This chapter was published on “Inuitech – Intuitech Technologies for Sustainability” on May 27, 2012.
The modern trend in radiopharmaceutical research for oncology is the development of RPTs that may be said to be tumour-seeking and tumour-specific. In therapeutic radiopharmaceutical applications—unlike the case of external radiation therapy where the radiation from an external sealed radioactive source is focused on the site to be irradiated—the product is administered to the patient orally or intravenously and is selectively taken up or localized in the site to be irradiated. Suitable agents have to be designed to exploit the metabolic and biological characteristics of tumours, so as to guide the RPT and ensure proper localized treatment. In developed countries (26 percent of world population) the frequency of diagnostic nuclear medicine is 1.9 percent per year, and the frequency of therapy with radioisotopes is about one tenth of this. In the USA there are some 18 million nuclear medicine procedures per year among 311 million people, and in Europe about 10 million among 500 million people. In Australia there are about 560,000 per year among 21 million people, 470,000 of these using reactor isotopes. The use of radiopharmaceuticals in diagnosis is growing at over 10 percent per year.
Nuclear medicine has a unique but effective technique which employs medicines with a trace amount of radioactive material, doctors can use pharmaceuticals that have been labeled with radionuclides (Radiopharmaceuticals) to specific locations and monitor if medications are producing hoped-for results.
Pharmaceuticals are substances used to diagnose, treat or prevent disease. Radiopharmaceuticals are radioactive pharmaceuticals used in nuclear medicine. These drugs are made up of two components; a radioactive isotope that can be injected safely into the body, and a carrier molecule which delivers the isotope to the area to be treated or examined. Once radiopharmaceuticals enter the body and travel to an organ, they begin to interact with the processes of that organ. The radioactive component emits signals which are picked up by cameras or computers and used to map the process. For example, an ultrasound can show an image of an organ and reveal if a tumor or other abnormality is present. Nuclear medicine can show how the process of glucose metabolism is functioning in the organ.
Radiopharmaceuticals also known as radioactive drugs are drugs that contain radionuclides that emit radiation(s). The distribution of the radiopharmaceutical within the body is determined by the physiochemical properties of the drug, the stability of the radiolabel, the purity of the radiopharmaceutical preparation, the pathophysiological state of the patient and the presence or absence of interfering drugs. Dynamic and static images of the distribution of the radiopharmaceutical within the body can be obtained using a gamma camera, or other suitable instrument appropriate for the radiopharmaceutical being imaged, e.g., positron emitting radiopharmaceuticals. Measurement of radioactivity in specified sites of accumulation or in biological samples following administration of the radiopharmaceutical can be performed for non-imaging procedures. High dose, non-penetrating radiation in localized sites of accumulation of the radiopharmaceutical can be useful for therapeutic procedures. Radiopharmaceuticals are medicinal formulations containing radioisotopes which are safe for administration in humans for diagnosis or for therapy. Although radiotracers were tried as a therapeutic medicine immediately after the discovery of radioactivity, the first significant applications came much later with the availability of cyclotrons for acceleration of particles to produce radioisotopes. Subsequently, nuclear reactors realized the ability to prepare larger quantities of radioisotopes. Radioiodine (iodine-131), for example, was first introduced in 1946 for the treatment of thyroid cancer, and remains the most efficacious method for the treatment of hyperthyroidism and thyroid cancer.
1. THERAPEUTIC RADIOPHARMACEUTICALS:
Therapeutic radiopharmaceuticals are directed at treatment of serious disease, typically cancers. These include the well-known use of cobalt-60 in cancer therapy, for example. Traditionally, other radionuclides, including iodine-131, phosphorus-32, and strontium-89, were used in the fields of oncology, endocrinology, and rheumatology. The incorporation of more radionuclides into the armamentarium of medical therapy during the last 30-40 years, however, has been slow for a variety of reasons.
