**10. Peptide radio-receptor therapy of neuroendocrine tumours**

Neuroendocrine tumours (NETs) derive from the neuroendocrine cell system, which is widely distributed in the body, and are a heterogeneous group of neoplasms characterized by embryological, biological and histo-pathological differences. The most frequent sites of NETs are the gastrointestinal tract (70%) and the bronco-pulmonary system (25%), followed by the skin, the adrenal glands, the thyroid and the genital tract.

Present classification is based on tumour biology and patho-histological features (cellular grading, primary tumour size and site, cell proliferation markers, local or vascular invasivity and the production of biologically active substances), which are crucial to guide the diagnostic work-up and therapeutic planning.

The great majority are benign (well-differentiated neuroendocrine tumours) or slowgrowing neoplasms with a low grade of malignancy. Poorly differentiated endocrine carcinomas have a high grade of malignancy and a poor prognosis. Furthermore, a few moderately differentiated tumours with cellular and structural types intermediate between well and poorly differentiated NETs have also been found.

A typical feature of differentiated NETs is the expression of several specific receptors on the cell membrane and in particular of somatostatin receptors (SSTR) which can be visualized by somatostatin receptor imaging with radiolabelled somatostatin analogues (111In-OCTREOSCAN, 68Ga-DOTANOC). These radiopharmaceuticals bind with high affinity to subtypes 2, 5 and 3 of SSTR and provide an approximation of somatostatin receptor density, having a positive predictive value of the therapeutic efficacy of the somatostatin analogues.

Peptide receptor radionuclide therapy (PRRT) is an effective tool for the treatment of tumours with a high somatostatin receptor density.

This approach is based on the administration of a therapeutic activity of radiolabelled somatostatin analogues. Radiopharmaceutical with various radionuclides and peptides are currently available.

High activities of 111In-DTPA-octreotide (OCTREOSCAN®), the same radiopharmaceutical used for imaging, have been used in pilot trials and in some experiences (Herberg, 2009, 2011). Besides the gamma radiation of 111In used for scintigraphic scans (γ photons of 172 and 245 keV), its therapeutic effect is due to the emission of Auger and conversion electrons with a medium-to-short tissue penetration range (0.02-10 and 200-500 μm, respectively). Its potential effect depends on the preservation of mechanism of octreotide-receptor complex internalization (through endocytosis) and its translocation to the nuclear compartment, where short path-length Auger or conversion electrons are able to reach the target (DNA). In clinical trials, 111In-DTPA-octreotide showed a low rate of tumour regression: the most accredited explanation is that 111In electrons fail to reach the DNA helix, possibly due to the lack of nuclear receptors that were never definitely demonstrated (Kwekkeboom, 2005).

The radiopeptides for PRRT that have been studied most extensively are 90Y-DOTATOC and 177Lu-DOTATATE. These beta-emitting radiolabelled peptides are preferred for their advantageous physical properties.

90Y (Emax = 2.28 MeV, Rmax = 11 mm, <E> = 0.935 MeV; half-life 2.67 days) has a pure beta emission with long range particles that, besides the direct action, lead to irradiation also of no-receptor expressing tumour-cell (cross-fire effect). For these reasons 90Y-peptides are

Radionuclide therapy as a palliative treatment of bone pain is efficient, although improved

Neuroendocrine tumours (NETs) derive from the neuroendocrine cell system, which is widely distributed in the body, and are a heterogeneous group of neoplasms characterized by embryological, biological and histo-pathological differences. The most frequent sites of NETs are the gastrointestinal tract (70%) and the bronco-pulmonary system (25%), followed

Present classification is based on tumour biology and patho-histological features (cellular grading, primary tumour size and site, cell proliferation markers, local or vascular invasivity and the production of biologically active substances), which are crucial to guide

The great majority are benign (well-differentiated neuroendocrine tumours) or slowgrowing neoplasms with a low grade of malignancy. Poorly differentiated endocrine carcinomas have a high grade of malignancy and a poor prognosis. Furthermore, a few moderately differentiated tumours with cellular and structural types intermediate between

