tested in clinical trials (Berthold, Sternberg, and Tannock 2005). Patients however may benefit from docetaxel chemotherapy in combination with prednisone. In a landmark study treatment with 75 mg/m2 docetaxel i.v. every three weeks with 5 mg prednisone twice daily p.o. was compared with mitoxantrone 12 mg/m2 every three weeks (Tannock et al. 2004). The median survival increased from 16.3 months in the mitoxantrone-group to 19.2 months in the docetaxel-group (Berthold et al. 2008). The group receiving docetaxel three weekly had a hazard ratio for death of 0.79 (95 percent confidence interval, 0.67 to 0.93; p=0.004) compared to the mitoxantrone-group (Berthold et al. 2008). Pain and quality of life improved significantly better in the docetaxel group and more patients (45% versus 32%; p<0.001) showed a 50% reduction of serum PSA levels (Tannock et al. 2004). However, docetaxel nor any other treatment will be curative in an advanced stage of prostate cancer.

Patients with hormone-refractory prostate cancer who have progressive disease after firstline chemotherapy may still benefit from several treatment options. At this stage of disease, patients can expect only a short duration of survival, and most patients become

Bone Seeking Radiopharmaceuticals for Metastatic Bone Pain 219

Repeated treatments are indicated after an initial response to treatment. The committee had the opinion that combined multimodality treatment should be performed in a trial setting.

Radionuclide therapy with bone seeking radiopharmaceutical agents has been long used. It evolved from agents like 32P-phosphate to newer agents like 188Re-HEDP or 223Ra (Table 2). Bone seeking radiopharmaceuticals consist of a radionuclide for the therapeutic effect and a carrier to reach the target site at the bone matrix level. Sometimes the carrier and the radionuclide are one and the same. This is the case for 32P-phosphate, 223Ra and 89Sr. These radiopharmaceuticals behave as physiologic phosphate (32P-phosphate) or Ca2+-analogues (223Ra and 89Sr). They do not need a non-radioactive substance as a carrier to reach the target. Carriers like hydroxyethylenediphosphonic acid (HEDP in 186Re-HEDP) and ethylenediaminetetramethylenephosphonic acid (EDTMP in 153Sm-EDTMP) are being used in other bone seeking radiopharmaceuticals. They behave as bisphosphonates. These differences influence the biodistribution and pharmacokinetics of the pharmaceutical. Other differences between these agents include the radiation type, the radiation energy and the

One thing that never changed during the last decades and stimulated the search for new agents was the conflict between efficacy and toxicity. The latter consisting of bone marrow suppression in particular. This has even led to a change of indication for the use of 32Pphosphate. It is not used anymore for the palliation of metastatic bone pain but instead for the treatment of myeloproliferative diseases, making use of its bone marrow suppressive potential (Berlin 2000; Cheung and Driedger 1980). Fortunately newer agents have proved to be feasible and relatively safe for the palliative treatment of osseous metastases with

Conclusion Evidence a Study type b

Level 1

A1 (Bauman et al. 2005; Finlay, Mason, and Shelley 2005; McQuay et al. 2008; Roque i

A2 (Han et al. 2002; Lewington et al. 1991; Maxon, III et al. 1991; Sartor et al. 2004; Serafini et al.

Figuls et al. 2008)

Level 1 A2 (Oosterhof et al. 2003; Quilty

B (Piffanelli et al. 2001)

et al. 1994)

Level 2 A2 (Sciuto et al. 2001)

1998)

Further research in that field is warranted (VIKC 2008).

acceptable and reversible bone marrow toxicity.

