**4.1 Radiation safety considerations**

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 its environment?

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

Bone Seeking Radiopharmaceuticals for Metastatic Bone Pain 223

family, residence times may be reduced and distances increased, lowering the correction factor to as low as 0.02 (2%), an almost eight-fold decrease in radiation burden to bystanders (Table 3). In the case of a patient and his or her child an estimated correction factor of about 0.43 (43%) should be applied without instructions and 0.11 (11%) with instructions. In all instances effective doses will be < 1 mSv and with proper instructions they will be < 0.1 mSv or even < 0.01 mSv (Tables 3 and 4). It may be concluded that patients treated with bone

> Correction factor a

playing 8/24 4 0.0019 8/24 4 0.0019

contact 1/24 0.1 0.375 0.25/24 0.1 0.094 dinner 2/24 0.5 0.03 2/24 2 0.0019 sleeping 10/24 - - 10/24 - other 3/24 2 0.0094 3/24 2 0.0094 total 0.43 0.11

a Correction factor applicable for measurements at 30 cm from the patient using the inverse-

Table 4. Effective dose (external radiation) of *a young child* with and without instructions.

However, an exception has to be made considering urinary excretion of activity and the possible internal contamination of bystanders. Besides radiation exposure to non-patients from direct emission by the patient, another potential radiation hazard is formed by excreted radioactivity. The calculated mean total urinary excretion percentage of 89Sr during the first 3 days after administration was 16% (Lam et al. 2009b). Using a hypothetical contamination scenario, that is used in radiation protection evaluation (VROM 2005), that 0.01% of the excreted amount of radioactivity will cause internal contamination to nonpatients closely related to the patient, an internal dosage of 0.0024 MBq for 89SrCl2 therapy (administered dose of 150 MBq) was calculated. For 186Re-HEDP therapy (administered dose of 1295 MBq), the corresponding amount of radioactivity will be 0.064 MBq (49% of the injected dose is excreted (de Klerk et al. 1992)). After treatment with 37 MBq/kg 153Sm-EDTMP 53.1% ± 15.1% of the administered dose was excreted in urine during the first 48 hours (Lam et al. 2007). Potential contamination with 0.01% of the excreted radioactivity will lead to an internal dosage of 0.15 MBq 153Sm-EDTMP. The dose conversion coefficient for ingestion of 89Sr is (eing) = 2.6 x 10-9 Sv/Bq, of 186Re (eing) = 1.5 10-9 Sv/Bq, and of 153Sm (eing) = 7.4 10-10 Sv/Bq. The present data show that the effective radiation absorbed dose, caused

EDTMP 0.69 0.18

HEDP 0.13 0.03

Chloride < 0.01 < 0.01

Without instruction With instruction

Effective dose (mSv) Effective dose (mSv)

Residence time (hrs/24hrs)

Distance (m)

Correction factor a

seeking radiopharmaceuticals do not pose any threat to others.

Distance (m)

Residence

close

153Sm-

186Re-

89Sr-

square law

time (hrs/24hrs)

individual variation in effective dose to bystanders and second the potential risk of internal contamination of bystanders.

The total effective dose, as given above, is estimated for bystanders who reside at exactly 30 cm from the patient for an indefinite time. Because this is never the case, these estimations must be corrected for variations in time and distance between bystanders and patients. In a Dutch Ministry of Housing, Spatial Planning and Environment publication accurate calculations were made to cover the various persons who may have contact with patients (VRO92; VROM 2005). These calculations are based on residence times T (in fractions of days) with the patient and distances R (in meters) from the patient. The actual effective doses for bystanders will depend on residence times and distances in relation to the patient. Estimations were made for residence times and distances during a 24-hour period. This was done in the case of an elderly patient in relation to his or her partner and in the case of a patient in relation to his or her child (Tables 3 and 4).


a Correction factor applicable for measurements at 30 cm from the patient using the inverse-square law

Table 3. Effective dose (external radiation) of *an elderly partner* with and without instructions.