A typical feature of differentiated NETs is the expression of several specific receptors on the cell membrane and in particular of somatostatin receptors (SSTR) which can be visualized by somatostatin receptor imaging with radiolabelled somatostatin analogues (111In-OCTREOSCAN, 68Ga-DOTANOC). These radiopharmaceuticals bind with high affinity to subtypes 2, 5 and 3 of SSTR and provide an approximation of somatostatin receptor density, having a positive predictive value of the therapeutic efficacy of the somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is an effective tool for the treatment of

This approach is based on the administration of a therapeutic activity of radiolabelled somatostatin analogues. Radiopharmaceutical with various radionuclides and peptides are

High activities of 111In-DTPA-octreotide (OCTREOSCAN®), the same radiopharmaceutical used for imaging, have been used in pilot trials and in some experiences (Herberg, 2009, 2011). Besides the gamma radiation of 111In used for scintigraphic scans (γ photons of 172 and 245 keV), its therapeutic effect is due to the emission of Auger and conversion electrons with a medium-to-short tissue penetration range (0.02-10 and 200-500 μm, respectively). Its potential effect depends on the preservation of mechanism of octreotide-receptor complex internalization (through endocytosis) and its translocation to the nuclear compartment, where short path-length Auger or conversion electrons are able to reach the target (DNA). In clinical trials, 111In-DTPA-octreotide showed a low rate of tumour regression: the most accredited explanation is that 111In electrons fail to reach the DNA helix, possibly due to the lack of nuclear receptors that were never definitely demonstrated (Kwekkeboom, 2005). The radiopeptides for PRRT that have been studied most extensively are 90Y-DOTATOC and 177Lu-DOTATATE. These beta-emitting radiolabelled peptides are preferred for their

90Y (Emax = 2.28 MeV, Rmax = 11 mm, <E> = 0.935 MeV; half-life 2.67 days) has a pure beta emission with long range particles that, besides the direct action, lead to irradiation also of no-receptor expressing tumour-cell (cross-fire effect). For these reasons 90Y-peptides are

dosimetry methods could help to improve the treatment further.

by the skin, the adrenal glands, the thyroid and the genital tract.

the diagnostic work-up and therapeutic planning.

tumours with a high somatostatin receptor density.

currently available.

advantageous physical properties.

well and poorly differentiated NETs have also been found.

**10. Peptide radio-receptor therapy of neuroendocrine tumours** 

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 and 90Y are compared.

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 during PRRT.

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 bremsstrahlung are represented in green.

Concerning peptides, several new somatostatin analogues have been introduced for therapeutic and diagnostic purposes, including the agonists DOTA-(1-NaI3)octreotide (DOTANOC) and DOTA-(BzThi3)octreotide (DOTABOC).

Internal Radiation Dosimetry: Models and Applications 43

are likely to have higher renal toxicity thresholds than 90Y, whose emitted electrons have a

Renal doses can be reduced by co-administration of basic amino acids, bovine gelatinecontaining solution Gelofusine or albumin fragments, which interfere with the radiopeptide reabsorption pathway to achieve kidney protection. Amino acids, in particular, are already commonly used in the clinical setting during PRRT, being able to reduce the kidney adsorbed dose consistently (25-65% with respect to baseline data). The dose fraction

The dose to kidneys should not exceed a limit value of 28 Gy, established for external beam radiotherapy, which results in a 50% probability of developing severe late renal failure. Nevertheless, for the difference between the two radiation therapy modalities, this recommendation has been questioned and the biological effective dose (BED) is considered

BED for a given organ or tissue was defined in Equation 18. We recall that BED is a function of the doses imparted in each PRRT cycle, and depends upon the effective half-time of the

Data in literature show that patients with risk factors, such as hypertension and diabetes, should not receive a BED higher than 28 Gy, while patients with no risk factors might have a

The risk of bone marrow toxicity increases with increasing therapeutic dose. Studies aimed to increase the therapeutic dose (more cycles, higher dose per cycle, improvement in specific activity of the compound) to the tumour in a renoprotective (and bone marrow-protective) regimen are needed to further improve PRRT with somatostatin analogues in the future.