It has been proven that treatment with bone seeking radiopharmaceuticals yields a better pain response than treatment with placebo in patients with painful osseous metastases from diverse cancers including prostate, breast and

It has been proven that no difference exists with regard to local pain response between treatment with 89Sr-Chloride or external beam radiotherapy in patients with painful osseous metastases from a

It is likely that no difference exists with regard to pain response between treatment with 89Sr-Chloride and 186Re-HEDP in patients with painful osseous

radionuclide half-life.

lung cancer.

prostate carcinoma.

metastases.

symptomatic. Most patients will cease docetaxel treatment because of progressive disease or unacceptable adverse events. To control symptoms after the cessation of chemotherapy should rely on optimizing medical therapy for palliation. This may be combined with radiotherapy applied to dominant painful bone lesions. External beam radiotherapy for painful skeletal metastases leads to a decrease of pain in 60 – 65% of the patients. In 33% of the patients a total remission of pain symptoms was observed (McQuay et al. 2008). Patients may be treated in one fraction (8 Gray). No difference has been found between such a singledose regimen and multiple fractions (Hartsell et al. 2005; Kaasa et al. 2006; Roos et al. 2005). Furthermore, when needed, patients may be treated a second time with a reported response rate between 66% and 84% (Mithal, Needham, and Hoskin 1994; Van der Linden et al. 2004). Besides chemotherapy further hormonal manipulation with prednisone or dexamethasone may have some benefit as well. Glucocorticoids may lead to PSA response and/or relief of symptoms in patients with late-stage prostate cancer (Tannock et al. 1989). Some investigators have suggested that the superior results of regimens with taxanes may be due in part to the dexamethasone that is administered to avoid toxic reactions to these drugs. However, most patients have already received substantial treatment with glucocorticoids concurrent with first-line chemotherapy, so their potential benefit in later stages is probably minimal.

Other treatment options in the advanced stage of prostatic cancer include ketoconazole and estrogens. Inhibition of steroid synthesis by ketoconazole may increase the probability of an anti-androgen withdrawal response, although this did not translate into improved survival (Small et al. 2004). Estrogens may improve symptoms but caution must be used because of their ability to stimulate thrombosis and cardiovascular events. Estrogens were found to be equivalent to estramustine (which contains estrogen), probably as its activity is largely due to the estrogen component (Small et al. 2000). Transdermal administration of oestrogens through a patch avoids the entero-hepatic circulation and therefore it should not be associated with the same level of cardiovascular toxicity. Early data confirm the safety and efficacy of oestrogen patches as hormonal treatment in prostate cancer patients (Langley et al. 2008).

Currently new non chemotherapeutic options are studied such as endotheline antagonists (James et al. 2008) and abiraterone acetate, a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis (Attard et al. 2008). Many other agents are being developed (Tu and Lin 2008).

#### **3. Bone seeking radiopharmaceuticals**

Bone seeking radiopharmaceuticals have proven to be useful for treatment of more generalized bone pain. All patients will finally progress to end stage disease with multiple skeletal metastases. These patients may receive bone seeking radiopharmaceuticals for generalized painful disease (Berthold, Sternberg, and Tannock 2005). The association of integrated cancer centres in the Netherlands (VIKC) developed an evidence based guideline on the diagnosis and treatment of pain in cancer patients. Radionuclide treatment of cancer patients with metastatic bone pain (so called bone seeking radiopharmaceuticals) was evaluated using all available literature (VIKC 2008). The conclusions are stated together with their level of evidence in Table 1.

Most of the patients who have participated in the mentioned trials were heavily pre-treated patients with previous radiotherapy, chemotherapy and/or hormone therapy. It was recommended that radionuclide treatment with bone seeking radiopharmaceuticals is indicated in patients with multifocal pain originating from osteoblastic skeletal metastases.