Assuming that the estimated distances and times are a reflection of reality, corrections were made for these circumstances. Estimations of the effective doses for these persons (partner and child) are given for the three most used radiopharmaceuticals. In the case of a patient and his or her partner, without instructions a correction factor of 0.15 (15%) was applied. This is explained by the fact that bystanders do not stay within 30 cm of patients 24 hours a day. Because of work and other activities a correction factor should be applied. As an example a correction factor of 0.15 may be applied. The effective dose may be further reduced by instructing the patients and their families to keep distance as much as reasonably possible (e.g. watching TV and sleeping apart). With proper instructions to

individual variation in effective dose to bystanders and second the potential risk of

The total effective dose, as given above, is estimated for bystanders who reside at exactly 30 cm from the patient for an indefinite time. Because this is never the case, these estimations must be corrected for variations in time and distance between bystanders and patients. In a Dutch Ministry of Housing, Spatial Planning and Environment publication accurate calculations were made to cover the various persons who may have contact with patients (VRO92; VROM 2005). These calculations are based on residence times T (in fractions of days) with the patient and distances R (in meters) from the patient. The actual effective doses for bystanders will depend on residence times and distances in relation to the patient. Estimations were made for residence times and distances during a 24-hour period. This was done in the case of an elderly patient in relation to his or her partner and in the case of a

Without instruction With instruction

Mean effective dose (mSv) Mean effective dose (mSv)

Residence time (hrs/24hrs)

Distance (m)

Correction factor a

Correction factor a

activities 3/24 - 0 3/24 - 0

EDTMP 0.24 0.03

HEDP 0.05 < 0.01

Chloride < 0.01 < 0.01

Table 3. Effective dose (external radiation) of *an elderly partner* with and without

TV 5/24 0.5 0.075 5/24 2 0.0047 dinner 2/24 1 0.0075 2/24 1 0.0075 sleeping 8/24 0.7 0.061 8/24 2 0.0075 other 6/24 3 0.0025 6/24 3 0.0025 total 0.15 0.02

a Correction factor applicable for measurements at 30 cm from the patient using the inverse-square law

Assuming that the estimated distances and times are a reflection of reality, corrections were made for these circumstances. Estimations of the effective doses for these persons (partner and child) are given for the three most used radiopharmaceuticals. In the case of a patient and his or her partner, without instructions a correction factor of 0.15 (15%) was applied. This is explained by the fact that bystanders do not stay within 30 cm of patients 24 hours a day. Because of work and other activities a correction factor should be applied. As an example a correction factor of 0.15 may be applied. The effective dose may be further reduced by instructing the patients and their families to keep distance as much as reasonably possible (e.g. watching TV and sleeping apart). With proper instructions to

internal contamination of bystanders.

Residence

outdoors

watching

153Sm-

186Re-

89Sr-

instructions.

time (hrs/24hrs)

patient in relation to his or her child (Tables 3 and 4).

Distance (m)

family, residence times may be reduced and distances increased, lowering the correction factor to as low as 0.02 (2%), an almost eight-fold decrease in radiation burden to bystanders (Table 3). In the case of a patient and his or her child an estimated correction factor of about 0.43 (43%) should be applied without instructions and 0.11 (11%) with instructions. In all instances effective doses will be < 1 mSv and with proper instructions they will be < 0.1 mSv or even < 0.01 mSv (Tables 3 and 4). It may be concluded that patients treated with bone seeking radiopharmaceuticals do not pose any threat to others.


a Correction factor applicable for measurements at 30 cm from the patient using the inversesquare law

Table 4. Effective dose (external radiation) of *a young child* with and without instructions.