Amato, E. et al. (2009). Absorbed fractions for photons in ellipsoidal volumes. *Phys Med Biol,*

Amato, E. et al. (2009). Absorbed fractions in ellipsoidal volumes for β− radionuclides

Amato, E. et al. (2011). Absorbed fractions for electrons in ellipsoidal volumes. *Phys Med* 

Amato, E. et al. (2011). An analytical model for improving absorbed dose calculation

Berenson, J. R. (2005). Recomendations for zoledronic acid treatment of patients with bone

Blake, G. et al. (1998). Strontium-89 therapy: measurements of absorbed dose to skeletal

Blake, G. M. et al. (1986). Sr-89 therapy: strontium kinetics in disseminated carcinoma of the

Blake, G. M. et al. (1987). 89Sr radionuclide therapy: dosimetry and haematological toxicity in two patients with metastasising prostatic carcinoma. *Eur J Nucl Med,* 13, 41-46. Bodei, L. et al. (2008). Long-term evaluation of renal toxicity after peptide receptor

radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of

accuracy in non spherical autonomous functioning thyroid nodule. *Quart. J. Nucl.* 

employed in internal radiotherapy. *Phys Med Biol,* 54, 4171-4180.

*Med. Mol. Imag.* EPUB 18-01-2011 PMID: 21242948.

associated risk factors. *Eur. J. Nucl. Med.* 35, 1847.

metastases. *Oncologist,* 10, 52-62.

metastases. *J Nucl Med,* 29, 549-557.

prostate. *Eur J Nucl Med,* 12, 447-454.

a more accurate quantity, with a good correlation with the loss of kidney function.

radiopeptide in the organ and upon its intrinsic radiosensitivity.

path length of 12 mm.

**11. References** 

54, N479-487.

*Biol,* 56, 357-365.

markedly influences the total tolerated dose.

renal BED threshold of 40 Gy (Bodei, 2008).

These compounds have a broader somatostatin receptor affinity profile than DOTATATE and DOTATOC because of a higher affinity for sst3 and sst5 in addition to their high affinity for sst2. This could increase the number of tumours that could benefit from PRRT in the future.

Recently, peptides targeting all the sst receptors (pansomatostatins) have shown high affinity of 90Y-DOTA-cyclo(D-diaminobutyric acid-Arg–Phe–Phe-D-Trp–Lys–Thr–Phe) (90Y-KE88) for all 5 sst receptors and, in future, they could improve the therapeutic potential of sst-targeted PRRT.

To date, the therapy administration protocols rely essentially on empirical criteria with injection of standard activities, as derived from escalation studies or clinical experience, at variable time intervals (6-12 weeks).

For therapy optimization and prevention of toxicity, dosimetry represent a precious guide, providing evaluation of biodistribution, pharmacokinetics, radiation doses and biological effective doses to healthy organs and tumours.

The gamma-emission of 111In and 177Lu-peptide enable imaging, dosimetry and therapy with the same compound. In the case of 90Y-peptide, for the lack of gamma emission, the same analogue radiolabeled with 111In or positron emitters as 86Y or 68Ga can be used as surrogates for dosimetric imaging. Some recent studies have been published for 90Y-peptide dosimetry with bremsstrahlung images through SPECT-TC systems, or exploiting the rare positron decay of 90Y imaged by new generation PET-CT scanners.

A dosimetric protocol consists in the acquisition of multiple planar whole-body (WB) scan to obtain biokinetics data over the time (at least 4-5 acquisitions at different times), complementary SPECT imaging to evaluate intra-organ activity distribution (especially at the level of the kidneys and in tumour lesion), WB transmission imaging for attenuation correction, blood and urine samples. Anatomical imaging (CT or ultrasonographic) provide important parameters for organ mass evaluation (Cremonesi, 2011).

Dose calculation can be performed in the framework of the MIRD formalism, in order to obtain average dose estimates at the organ level assuming standard phantom models, with possible organ mass adjustments according to patient data. Voxel dosimetry method or direct Monte Carlo simulation can provide more reliable dose estimates.