In recent years, however, the medical community has seen a renaissance of therapeutic radiation applications, particularly of strontium-89 for metastatic bone pain. The change has come about largely through advances over the past decade in the radiopharmaceutical industry, the greater availability of radionuclides with improved nuclear and chemical characteristics for medical uses, and encouraging results from clinical studies on uses of radiopharmaceuticals for therapy.
Radiopharmaceuticals used as therapeutic agents (frequently known as RPTs) are designed to deliver high doses of radiation to selected malignant sites in target organs or tissues, while minimizing the radiation doses to surrounding healthy cells. Over the past several years, several types of RPTs with special properties, including compounds for labeling monoclonal antibodies, have been used in animal and human clinical trials with promising results.
The modern trend in radiopharmaceutical research for oncology is the development of RPTs that may be said to be tumour-seeking and tumour-specific. In therapeutic radiopharmaceutical applications—unlike the case of external radiation therapy where the radiation from an external sealed radioactive source is focused on the site to be irradiated—the product is administered to the patient orally or intravenously and is selectively taken up or localized in the site to be irradiated. Suitable agents have to be designed to exploit the metabolic and biological characteristics of tumours, so as to guide the RPT and ensure proper localized treatment. 1.1 Radiopharmaceuticals for Cancer Therapy:
Over the past number of years, considerable interest has emerged in the use of radiopharmaceuticals to relieve intense bone pain resulting from metastasis from breast, prostate, and lung cancer. Their application has been demonstrated in clinical practice, and a number of governmental and commercial laboratories are actively engaged in the development and clinical evaluation of RPTs for the treatment of patients with painful skeletal metastasis.
The prevalence of metastatic bone cancer in nearly all countries creates a large need for the development of new palliative agents. It is estimated that about half of all patients with carcinomas of the prostate, breast, and lung eventually develop skeletal metastasis. The disease causes intense pain and suffering for patients. The pain is frequently relieved by the use of analgesics or even narcotics such as morphine when the pain is intolerable. For terminal patients, the use of bone-seeking RPT may be a desirable alternative to narcotics.
The most appropriate radionuclides for bone therapy are those decaying by the emission of medium energy beta particles. Beta particles of energy between 1 to 2 MeV have been shown to be effective since they are able to penetrate only the required few millimeters of the malignant tissue without compromising the bone marrow too much, a consideration of paramount importance when designing new RPT for bone therapy.
Besides phosphorus-32 and strontium-89, a number of radionuclides are rapidly drawing interest for bone cancer therapy. These include samarium-153, rhenium-186, and to a lesser extent holmium-166 and dysprosium-165.
Rhenium-186, samarium-153, and a number of other bone-seeking radionuclides can be produced in research reactors of medium and high neutron flux by neutron irradiation of appropriated targets. Although their availability is limited within the developing world, research reactors having a high neutron flux are operating in Indonesia, Peru, China, and India, for example.
Over the past few years, a number of bone-seeking compounds of rhenium and samarium have been investigated for the relief of bone pain. Some of these compounds now are undergoing clinical trials in the United States, Europe, China, Japan, and Australia. The studies show that these compounds of rhenium and samarium are effective in alleviating the pain in disseminated bone metastasis at injected doses in the range of 0.2 to 1.0 milli-curies per kilogram of body weight.
2. OVERALL IMPACT AND PRECAUTIONS:
2.1 Biological Effects:
Interaction of x-rays or gamma rays with matter causes ionization, resulting in the production of negatively charged electrons and positively charged ions. Electrons will travel short distances, and can produce further ionization. Positive ions can bring about chemical changes, which are the prime cause of radiation injury.
The most significant effect of the interaction of radiation with tissues is radiolysis of water. Initially, absorption of energy by water molecules leads to the ejection of electrons. The resulting positively charged ion dissociates to produce a hydrogen ion and a hydroxide free radical. Electrons react with further water molecules to produce hydroxide ions and hydrogen free radicals. It is the production of these highly reactive free radicals, either electron-acceptors or electron donors, which induces subsequent damage.