However, an exception has to be made considering urinary excretion of activity and the possible internal contamination of bystanders. Besides radiation exposure to non-patients from direct emission by the patient, another potential radiation hazard is formed by excreted radioactivity. The calculated mean total urinary excretion percentage of 89Sr during the first 3 days after administration was 16% (Lam et al. 2009b). Using a hypothetical contamination scenario, that is used in radiation protection evaluation (VROM 2005), that 0.01% of the excreted amount of radioactivity will cause internal contamination to nonpatients closely related to the patient, an internal dosage of 0.0024 MBq for 89SrCl2 therapy (administered dose of 150 MBq) was calculated. For 186Re-HEDP therapy (administered dose of 1295 MBq), the corresponding amount of radioactivity will be 0.064 MBq (49% of the injected dose is excreted (de Klerk et al. 1992)). After treatment with 37 MBq/kg 153Sm-EDTMP 53.1% ± 15.1% of the administered dose was excreted in urine during the first 48 hours (Lam et al. 2007). Potential contamination with 0.01% of the excreted radioactivity will lead to an internal dosage of 0.15 MBq 153Sm-EDTMP. The dose conversion coefficient for ingestion of 89Sr is (eing) = 2.6 x 10-9 Sv/Bq, of 186Re (eing) = 1.5 10-9 Sv/Bq, and of 153Sm (eing) = 7.4 10-10 Sv/Bq. The present data show that the effective radiation absorbed dose, caused

Bone Seeking Radiopharmaceuticals for Metastatic Bone Pain 225

EDTMP. An evidence based approach would be a choice between these radiopharmaceuticals. One of the differences between these two is the magnitude and rate of renal excretion. Both may be used without confining a patient to the hospital but from a radiation safety perspective it is advised to keep the patient in a controlled setting for at least 8 hours after injection in the case of 153Sm-EDTMP. This could influence the choice on practical grounds in favour of 89SrCl2.

Other differences include the longer half-life and higher energy (with higher range in tissue) of 89SrCl2 compared to 153Sm-EDTMP. 153Sm-EDTMP and 186Re-HEDP are highly comparable with regard to energy and half-life. Most comparative randomized studies have been performed using 89SrCl2 and 186Re-HEDP. It was found that no difference exist with regard to pain response between treatment with 89Sr-Chloride and 186Re-HEDP in patients with painful osseous metastases (Piffanelli et al. 2001; Sciuto et al. 2001). And 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 carcinoma (Sciuto et al. 2001). So one might argue that when a faster pain response is indicated one should use 186Re-HEDP or 153Sm-EDTMP. Other differences are the longer duration of response of 89Sr-Chloride on one hand, and the prolonged bone marrow toxicity of 89Sr-Chloride on the other hand. These differences were not investigated in direct comparative studies but should be considered

Longer duration of response (suitable in relatively good clinical condition in which a

Fast response (suitable in bad clinical condition in which immediate response is

 Favourable toxicity profile (suitable in heavily pre-treated patients, in wide spread metastatic disease and possibly in combination with other myelotoxic treatments) In most cases today a fast response is needed. Besides that most patients, including prostate cancer patients, are heavily pre-treated. They have end stage disease with minimal bone marrow reserve. And last but not least short-living bone seeking radiopharmaceuticals like 186Re-HEDP, 153Sm-EDTMP and others may prove to be more suitable in combination with other treatment modalities, not just because of their toxicity profile but also because of their

A major concern in the treatment of prostate cancer patients in the more advanced stage of the disease is the delicate balance between efficacy and toxicity. Treatment of metastatic bone pain with analgesics or localized external beam radiotherapy is relatively safe and easy. Treatment with bone seeking radiopharmaceuticals may be more appropriate in selected cases but efficacy is sometimes disappointing and bone marrow toxicity may be high in individual patients. Enhancement of overall efficacy without increasing toxicity could push the clinical decision algorithm in a positive direction with regard to the use of

One way of improving overall efficacy is combined treatment. Combined treatment regimens may deliver the beneficial effect of two different treatment modalities. These

Not all nuclear medicine departments have such facilities.

nevertheless. In summary: in favour of 89Sr-Chloride are:

high dose rate, offering an effective treatment with fast recovery.

No confinement necessary

**5. Enhancement of efficacy** 

bone seeking radiopharmaceuticals.

wanted)

prompt response is not warranted) In favour of 186Re-HEDP or 153Sm-EDTMP are:

by a potential internal contamination (0.01% of the administered dose), is 6.2 microSv for 89Sr, 96 microSv for 186Re and 111 microSv for 153Sm. These numbers are in the same order of magnitude as the numbers given for external exposure (Table 3 and 4).