Pharmacokinetic studies have shown fast blood clearance and urinary elimination. The higher uptake has been noticed in the spleen, kidneys and liver and no uptake is visible in the bone marrow in normal conditions. Pharmacokinetic data of different radiopeptides are similar but not identical: as the peptide influences biokinetics, for the single patient the data need to be assessed specifically with regard to the radiopharmaceutical.

Furthermore, dosimetric data should be collected during therapeutic cycles because many factors can influence the results.

The adsorbed doses, especially with regards to the tumour, are affected by wide intrapatient variation between treatment cycles. The adsorbed dose to the tumour is higher during the first two cycles with a gradually reduced uptake in the following treatments, probably due to saturation or down-regulation of peptide receptors. Tumour adsorbed dose should exceed 100 Gy to obtain a therapeutic effect, with better results for higher doses (about 230 Gy).

Nephrotoxicity is the dose-limiting factor, due to renal reabsorption and retention of radiolabeled peptides that results in high kidney radiation doses.

The renal adsorbed dose is influenced by the radionuclide emission: using a microdosimetry model, Konijnenberg et al. (2004) found that 111In- and 177Lu-labelled somatostatin analogues

These compounds have a broader somatostatin receptor affinity profile than DOTATATE and DOTATOC because of a higher affinity for sst3 and sst5 in addition to their high affinity for sst2. This could increase the number of tumours that could benefit from PRRT in the

Recently, peptides targeting all the sst receptors (pansomatostatins) have shown high affinity of 90Y-DOTA-cyclo(D-diaminobutyric acid-Arg–Phe–Phe-D-Trp–Lys–Thr–Phe) (90Y-KE88) for all 5 sst receptors and, in future, they could improve the therapeutic potential of

To date, the therapy administration protocols rely essentially on empirical criteria with injection of standard activities, as derived from escalation studies or clinical experience, at

For therapy optimization and prevention of toxicity, dosimetry represent a precious guide, providing evaluation of biodistribution, pharmacokinetics, radiation doses and biological

The gamma-emission of 111In and 177Lu-peptide enable imaging, dosimetry and therapy with the same compound. In the case of 90Y-peptide, for the lack of gamma emission, the same analogue radiolabeled with 111In or positron emitters as 86Y or 68Ga can be used as surrogates for dosimetric imaging. Some recent studies have been published for 90Y-peptide dosimetry with bremsstrahlung images through SPECT-TC systems, or exploiting the rare positron

A dosimetric protocol consists in the acquisition of multiple planar whole-body (WB) scan to obtain biokinetics data over the time (at least 4-5 acquisitions at different times), complementary SPECT imaging to evaluate intra-organ activity distribution (especially at the level of the kidneys and in tumour lesion), WB transmission imaging for attenuation correction, blood and urine samples. Anatomical imaging (CT or ultrasonographic) provide

Dose calculation can be performed in the framework of the MIRD formalism, in order to obtain average dose estimates at the organ level assuming standard phantom models, with possible organ mass adjustments according to patient data. Voxel dosimetry method or

Pharmacokinetic studies have shown fast blood clearance and urinary elimination. The higher uptake has been noticed in the spleen, kidneys and liver and no uptake is visible in the bone marrow in normal conditions. Pharmacokinetic data of different radiopeptides are similar but not identical: as the peptide influences biokinetics, for the single patient the data

Furthermore, dosimetric data should be collected during therapeutic cycles because many

The adsorbed doses, especially with regards to the tumour, are affected by wide intrapatient variation between treatment cycles. The adsorbed dose to the tumour is higher during the first two cycles with a gradually reduced uptake in the following treatments, probably due to saturation or down-regulation of peptide receptors. Tumour adsorbed dose should exceed 100 Gy to obtain a therapeutic effect, with better results for higher doses

Nephrotoxicity is the dose-limiting factor, due to renal reabsorption and retention of

The renal adsorbed dose is influenced by the radionuclide emission: using a microdosimetry model, Konijnenberg et al. (2004) found that 111In- and 177Lu-labelled somatostatin analogues

future.

sst-targeted PRRT.

variable time intervals (6-12 weeks).

factors can influence the results.