symptomatic. Most patients will cease docetaxel treatment because of progressive disease or unacceptable adverse events. To control symptoms after the cessation of chemotherapy should rely on optimizing medical therapy for palliation. This may be combined with radiotherapy applied to dominant painful bone lesions. External beam radiotherapy for painful skeletal metastases leads to a decrease of pain in 60 – 65% of the patients. In 33% of the patients a total remission of pain symptoms was observed (McQuay et al. 2008). Patients may be treated in one fraction (8 Gray). No difference has been found between such a singledose regimen and multiple fractions (Hartsell et al. 2005; Kaasa et al. 2006; Roos et al. 2005). Furthermore, when needed, patients may be treated a second time with a reported response rate between 66% and 84% (Mithal, Needham, and Hoskin 1994; Van der Linden et al. 2004). Besides chemotherapy further hormonal manipulation with prednisone or dexamethasone may have some benefit as well. Glucocorticoids may lead to PSA response and/or relief of symptoms in patients with late-stage prostate cancer (Tannock et al. 1989). Some investigators have suggested that the superior results of regimens with taxanes may be due in part to the dexamethasone that is administered to avoid toxic reactions to these drugs. However, most patients have already received substantial treatment with glucocorticoids concurrent with

first-line chemotherapy, so their potential benefit in later stages is probably minimal.

patches as hormonal treatment in prostate cancer patients (Langley et al. 2008).

agents are being developed (Tu and Lin 2008).

**3. Bone seeking radiopharmaceuticals** 

with their level of evidence in Table 1.

Other treatment options in the advanced stage of prostatic cancer include ketoconazole and estrogens. Inhibition of steroid synthesis by ketoconazole may increase the probability of an anti-androgen withdrawal response, although this did not translate into improved survival (Small et al. 2004). Estrogens may improve symptoms but caution must be used because of their ability to stimulate thrombosis and cardiovascular events. Estrogens were found to be equivalent to estramustine (which contains estrogen), probably as its activity is largely due to the estrogen component (Small et al. 2000). Transdermal administration of oestrogens through a patch avoids the entero-hepatic circulation and therefore it should not be associated with the same level of cardiovascular toxicity. Early data confirm the safety and efficacy of oestrogen

Currently new non chemotherapeutic options are studied such as endotheline antagonists (James et al. 2008) and abiraterone acetate, a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis (Attard et al. 2008). Many other

Bone seeking radiopharmaceuticals have proven to be useful for treatment of more generalized bone pain. All patients will finally progress to end stage disease with multiple skeletal metastases. These patients may receive bone seeking radiopharmaceuticals for generalized painful disease (Berthold, Sternberg, and Tannock 2005). The association of integrated cancer centres in the Netherlands (VIKC) developed an evidence based guideline on the diagnosis and treatment of pain in cancer patients. Radionuclide treatment of cancer patients with metastatic bone pain (so called bone seeking radiopharmaceuticals) was evaluated using all available literature (VIKC 2008). The conclusions are stated together

Most of the patients who have participated in the mentioned trials were heavily pre-treated patients with previous radiotherapy, chemotherapy and/or hormone therapy. It was recommended that radionuclide treatment with bone seeking radiopharmaceuticals is indicated in patients with multifocal pain originating from osteoblastic skeletal metastases. Repeated treatments are indicated after an initial response to treatment. The committee had the opinion that combined multimodality treatment should be performed in a trial setting. Further research in that field is warranted (VIKC 2008).

Radionuclide therapy with bone seeking radiopharmaceutical agents has been long used. It evolved from agents like 32P-phosphate to newer agents like 188Re-HEDP or 223Ra (Table 2). Bone seeking radiopharmaceuticals consist of a radionuclide for the therapeutic effect and a carrier to reach the target site at the bone matrix level. Sometimes the carrier and the radionuclide are one and the same. This is the case for 32P-phosphate, 223Ra and 89Sr. These radiopharmaceuticals behave as physiologic phosphate (32P-phosphate) or Ca2+-analogues (223Ra and 89Sr). They do not need a non-radioactive substance as a carrier to reach the target. Carriers like hydroxyethylenediphosphonic acid (HEDP in 186Re-HEDP) and ethylenediaminetetramethylenephosphonic acid (EDTMP in 153Sm-EDTMP) are being used in other bone seeking radiopharmaceuticals. They behave as bisphosphonates. These differences influence the biodistribution and pharmacokinetics of the pharmaceutical. Other differences between these agents include the radiation type, the radiation energy and the radionuclide half-life.