At the molecular level, free radicals can initiate strand breakage in DNA, or disruption in the structure of protein molecules. An outward manifestation of this molecular damage can occur at different times after the event, depending on the extent of the initial exposure and the nature of the molecular damage. For instance, if double-strand breakage in a DNA molecule occurs, there is little chance of repair. Cell death may occur, or cell abnormality and mutation may be transmitted to daughter cells, leading to possible malignancy. Abnormality in germinal cells may lead to offspring inheriting abnormal characteristics.
2.2 Radiation Risks:
All clinical procedures involving the exposure of subjects to ionizing radiations involve risk. It is part of the philosophy of current regulations and guidance that the risk is minimized and also justified. In other words, an assessment of the associated risks and benefits of any procedure should be made before that procedure is performed.
Therapeutic procedures will naturally carry a much greater intrinsic risk than diagnostic ones, simply because the administered doses are so much higher, sometimes by several orders of magnitude. The potential benefits are, however, also very high, because in many instances treatment of medical conditions with ionizing radiation is performed in cases of life-threatening disease.
The risks associated with all nuclear medicine procedures have been quantified and have associated with them a factor known as the “effective dose”, expressed in units of milli-Sieverts. This is defined as the sum of equivalent doses in all tissues and organs, weighted using tissue weighting factors specified by the International Commission on Radiological Protection. Adherence to these levels of exposure is assured through a system of prior authorizations on the part of doctors performing the procedures. The system sets out reference levels for the doses of radioactive substance, which should not normally be exceeded during the performance of any diagnostic procedure.
Direct influences relate to the potential alteration in bio distribution, which can lead to the delivery of unnecessary radiation doses to organs or areas of the body.
Indirect influences also arise from changes in bio distribution, but relate to interpretation of the images produced by these altered bio distributions. Pathological conditions may be masked, leading to misinterpretation and incomplete or inaccurate reporting. This, in turn can result in the adoption of inappropriate patient management regimes, or may require investigations to be repeated, resulting in additional radiation exposure. In order to understand the significance of inappropriate product quality, it is necessary to know some biological effects of radiation.
2.3 Quality Assurance:
Quality assurance of radiopharmaceuticals can be defined under a number of headings. Some of these are familiar in the sense that they represent criteria, which apply to all pharmaceutical products, and this category would include considerations such as sterility, apyrogenicity, and absence of foreign particulate matter. It is not proposed to consider these factors other than in passing because their importance in relation to patient safety is well established.
Some factors have a specific relevance to radiopharmaceuticals and it is proposed to examine these in more detail, exploring each in turn for its relevance to the clinical outcome of diagnosis or treatment using radiopharmaceutical products. Radiopharmaceuticals are generally expected to conform to specifications under the following headings:
- Radionuclide concentration;
- Radiochemical purity;
- Chemical purity;
- Absence of foreign particulate matter;
- Particle size (if appropriate);
- pH; and
- Biological distribution.
Some of these parameters may be measured directly on products prior to use. However, one of the characteristics of many diagnostic radiopharmaceuticals is the inclusion of short-lived radionuclides. These radioactive elements often have half-lives measured in hours, minutes or even seconds, making meaningful testing of the end products impractical. Most diagnostic radiopharmaceuticals contain the radionuclide technetium-99m, an artificial radioactive element with a half-life of six hours. In these circumstances, great emphasis must be placed on adoption of an effective programme of quality assurance.
3. COMMON RADIOISOTOPES IN MEDICAL APPLICATIONS:
One of the major goals for setting up nuclear research reactors was for the preparation of radioisotopes. Among the several applications of radioisotopes, medical applications were considered to be of the highest priority. Most of the medium flux and high flux research reactors now are routinely used to produce radioisotopes for medical, and also industrial, applications.