(about 230 Gy).

effective doses to healthy organs and tumours.

decay of 90Y imaged by new generation PET-CT scanners.

important parameters for organ mass evaluation (Cremonesi, 2011).

direct Monte Carlo simulation can provide more reliable dose estimates.

need to be assessed specifically with regard to the radiopharmaceutical.

radiolabeled peptides that results in high kidney radiation doses.

are likely to have higher renal toxicity thresholds than 90Y, whose emitted electrons have a path length of 12 mm.

Renal doses can be reduced by co-administration of basic amino acids, bovine gelatinecontaining solution Gelofusine or albumin fragments, which interfere with the radiopeptide reabsorption pathway to achieve kidney protection. Amino acids, in particular, are already commonly used in the clinical setting during PRRT, being able to reduce the kidney adsorbed dose consistently (25-65% with respect to baseline data). The dose fraction markedly influences the total tolerated dose.

The dose to kidneys should not exceed a limit value of 28 Gy, established for external beam radiotherapy, which results in a 50% probability of developing severe late renal failure. Nevertheless, for the difference between the two radiation therapy modalities, this recommendation has been questioned and the biological effective dose (BED) is considered a more accurate quantity, with a good correlation with the loss of kidney function.

BED for a given organ or tissue was defined in Equation 18. We recall that BED is a function of the doses imparted in each PRRT cycle, and depends upon the effective half-time of the radiopeptide in the organ and upon its intrinsic radiosensitivity.

Data in literature show that patients with risk factors, such as hypertension and diabetes, should not receive a BED higher than 28 Gy, while patients with no risk factors might have a renal BED threshold of 40 Gy (Bodei, 2008).

The risk of bone marrow toxicity increases with increasing therapeutic dose. Studies aimed to increase the therapeutic dose (more cycles, higher dose per cycle, improvement in specific activity of the compound) to the tumour in a renoprotective (and bone marrow-protective) regimen are needed to further improve PRRT with somatostatin analogues in the future.

### **11. References**


Internal Radiation Dosimetry: Models and Applications 45

Konijnenberg, M. W. et al. (2004). A stylized computational model of the rat for organ

Kraeber-Bodere, F. et al. (2000). Treatment of bone metastases of prostate cancer with

Krishnamurthy, G. T. et al. (1997). Tin-117m(4+)DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain. *J Nucl Med,* 38, 230-237. Krishnamurthy, G. T. et al. (2000). Radionuclides for metastatic bone pain palliation:a need for rational re-evaluation in the new millenium. *J Nucl Med,* 41, 688-691.

Lam, M. J. E. H. et al. (2004). 186Re-HEDP for metastatic bone pain in breast cancer patients.

Lassmann, M. (2010). *Dosimetry Concepts of radioiodine therapy for the Treatment of differentiated* 

Leondi, A. H. et al. (2004). Palliative treatment of painful disseminated bone metastases with 186Rhenium-HEDP in patients with lung cancer. *Q J Nucl Med,* 48, 211-219. Lewington, V. J. (1993). Targeted radionuclide therapy for bone metastases. *Eur J Nucl Med,*

Maigne, L. et al. (2011). Comparison of GATE/GEANT4 with EGSnrc and MCNP for

Mainegra-Hing, E. et al. (2005). Calculation of photon energy deposition kernels and

Maini, C. L. et al. (2003). Radionuclide therapy with bone seeking radionuclides in palliation

Maini, C. L. et al. (2004). 153Sm-EDTMP for bone pain palliation in skeletal metastases. *Eur J* 

Mazzaferri E. L. (1997). Thyroid Remnant 131I Ablation for Papillary and Follicular Thyroid

Minutoli, F. et al. (2006). 186Re-HEDP in the palliation of painful bone metastases from

Nilsson, S. et al. (2005). First clinical experience with alpha-emitting radium-223 in the