The total effective dose for non-patients may be caused by both external radiation exposure and internal contamination. In contrast to the mean effective dose caused by external radiation, the effective dose after ingestion of 0.01% of the administered dose is hypothetical and may be much higher or much lower. In the case of 131I it proved to be less. The uptake of 131I in the thyroid of family members was measured (Buchan and Brindle 1970). A maximum uptake of 3.8 Bq per MBq administered was found. So on one hand it must be considered that 0.01% is a hypothetical figure, while the external radiation exposure is a fact. On the other hand, internal contamination poses a real threat to non-patients. Patients that were treated with bone-seeking radiopharmaceuticals are often severely disabled (in contrast to 131I patients). Especially in the case of prostate cancer patients, they often have dysurea. Personal hygiene is not as obvious as it is to others. It is therefore advisable to give the patients simple, easy-to-follow instructions, in order to reduce the risk for non-patients. Using a separate toilet, sitting while urinating and washing hands afterwards, are highly recommended. In the case of incontinence, patients must be catheterized for a certain time depending on urinary excretion of the administered activity. Due to fast renal excretion this may be 12 hours after injection of 186Re-HEDP and 153Sm-EDTMP. 89SrCl2 is being administered in relatively low doses and therefore has a relatively low risk for high effective dose due to ingestion of this radiopharmaceutical (6.2 microSv for 89Sr). These patients do not have to be catheterized. The risk for significant internal contamination of non-patients is much lower and acceptable for this radiopharmaceutical.

In general it is advised to hospitalize patients treated with 186Re-HEDP and 153Sm-EDTMP for at least 8 hours. This is mostly based on urinary excretion and the risk for internal contamination, because the radiation exposure to non-patients is < 20 microSv/hour (1 meter from the patients) directly or within a few hours after administration in all cases. In the case of incontinence it is advised to treat patients with either 186Re-HEDP or 153Sm-EDTMP with a urinary catheter for 12 hours after administration. Patients treated with 89SrCl2 may return home directly.

After discharge it is advisable to keep distance where possible (Table 3 and 4), following the ALARA ('as low as reasonably achievable') principles. This means, for example, that older patients (> 60 years) may still sleep close to their older partner, while being more stringent towards younger relatives to avoid any unnecessary radiation dose. The ICRP has proposed an effective dose limit of 1 mSv per year for individuals. In special circumstances a higher value may be allowed in a single year provided that the average over 5 years does not exceed 1 mSv per year. In clinical practice, the use of bone-seeking radiopharmaceuticals will give rise to a degree of radiation exposure to all those in contact with patients, albeit in very low doses. The present results further confirm the safety of treatment with boneseeking radiopharmaceuticals.

#### **4.2 Treatment recommendations**

89SrCl2 (Metastron®) and 153Sm-EDTMP (Quadramet®) are both FDA approved and registered in the Netherlands. Together with 186Re-HEDP (registered in some countries, not in the Netherlands) these bone seeking radiopharmaceuticals are mostly used. Most of the randomized double-blind placebo controlled trials have been performed using 89SrCl2 or 153SmEDTMP. An evidence based approach would be a choice between these radiopharmaceuticals. One of the differences between these two is the magnitude and rate of renal excretion. Both may be used without confining a patient to the hospital but from a radiation safety perspective it is advised to keep the patient in a controlled setting for at least 8 hours after injection in the case of 153Sm-EDTMP. This could influence the choice on practical grounds in favour of 89SrCl2. Not all nuclear medicine departments have such facilities.

Other differences include the longer half-life and higher energy (with higher range in tissue) of 89SrCl2 compared to 153Sm-EDTMP. 153Sm-EDTMP and 186Re-HEDP are highly comparable with regard to energy and half-life. Most comparative randomized studies have been performed using 89SrCl2 and 186Re-HEDP. It was found that no difference exist with regard to pain response between treatment with 89Sr-Chloride and 186Re-HEDP in patients with painful osseous metastases (Piffanelli et al. 2001; Sciuto et al. 2001). And 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 carcinoma (Sciuto et al. 2001). So one might argue that when a faster pain response is indicated one should use 186Re-HEDP or 153Sm-EDTMP. Other differences are the longer duration of response of 89Sr-Chloride on one hand, and the prolonged bone marrow toxicity of 89Sr-Chloride on the other hand. These differences were not investigated in direct comparative studies but should be considered nevertheless. In summary: in favour of 89Sr-Chloride are:

No confinement necessary

224 Prostate Cancer – Diagnostic and Therapeutic Advances

by a potential internal contamination (0.01% of the administered dose), is 6.2 microSv for 89Sr, 96 microSv for 186Re and 111 microSv for 153Sm. These numbers are in the same order of

The total effective dose for non-patients may be caused by both external radiation exposure and internal contamination. In contrast to the mean effective dose caused by external radiation, the effective dose after ingestion of 0.01% of the administered dose is hypothetical and may be much higher or much lower. In the case of 131I it proved to be less. The uptake of 131I in the thyroid of family members was measured (Buchan and Brindle 1970). A maximum uptake of 3.8 Bq per MBq administered was found. So on one hand it must be considered that 0.01% is a hypothetical figure, while the external radiation exposure is a fact. On the other hand, internal contamination poses a real threat to non-patients. Patients that were treated with bone-seeking radiopharmaceuticals are often severely disabled (in contrast to 131I patients). Especially in the case of prostate cancer patients, they often have dysurea. Personal hygiene is not as obvious as it is to others. It is therefore advisable to give the patients simple, easy-to-follow instructions, in order to reduce the risk for non-patients. Using a separate toilet, sitting while urinating and washing hands afterwards, are highly recommended. In the case of incontinence, patients must be catheterized for a certain time depending on urinary excretion of the administered activity. Due to fast renal excretion this may be 12 hours after injection of 186Re-HEDP and 153Sm-EDTMP. 89SrCl2 is being administered in relatively low doses and therefore has a relatively low risk for high effective dose due to ingestion of this radiopharmaceutical (6.2 microSv for 89Sr). These patients do not have to be catheterized. The risk for significant internal contamination of non-patients is

In general it is advised to hospitalize patients treated with 186Re-HEDP and 153Sm-EDTMP for at least 8 hours. This is mostly based on urinary excretion and the risk for internal contamination, because the radiation exposure to non-patients is < 20 microSv/hour (1 meter from the patients) directly or within a few hours after administration in all cases. In the case of incontinence it is advised to treat patients with either 186Re-HEDP or 153Sm-EDTMP with a urinary catheter for 12 hours after administration. Patients treated with

After discharge it is advisable to keep distance where possible (Table 3 and 4), following the ALARA ('as low as reasonably achievable') principles. This means, for example, that older patients (> 60 years) may still sleep close to their older partner, while being more stringent towards younger relatives to avoid any unnecessary radiation dose. The ICRP has proposed an effective dose limit of 1 mSv per year for individuals. In special circumstances a higher value may be allowed in a single year provided that the average over 5 years does not exceed 1 mSv per year. In clinical practice, the use of bone-seeking radiopharmaceuticals will give rise to a degree of radiation exposure to all those in contact with patients, albeit in very low doses. The present results further confirm the safety of treatment with bone-

89SrCl2 (Metastron®) and 153Sm-EDTMP (Quadramet®) are both FDA approved and registered in the Netherlands. Together with 186Re-HEDP (registered in some countries, not in the Netherlands) these bone seeking radiopharmaceuticals are mostly used. Most of the randomized double-blind placebo controlled trials have been performed using 89SrCl2 or 153Sm-

magnitude as the numbers given for external exposure (Table 3 and 4).

much lower and acceptable for this radiopharmaceutical.

89SrCl2 may return home directly.

seeking radiopharmaceuticals.

**4.2 Treatment recommendations** 

 Longer duration of response (suitable in relatively good clinical condition in which a prompt response is not warranted)

In favour of 186Re-HEDP or 153Sm-EDTMP are:


In most cases today a fast response is needed. Besides that most patients, including prostate cancer patients, are heavily pre-treated. They have end stage disease with minimal bone marrow reserve. And last but not least short-living bone seeking radiopharmaceuticals like 186Re-HEDP, 153Sm-EDTMP and others may prove to be more suitable in combination with other treatment modalities, not just because of their toxicity profile but also because of their high dose rate, offering an effective treatment with fast recovery.