Many of the chemical elements have a number of isotopes. The isotopes of an element have the same number of protons in their atoms (atomic number) but different masses due to different numbers of neutrons. In an atom in the neutral state, the number of external electrons also equals the atomic number. These electrons determine the chemistry of the atom. The atomic mass is the sum of the protons and neutrons. There are 82 stable elements and about 275 stable isotopes of these elements.
When a combination of neutrons and protons, which does not already exist in nature, is produced artificially, the atom will be unstable and is called a radioactive isotope or radioisotope. There are also a number of unstable natural isotopes arising from the decay of primordial uranium and thorium. Overall there are some 1800 radioisotopes.
At present there are up to 200 radioisotopes used on a regular basis, and most must be produced artificially. Here are the commonly used reactor produced isotopes in medical applications:
3.1 Molybdenum-99 (Production of Technetium-99m):
Molybdenum-99 is a reactor-produced radioisotope of molybdenum. It is used in radionuclide generators for the production of technetium-99m (99TC). It is produced from the nuclear fission of Uranium-235 using neutron bombardment. 99TC is the most widely used isotope in Nuclear Medicine. 99TC generators short half-life of six hours and the energy emitted (140 keV) make it an ideal imaging agent.
The radioisotope most widely used in medicine is 99TC, employed in some 80 percent of all nuclear medicine procedures – hence some 30 million per year, of which 6-7 million are in Europe, 15 million in North America, 6-8 million in Asia/Pacific (particularly Japan), and 0.5 million in other regions. It is an isotope of the artificially-produced element technetium and it has almost ideal characteristics for a nuclear medicine scan. These are:
- It has a half-life of six hours which is long enough to examine metabolic processes yet short enough to minimize the radiation dose to the patient;
- 99TC decays by a process called “isomeric”; which emits gamma rays and low energy electrons. Since there is no high-energy beta emission the radiation dose to the patient is low;
- The low energy gamma rays it emits easily escape the human body and are accurately detected by a gamma camera. Once again the radiation dose to the patient is minimized; and
- The chemistry of technetium is so versatile it can form tracers by being incorporated into a range of biologically-active substances to ensure that it concentrates in the tissue or organ of interest.
Its logistics also favour its use. Technetium generators, a lead pot enclosing a glass tube containing the radioisotope, are supplied to hospitals from the nuclear reactor where the isotopes are made. They contain molybdenum-99, with a half-life of 66 hours, which progressively decays to 99TC. The 99TC is washed out of the lead pot by saline solution when it is required. After two weeks or less the generator is returned for recharging. It is used as a medical tracer in radioactive isotope medical tests. 99TC is used in the treatment of the following diseases: Brain; Myocardium; Thyroid; Lungs; Liver; Gallbladder; Kidney; Skeleton; Blood; Tumors; etc.
Up until recently, Canada produced approximately half the world’s supply of molybdenum-99, and the US imported approximately 50 percent to 80 percent of its supply from Canada. In 2008, there were no facilities in the US manufacturing molybdenum-99. Global efforts to reduce the proliferation of nuclear weapons and deter terrorism are believed, in part, to account for the lack of medical isotope production facilities.
Concerns about the long-term supply of medical isotopes have been further confounded by the decision in early 2008, by Atomic Energy of Canada Limited, to cancel the construction of the two MAPLE reactors. Once completed, these reactors would have been the world’s first reactors dedicated exclusively to medical isotope production and could have supplied the entire global demand for molybdenum-99. Approximately $300 million was spent over a period of 15 years on their construction.
3.2 Iodine-131 (Radioiodine I-131):
Iodine-131 (131I), an isotope of iodine that emits radiation, is used for medical purposes. When a small dose of 131I is swallowed, it is absorbed into the bloodstream in the gastrointestinal (GI) tract and concentrated from the blood by the thyroid gland, where it begins destroying the gland’s cells.