Nilsson, S. et al. (2007). Bone-targeted radium-223 in symptomatic, hormone-refractory

Regalbuto, C. et al. (2009). Radiometabolic treatment of hyperthyroidism with a calculated dose of 131-iodine: results of one-year follow-up. *J. Endocrinol. Invest,* 32, 134-138.

prostate cancer: a randomised, multicentre, placebo-controlled phase II study.

cancers other than prostate and breast. *Q J Nucl Med*, 50, 355-362.

treatment of skeletal metastases. *Clin Cancer Res*, 11, 4451-4459.

electron dose point kernels in water. *Med. Phys,* 32, 685-699.

of painful bone metastases. *J Exp Clin Cancer Res,* 22, 71-74.

*Nucl Med Mol Imaging,* 31, S171-S178.

Carcinoma. *Thyroid,* 7, 265271.

*Lancet Oncology,* 8, 587-594.

electron dose calculations at energies between 15 keV and 20 MeV. *Phys. Med. Biol,*

Lewington, V. J. (2005). Bone-seeking radionuclides for therapy. *J Nucl Med,* 46, 38S-47S. Lewington, V.J. (1996). Cancer therapy using bone-seeking isotopes. *Phys Med Biol,* 41, 2027-

therapy with (90)Y, (111)In, or (177)Lu. *J Nucl Med,* 45, 1260–1269.

*Med* 27, 1487-1493.

Kwekkeboom, D. J. et al. (2005).

20, 66-74.

2042.

56, 811.

. *J. Nucl. Med.* 46, 62S.

Radiolabeled Somatostatin Analogs

*Eur J Nucl Med Mol Imaging,* 31, S162-S170.

*thyroid cancer,* EANM Dosimetry Committee

dosimetry in support of preclinical evaluations of peptide receptor radionuclide

strontium-89chloride: efficacy in relation to degree of bone involvement. *Eur J Nucl* 

Overview of Results of Peptide Receptor Radionuclide Therapy with 3


Bodei, L. et al. (2008). EANM procedure guideline for treatment of refractory metastatic

Bolch, W.E. et al. MIRD Pamphlet No. 17: the dosimetry of nonuniform activity distributions

Breen, S. L. et al. (1992). Dose estimation in strontium-89 radiotherapy of metastatic prostatic

Brenner, W. et al. (2001). Skeletal uptake and soft-tissue retention of 186Re-HEDP and 153Sm-EDTMP in patients with metastatic bone disease. *J Nucl Med,* 42, 230-236. Cremonesi, M. et al. (2011). Recent issues on dosimetry and radiobiology for peptide receptor radionuclide therapy. *Quart. J. Nucl. Med. Mol. Imag,* 55(2), 155-167. Dafermou, A. et al. (2001). A multicentre observational study of radionuclide therapy in

Dieudonnè, A. et al. (2010). Fine-resolution voxel S values for constructing absorbed dose

Englaro, E.E. et al. (1992). Safety and efficacy of repeated sequential administrations of

Eschmann, S. M. et al. (2002). Evaluation of dosimetry of radioiodine therapy in benign and

Farhangi, M. et al. (1992). Samarium-153-EDTMP: pharmacokinetic, toxicity and pain

Furhang, E. E. et al. (1997). Implementation of a Monte Carlo dosimetry method for patient-

Hellmann, S. and Weichsellbaum, R. R. (1994). Radiation oncology. *JAMA*, 271, 1712-1714. Herberg, A. et al. (2009). 90Y-DOTATOC and/or 111In-Pentetreotide in the treatment of

Herberg, A. et al. (2011). 111In-Pentetreotide for the treatment of neuroendocrine tumours:

Hillner, B.E. et al. (2003). American Society of Clinical Oncology 2003 update on the role of

Hindorf, C. et al. (2008). A biodistribution and dosimetry study of therapeutic 223RA-

Hindorf, C. et al. (2008). Quantitative imaging of 223Ra during radionuclide therapy of

Hindorf, C. et al. (2011). Clinical dosimetry in the treatment of bone tumors: old and new