One thing that never changed during the last decades and stimulated the search for new agents was the conflict between efficacy and toxicity. The latter consisting of bone marrow suppression in particular. This has even led to a change of indication for the use of 32Pphosphate. It is not used anymore for the palliation of metastatic bone pain but instead for the treatment of myeloproliferative diseases, making use of its bone marrow suppressive potential (Berlin 2000; Cheung and Driedger 1980). Fortunately newer agents have proved to be feasible and relatively safe for the palliative treatment of osseous metastases with acceptable and reversible bone marrow toxicity.


Bone Seeking Radiopharmaceuticals for Metastatic Bone Pain 221

All patients with proven osteoblastic (or mixed type) skeletal metastases that accumulate 99mTc-HDP on skeletal scintigraphy may be candidates for treatment with bone seeking radiopharmaceuticals. They may be cancer patients with advanced disease originating from prostate cancer, breast cancer, lung cancer, medullary thyroid carcinoma, or other tumors (i.e. bronchial carcinoid tumors, medulloblastoma). In routine clinical practice the vast majority of patients are prostate cancer patients. In these patients the incidence of skeletal metastases is very high. They cause high morbidity and mortality (DePuy et al. 2007; Saarto et al. 2002). Metastases originating from prostate cancer are pure osteoblastic with relatively high radionuclide uptake, resulting in high tumor to non-tumor ratio's. And last but not

In the growing field of radionuclide therapy many new radiopharmaceuticals are being developed. At the moment 89SrCl2 (Metastron®) and 153Sm-EDTMP (Quadramet®) are both FDA approved. Together with 186Re-HEDP (registered in some countries, not in the

Patients treated with any kind of radionuclide treatment must be regarded as a potential risk for public health because of a potential radiation hazard. Good understanding of the radionuclide used, its physical characteristics, its biodistribution and its pharmacokinetics, will allow us to draw proper guidelines for this kind of treatment. Does the patient need to be confined after treatment? Are we able to identify the radiation hazard from a qualitative and quantitative perspective? What does that mean for an individual patient in relation to

Patients treated with 89SrCl2, 186Re-HEDP or 153Sm-EDTMP are a source of radiation, including beta-radiation that has proven to be measurable outside the patient. Betaparticles in superficial tissue (such as in bones, blood vessels) cross the skin and contribute to the ambient equivalent dose. This aspect must be considered when using beta-emitting radiopharmaceuticals in general. The calculated effective doses for bystanders are well below the recommended values and do not lead to unacceptable additional radiation burden to health care workers and patients' families. The mean total effective doses absorbed by bystanders at 30 cm distance from a patient are approximately 0.02 mSv for 89SrCl2, 0.3 mSv for 186Re-HEDP, and 1.6 mSv for 153Sm-EDTMP (Lam et al. 2009b). These observations however should be placed in some perspective. First the

max (mean)

γ-emission keV (%)

Radiopharmaceutical Half-life (days) β-emission MeV

188Re-HEDP 0.7 2.12 (0.76) 155 (15%) 153Sm-EDTMP 1.93 0.81 (0.23) 103 (29%) 186Re-HEDP 3.7 1.07 (0.35) 137 (9%) 177Lu-EDTMP 6.7 0.497 (0.15) 208 (11%) 223Ra 11.4 Emits alfa-particles of circa 5.7 MeV 117mSn-DTPA 13.6 Emits conversion electrons 127 – 152 keV

32P-Phosphate 14.3 1.71 (0.70) None 89Sr 50.5 1.46 (0.58) 910 (0.01%)

least other treatment options are limited in advanced stages of this disease.

Netherlands) these bone seeking radiopharmaceuticals are mostly used today.