Iodine -131 also called Radioiodine (131I) therapy which is a treatment for an overactive thyroid, a condition called hyperthyroidism. Hyperthyroidism can be caused by Graves’ disease, in which the entire thyroid gland is overactive, or by nodules within the gland which are locally overactive in producing too much thyroid hormone.
Nuclear medicine uses small amounts of radioactive material to diagnose and determine the severity of or treat a variety of diseases, including many types of cancers, heart disease, gastrointestinal, endocrine, neurological disorders and other abnormalities within the body. Because nuclear medicine procedures are able to pinpoint molecular activity within the body, they offer the potential to identify disease in its earliest stages as well as a patient’s immediate response to therapeutic interventions.The thyroid is a gland in the neck that produces two hormones that regulate all aspects of the body’s metabolism, the chemical process of converting food into energy. When a thyroid gland is overactive, it produces too much of these hormones, accelerating the metabolism.
Radioactive iodine may also be used to treat thyroid cancer.
3.3 Phosphorus-32 (32P):
Phosphorus-32 (32P) is a radioactive isotope of phosphorus. The nucleus of 32P contains 15 protons and 17 neutrons, one more neutron than the most common isotope of phosphorus, phosphorus-31. Phosphorus-32 only exists in small quantities on Earth as it has a short half-life and so decays rapidly. Phosphorus is found in many organic molecules and so 32P has many applications in medicine, biochemistry and molecular biology where it can be used to trace phosphorylated molecules, e.g. in elucidating metabolic pathways, and radioactively label DNA.
Phosphorus has a short half-life of 14.29 days and decays into sulfur-32 by beta decay. Its short half-life means useful quantities have to be produced synthetically. 32P can be generated synthetically by irradiation of sulfur-32 with moderately fast neutrons. The sulfur-32 nucleus captures the neutron and emits a proton, reducing the atomic number by one while maintaining the mass number of 32.
Phosphorus is abundant in biological systems and, as a radioactive isotope is almost chemically identical with stable isotopes of the same element, phosphorus-32 can be used to label biological molecules. The beta radiation emitted by the 32P is sufficiently penetrating to be detected outside the organism or tissue which is being analyzed.
Many radioisotopes are used as tracers in nuclear medicine, including iodine-131, phosphorus-32, and technetium-99m. 32P is of particular use in the identification of malignant tumours because cancerous cells have a tendency to accumulate more phosphate than normal cells. The location of the 32P can be traced from outside the body to identify the location of potential malignant tumors.
The radiation emitted by 32P can be used for therapeutic as well as diagnostic purposes. The use of 32P -chromic phosphate has been explored as a possible chemotherapy agent to treat disseminated ovarian cancer. In this situation it is the long-term toxic effects of beta radiation from phosphorus-32 accumulating in the cancerous cells which has the therapeutic effect.
3.4 Chromuim-51 (51Cr):
Chromium 51 (51Cr) a radioactive isotope of chromium having a half-life of 27.7 days and decaying by electron capture with emission of gamma rays (0.32 MeV); it is used to label red blood cells for measurement of mass or volume, survival time, and sequestration studies, for the diagnosis of gastrointestinal bleeding, and to label platelets to study their survival. There are 24 protons in Chromium (including 54Chromium) of any isotope. Isotopes are just elements with different numbers of neutrons. If it is called chromium it has 24 protons. The atomic number of an element is the same as the number of protons.
Gray & Sterling (1950) introduced 51Cr as a red cell label, and to-day it is the isotope which is most widely used for this purpose. The reason for this is that it is easy to label cells with 51Cr, the y-ray emitted is easy to detect, and the radiation dose received by the patient is small, being of the same order as that received during the taking of a chest X-ray. However, 51Cr has the disadvantage that it does not remain firmly bound to the red cells but slowly elutes out again while the red cells are surviving in the circulation.