ICRP, (1987). International Commission on Radiological Protection. Radiation dose to

patients from radiopharmaceuticals. Oxford, UK; Pergamon Press.

to hormone refractory prostate cancer. *J Nucl Med,* 49, 145P.

bone metastases. *J Nucl Med,* 49, 326P.

agents. *Q J Nucl Med Mol Imaging,* 55, 198-204.

distributions at variable voxel size. *J Nucl Med,* 51, 1600-1607.

specific internal emitter therapy. *Med. Phys,* 24, 1163-1172.

reports of two patients. *Clin Nucl Med,* 17, 41-44.

patients with painful bone metastases of prostate cancer. *Eur J Nucl Med Mol* 

Re186(Sn)HEDP as palliative therapy for painful skeletal metastases. Initial case

malignant thyroid disorders by means of iodine-124 and PET. *Eur. J. Nucl. Med.* 

response using escalation doses schedule in treatment of metastatic bone cancer. *J* 

somatostatin receptors-expressing tumors (SSTR): our experience. *Eur J Nucl Med* 

an alternative therapeutic option in particular cases. *Quart J Nucl Med Mol Imaging*,

bisphosphonates and bone health issues in women with breast cancer. *J Clin Oncol,*

chloride (Alpharadin) in patientts with osteoblastic skeletal metastases secondary

– radionuclide S values at the voxel level. *J Nucl Med,* 40, 11S-36S.

bone pain. *Eur J Nucl Med Mol Imaging,* 35, 1934-1940.

carcinoma. *J Nucl Med,* 33, 1316-1323.

*Imaging,* 28, 788-798.

*Mol. Imaging,* 29, 760-767.

*Nucl Med,* 33, 1451-1458.

Giovannella (2000). *Radiol. Med.*, 105, 12

*Mol Imaging*, 36 S.2, S418.

52 S.1, 131.

21, 4042-4057.


**1. Introduction** 

1. Low activity 2. Low energy 3. Short half life

this way:

make T���

4. Decay to a stable daughter

as Effective Half Life Time T���

**3** 

**Medical Cyclotron** 

In this chapter we intend to illustrate the reader about the use of Cyclotrons to produce easy handle radioisotopes, to be used for medical diagnostics or therapies in Nuclear Medicine. Firstofall, we will describe different activation processes to generate artificial radioisotopes, characteristics needed to be safely used in medicine, such as the relationship between fathers and daughters that can compromise patient or environment health. It also will be describe radioisotopes desire behavior inside human body in order to clarify which isotopes can be activated or not in a cyclotron facility to be used in human medical applications. Nuclear Medicine radioisotopes must fulfill four main characteristics in order to be easy handle by operators and be easily and quickly disposed by patients and not to represent

In Nuclear Medicine, equipment also has to have a high sensitivity to small amounts of radiation and to different types of radioisotopes. The ideal radioisotopes must be easily eliminated by the patient just after the study has been done in a short period of time which is a function of the physical half life of the isotope and the patient excretion system. The total time elapse for patient elimination of any trace of radioisotope used for study is known

��� and is related to the time isotope population is reduced to its

1 ���� ���

environmental radioactive contamination harm, so they have to have:

half due to the radioactive decay of father to daughter (Physical Half Life) T���

1 ����

patient systems needs to eliminated of isotope from it system (Biological Half Life) ����

So it is not easy to find natural occurrence radioisotopes to fulfill this equation in order to

there was a huge development of activation processes when man learn how to manipulate atom and its nuclei, so now we have a big amount of radioisotopes for an equally big amount of pacific applications. There are two kinds of manmade machinery capable of modify stable nuclide: Nuclear reactors and particle accelerators. Accelerator can also be

��� shorter than biological times of cellular repair. Fortunately in mid 20Th century,

��� <sup>=</sup> <sup>1</sup> ���� ��� +

Reina A. Jimenez V *Policlínica Metropolitana,* 

*Venezuela* 

��� and the time

��� in


Reina A. Jimenez V *Policlínica Metropolitana, Venezuela* 