**4. Bone seeking radiopharmaceuticals in clinical practice** 

**4.1 Radiation safety considerations** 

its environment?

Table 2. Bone seeking radiopharmaceuticals categorized by half-life.


a Level of evidence: 1) A1 or at least two independent and consistent A2 studies; 2) One A2 study or at least two independent and consistent B studies; 3) One B or C study; 4) Professional opinion. b Quality and methodology of studies: A1) Systemic review of at least two independent A2 trials; A2) Double-blind randomized trial of sufficient size and quality (comparison with a reference test ('gold standard'), defined endpoints, independent evaluation of both tests, no confounding); B) Comparative trial not meeting A2 criteria;

c Non-comparative trial; D) Professional opinion.

Table 1. Evidence based conclusions on treatment with bone seeking radiopharmaceuticals (VIKC 2008).


It is likely that the onset of the pain response of 186Re-HEDP is faster than the onset of the pain response of 89Sr-Chloride in patients with painful osseous metastases from a breast

It is likely that combined treatment with

It has been suggested that adding 89Sr-Chloride to chemotherapy may lead to improved survival and a longer duration of the pain response compared to treatment with chemotherapy alone.

It has been suggested that no difference exists with regard to the pain response after treatment with chemotherapy or 89Sr-Chloride in patients with painful osseous metastases from a prostate

No conclusions can be drawn on the value of adding 89Sr-Chloride to external beam radiotherapy in patients with painful osseous metastases from a

c Non-comparative trial; D) Professional opinion.

prostate carcinoma because of

conflicting results.

trial not meeting A2 criteria;

(VIKC 2008).

89Sr-Chloride and chemotherapy (platinum based) yields a better pain response than treatment without chemotherapy in patients with painful osseous metastases from a prostate

carcinoma.

carcinoma.

carcinoma.

Conclusion Evidence a Study type b 

a Level of evidence: 1) A1 or at least two independent and consistent A2 studies; 2) One A2 study or at

Table 1. Evidence based conclusions on treatment with bone seeking radiopharmaceuticals

least two independent and consistent B studies; 3) One B or C study; 4) Professional opinion. b Quality and methodology of studies: A1) Systemic review of at least two independent A2 trials; A2) Double-blind randomized trial of sufficient size and quality (comparison with a reference test ('gold standard'), defined endpoints, independent evaluation of both tests, no confounding); B) Comparative

Level 2 A2 (Sciuto et al. 2001)

Level 2 A2 (Sciuto et al. 2002)

Level 3 B (Tu et al. 2001)

Level 3 B (Nilsson et al. 2005)

et al. 2003)

A2 (Porter et al. 1993; Smeland

C (Sciuto et al. 1996)


Table 2. Bone seeking radiopharmaceuticals categorized by half-life.

All patients with proven osteoblastic (or mixed type) skeletal metastases that accumulate 99mTc-HDP on skeletal scintigraphy may be candidates for treatment with bone seeking radiopharmaceuticals. They may be cancer patients with advanced disease originating from prostate cancer, breast cancer, lung cancer, medullary thyroid carcinoma, or other tumors (i.e. bronchial carcinoid tumors, medulloblastoma). In routine clinical practice the vast majority of patients are prostate cancer patients. In these patients the incidence of skeletal metastases is very high. They cause high morbidity and mortality (DePuy et al. 2007; Saarto et al. 2002). Metastases originating from prostate cancer are pure osteoblastic with relatively high radionuclide uptake, resulting in high tumor to non-tumor ratio's. And last but not least other treatment options are limited in advanced stages of this disease.

In the growing field of radionuclide therapy many new radiopharmaceuticals are being developed. At the moment 89SrCl2 (Metastron®) and 153Sm-EDTMP (Quadramet®) are both FDA approved. Together with 186Re-HEDP (registered in some countries, not in the Netherlands) these bone seeking radiopharmaceuticals are mostly used today.