In both clinical practice and, experimental research, isotope dilution methods are being used routinely for the determination of total blood volume. The isotopes most commonly used are chromium. 51Cr and Radioiodine-131 are γ-emitting isotopes. 51Cr – labelled red blood cells are used to obtain the total red blood cell circulating mass, which, in conjunction with the haematocrit, allows for an indirect determination of the total blood volume. Conversely, radioactive iodinated serum albumin gives a measure of total plasma volume and, with the hæmatocrit, an indirect measurement of the total blood volume. The use of either of these methods alone is subject to criticism, since the final calculations for total blood volume are based on the assumption that the peripheral hæmatocrit is the same as, or represents, a constant percentage of the total body hæmatocrit. It has been demonstrated that these assumptions are not valid. The ideal method for excluding hæmatocrit error would be to measure the red cell portion and the plasma portion of the vascular compartment separately, the total blood volume then being the sum of these two independent measurements. Several methods have appeared utilizing 54Cr-tagged red cells and radioactive iodinated serum albumin in the same subject for measurements of total circulating red cell mass and total plasma volume, respectively.
Some methods have combined repetitive injections of the respective isotopes; whereas others, the simultaneous injection of both. In those methods where the isotopes are injected separately, it is necessary to obtain repeated samplings of the subject’s blood, which in clinical practice may be only a slight inconvenience to the patient, but is, with small animals, a significant handicap. Repeated bleeding and intravenous injecting of small laboratory animals are not only difficult but also may create stress in the animals which could influence the results in the final determinations.
3.5 Strontium-89 (89Sr):
Strontium 89 (89Sr) a radioactive isotope of strontium having a half-life of 50.55 days and decaying by beta emission; used in the form of the chloride as a radiation source in palliation of bone pain caused by metastatic lesions.
89Sr is useful in prostatic and breast cancer. Although it may not necessarily reduce pain from existing bony metastases, it appears to decrease the number of new sites developing. 89Sr appears to have similar clinical response rates to other radiopharmaceuticals with selective bone localization.Most secondary bone lesions arise from primary carcinoma of the prostate, breast or lung, and external beam radiation therapy palliates 70 percent of lesions. However, this is not always adequate treatment for patients with multiple lesions and end-stage disease. In such cases pain relief is an important aspect of treatment. Radiopharmaceutical therapy can be given as an adjunct to external beam radiation for managing pain caused by skeletal metastases. Several radiopharmaceuticals, including strontium chloride 89 exist with selective bone localization and the ability to irradiate bony metastases from within by short-range radiation.
Palliative treatments include:
a) Local field radiotherapy:
- Effective in patients with single defined sites of pain;
- Onset of pain relief: 3-4 days;
- Mean duration of response: > 4 months;
- Complete pain relief at site treated: 30-60 percent; and
- Toxicity: rare.
b) Wide field radiotherapy:
- Multiple sites of pain;
- Complete pain relief: about 20 percent;
- Partial pain relief: 50-100 percent;
- Pain relief: rapidly, within days, lasts between 8 and 14 weeks;
- Retreatment is not an option; and
- Toxicity: pancytopenia, pneumonitis, diarrhea, vomiting.
3.6 Samarium-153 (153Sm):
Samarium-153 (153Sm) is an isotope of samarium. It emits beta particles and gamma rays. (The therapeutic component is largely due to the beta particles, but the gamma rays make it easier to locate the distribution). It is used in Samarium (153Sm) lexidronam. It is treated by the body in a similar manner to calcium, and it localizes selectively to bone. It is used in palliation of bone cancer.
153Sm is produced by the neutron bombardment of isotopically enriched 152Sm2O3 in a nuclear reactor. Soluble ionic 153Sm3+ when administered intravenously has very little propensity for bone, but when chelated by a variety of aminocarboxylate and aminophosphonate ligands it can be quite effectively targeted to the skeleton. Goeckeler and colleagues demonstrated that the complex formed with EDTMP had a combination of biologic properties necessary for a bone-targeted radiotherapeutic agent. These include rapid clearance from the vascular compartment following intravenous injection, high uptake and retention in the skeleton, and rapid renal clearance and urinary excretion of the portion not bound to bone.In addition, it was found that localization of the complex to newly formed bone, such as that laid down by osteoblastic bone metastases, was 10- to 20-fold higher per gram than that found in normal bone.
Preclinical escalating single (0.5–2.0 mCi/kg) and multiple (1.0 mCi/kg) dose studies in dogs showed that the only apparent toxicity related to the administration of samarium 89Sr lexidronam was a decrease in circulating levels of white blood cells (WBCs) and PLTs. Dose-related decreases in WBCs and PLTs were observed following administration, reaching a nadir at 2 to 4 weeks, recovering to pretreatment levels by 5 to 6 weeks. In a separate study, very high (up to 30 mCi/kg) single doses were administered to dogs with the intent of ablating bone marrow. Unexpectedly, spontaneous recovery of marrow function was observed in all animals. Pathologic analyses showed that marrow function was retained in the mid-shaft of the long bones presumably as a result of the inability of the beta particle emissions from the 153Sm deposited in these areas of predominantly cortical bone to uniformly penetrate the marrow space.
In all clinical studies of samarium Sm 153 lexidronam, the only clinically significant toxicity reported has been mild and transient myelosuppression. WBC and PLT counts decrease beginning at 1 to 2 weeks to a nadir of approximately 50 percent of the baseline level at 3 to 5 weeks post administration. Recovery to pre-treatment levels is typically observed by week 8. No differences have been seen in hemoglobin levels between patients receiving 1.0 mCi/kg active drug and those administered a placebo. Pooled WBC and PLT levels as a function of time for 1.0 mCi/kg and placebo patients in the 2 placebo-controlled studies.
3.7 Rhenium-186 (186Re):
Rhenium 186 (186Re) hydroxyethylidenediphosphonate (HEDP) and rhenium 188 HEDP are radiopharmaceuticals that have been used for palliation of painful bone metastases resulting from prostate and breast cancer. The 186Re HEDP can achieve noticeable pain relief in 70 percent–90 percent of patients after administration of local radiation doses of 10–100 Gy. The therapeutic effects of 186Re HEDP result from the beta emission, which has a maximal energy of 1.07 MeV and a maximal distance of 4.5 mm in soft tissue.The 186Re also has a 9 percent gamma emission (135 keV), which allows whole-body imaging, with a standard gamma camera, and dose estimations. The physical half-life of186Re is 89.3 hours, which makes this radioisotope suitable for repetitive therapy within a short time. More than 50 percent of the administered activity is cleared through the kidneys within the first 24 hours (14). Similar to phosphonates such as technetium 99m (99mTc) dicarboxypropane diphosphonate (DPD), which is used for bone scanning, the 186Re HEDP adheres to the hydroxyapatite crystal mediated by the metabolic activity of osteoblastic cells. Therefore, hyper metabolic regions of the bone and joints will receive a significantly higher radiation dose than will regions of the skeleton that have normal metabolism.
A study was conducted and the purpose of this study was to evaluate the effect of systemic radiation therapy with 186Re HEDP on pain and activity of patients with the polyarthritis of rheumatoid disease who do not respond to treatment with medication.
To prevent extravasation and excessive doses in the fingers, the radiopharmaceutical was administered by using an intravenous infusion system. The syringe was shielded to reduce the radiation dose. Each patient received at least one treatment with 555–740 MBq (15–20 mCi) of 186Re HEDP. The amount of required activity was estimated on the basis of results at pre-treatment bone scintigraphy, with a maximum dose of 20 mCi. For patients to be admitted to therapy, dose estimations to the affected joints had to show a minimum radiation dose of 5 Gy. For this purpose, sequential bone scintigraphy was performed, and the accumulated activity of a reference joint was calculated. A radiograph was obtained to help determine the volume of the concerned joint. Multiplication of the radionuclide-specific S-value by the accumulated activity per mass unit equals the estimated radiation dose to the reference joint.
The patient was well hydrated after injection of the 186Re HEDP. Owing to local radiation protection laws, the patients remained in the isolation ward for 48 hours. Twelve hours after injection, whole-body scintigraphy was performed to document the accumulation of 186Re HEDP. The dose of 186Re HEDP for each patient was normalized to a standard body surface area of 1.73 m2. No therapeutic complications occurred.
3.8 Lutetium-177 (177Lu):
Lutetium (177Lu) is increasingly important as it emits just enough gamma for imaging while the beta radiation does the therapy on small (e.g. endocrine) tumours. Its half-life is long enough to allow sophisticated preparation for use.Lutetium-177 (177Lu) is a radionuclide with exciting potential. 177Lu can be used in a similar manner as Yttrium-90 for Smart Drug research and other applications. However 177Lu is quite different from Yttrium-90 in ways that offer some advantages:
- 177Lu has both gamma and beta properties – enabling it to be used in imaging as well as treatment studies.
- 177Lu has a shorter radius of penetration than Y-90, making 177Lu an ideal candidate for radiotherapy for smaller tumors.
In Rotterdam at the Erasmus Clinic they have been using PRRT for the past 8 years with good effect. From January 2000 until August 2006, 1772 treatments with lutetium-octreotate were given to a sum of 504 patients. Most patients had neuroendocrine tumours. A preliminary analysis in 310 patients with so-called gastroenteropancreatic tumours was performed after obtaining all results after finishing the treatment. This showed a decrease in the size of the tumours in 46 percent of patients, stable disease in 35 percent and progression of the tumour despite treatment in 20 percent.
A significant improvement of quality of life in those patients with tumour regression was also noted. The average duration of the effect of therapy was 40 months, calculated from the start of therapy. In addition, there are strong indications that patients treated with Lutetium-octreotate, on average, survive several years longer (3-6 years) than patients who did not get this treatment.
Recent advances in the life sciences have stimulated development of better strategies for detecting and treating disease based on an individual’s unique profile, an approach that is called “personalized medicine.” The growth of personalized medicine will be aided by research that provides a better understanding of normal and pathological processes; greater knowledge of the mechanisms by which individual diseases arise; superior identification of disease subtypes; and better prediction of an individual patient’s responses to treatment.
However, the process of advancing patient care is complex and slow. Expanded use of nuclear medicine techniques has the potential to accelerate, simplify, and reduce the costs of developing and delivering improved health care and could facilitate the implementation of personalized medicine.
Another important aspect to consider is that the time and expense required to bring a drug to market may be reduced by using nuclear medicine imaging technologies to identify which drugs should advance from animal to human studies, reveal mechanisms of drug action, evaluate drug distribution to target tissue; establish the drug occupancy of receptor sites; assess the actions of new agents on specific molecular targets or pathways; and determine appropriate dose range and regimen.
Furthermore, the value of molecular imaging in drug discovery and development has been recognized by big Pharma with nearly 65 percent of drugs losing their patent protection by 2010, which represents a $70 billion loss in revenue per year. Merck, Glaxo, Pfizer Bristol-Myers-Squibb, Genentech, and Johnson and Johnson are among the companies with active in-house or collaborative programs for conducting radiotracer imaging as a guide to drug discovery and development. The types of studies being conducted relate to both pharmacokinetics, through labeling of drugs of interest, and pharmacodynamics, using molecular imaging for key processes (e.g., glycolysis, proliferation, and hypoxia) fundamental to oncology and other medical specialties, as ways to observe the effects of drugs in vivo. In some of the larger programs, such as those of Merck and Glaxo, the staff, is measured in the dozens, and includes nuclear medicine physicians, medicinal chemists, kineticists, radiochemists, pharmacologists, and imaging technicians.
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