Treatment of Bone Pain

A common complication in cancer patients is the spread of cancer to the bone (bone metastasis) resulting in severe pain. Osseous metastasis is found in 85% of terminally ill patients with breast, prostate, and lung cancer and to a lesser extent with other malignancies. Palliation of bone pain in these patients is the common goal to improve the quality of life. To this end, several strategies are adopted, e.g., use of analgesics, external radiation beam therapy, and internal radionuclide therapy. The latter is discussed below. Radionuclide therapy in bone pain palliation is based on the avidity of various radiopharmaceuticals preferentially localizing in bone. 32Porthophosphate has been in use for a long time for bone pain therapy. Two current radiopharmaceuticals, 89Sr-SrCl2 and 153 Sm-EDTMP, have been found to be useful in palliative therapy of bone pain, because they preferentially localize in osteoblastic sites and destroy the malignant cells with radiations.
32

P-Sodium Orthophosphate

Phosphorus-32 decays by b emission with a half-life of 14.3 days. Its maximum b energy is 1.70 MeV. Following intravenous administration, 85% of the injected dosage is accumulated in the hydroxyapatite crystals and the remainder localizes in the nonosseous tissues. Since it is incorporated in the structure of DNA and RNA, these structures are damaged by b radiations. Bone marrow is the most seriously damaged tissues by 32P radiations. Approximately 612 mCi (222444 MBq) 32P-sodium orthophosphate is administered intravenously and often multiple administrations are made based on the response to the initial treatment. Frequently androgen is given for a week prior to administration of 32P to enhance the bone uptake of the tracer. The response rate of 32P therapy is about 80% and the mean period of response is about 5.1 2.6 months. The common side effect is hematologic toxicity due to bone marrow suppression. Occasionally, an increase in bone pain (bone flare) is seen, which is primarily due to androgen given prior to 32P administration. However, 32P-therapy has not been accepted widely for palliation of bone pain because of myelotoxicity.
89

Sr-Strontium Chloride (Metastron)

Strontium-89 has a half-life of 50.6 days decaying with the emission of a b particle, having a maximum energy of 1.43 MeV. After intravenous administration, it localizes in reactive bone and is excreted in the urine (80%) and feces (20%) with a biological half-life of 45 days. Approximately 3035% of the

injected dosage remains in normal bone for 1014 days post-injection. However, the retention in osteoblastic areas is as high as 8590% at 3 months postinjection. Approximately 4 mCi (148 MBq) 89Sr-SrCl2 is injected into patients for the relief of bone pain due to metastasis from various cancers. Injection is made slowly over a period of 12 min. Patients should have a platelet count of at least 60,000 and a leukocyte count of 2400 at the time of administration. Myelosuppression may occur particularly with higher dosages, thus reducing the platelet and leukocyte counts by almost 2530%. Initial relief of pain is usually noticed within 3 days of administration, but it may be as late as 25 days. The mean duration of pain relief is of the order of 36 months and, therefore, retreatments with 89Sr may be considered every 36 months. Complete remission of pain is found in 520% of the patients after 89Sr treatment, and almost 80% of the patients experience some relief of pain from osteoblastic metastasis (Robinson et al. 1995). In 10% of the patients, there is an initial increase in bone pain within ~3 days of therapy that subsides in about a week.
153

Sm-EDTMP (Quadramet)

Samarium-153 is a b emitter with a maximum energy of 0.81 MeV and decays with a half-life of 1.9 days. It emits a g-ray photon of 103 keV (28%) that is suitable for scintigraphic imaging. A dosage of 1 mCi/kg (37 MBq/kg) 153 Sm-EDTMP or Lexidronam is administered intravenously to patients targeted for bone pain palliation. 153Sm-EDTMP is rapidly cleared from the blood and avidly localizes in bone. Almost 35% of the injected tracer is excreted in the urine by 6 h postinjection. It appears to be deposited as an insoluble complex on the hydroxyapatite crystals. Relief of pain is found in about 65% of the patients within 111 months and may last for a year (Farhanghi et al. 1992). Further relief of pain is achieved with repeat treatments. Myelotoxicity is observed in these patients, and is related to the dosage administered.

Radiopharmaceuticals and Imaging Techniques

99m

Tc-Phosphonate Compounds

The rationale for using phosphonate compounds for bone scanning lies in the composition of the bone matrix containing calcium phosphate that can be exchanged with phosphonate compounds. Two compounds, 99mTc-MDP and 99m Tc-HDP, are commercially available for bone imaging, of which 99mTc-MDP is most commonly used. Following IV administration, 99mTc-MDP is cleared from the plasma with a half-time of 34 min. About 10% of the injected dosage remains in the blood at 1 h post-injection and less than 1% at 24 h. Urinary excretion is 50% and the remaining 50% is retained by the skeleton in 24 h. Approximately 1020 mCi (370740 MBq) 99mTc-MDP or 99mTc-HDP is injected intravenously and scanning is performed with the patient supine 23 h after injection. The 2- to 3-h waiting period is needed to reduce the background against the bone, and the patient is asked to void before imaging so that the bladder activity does not blur the pelvic region on the image.

Whole-body scanning is performed by moving the detector from head to toe of the patient using either a single-head or a dual-head camera equipped with

298

13. Diagnostic Uses of Radiopharmaceuticals in Nuclear Medicine

a low-energy, all-purpose parallel hole collimator. Static spot images are obtained with a single-head camera, whereas both anterior and posterior scans are obtained simultaneously using a dual-head whole-body camera. To distinguish between cellulitis and osteomyelitis in the distal extremities, three-phase bone images (flow, blood pool, and bone uptake) are obtained by giving a bolus injection of 30 mCi (1.11 GBq) 99mTc-MDP. In the flow phase, images are obtained every 2 s for 60 s, followed by blood pool imaging immediately and bone uptake imaging at 35 h after injection. Due to hyperemia in cellulitis, the tracer localizes in both the flow and blood pool phases, but disappears in the delayed bone uptake phase. On the other hand, in osteomyelitis, wherein some associated hyperemia exists, the tracer uptake is seen in the flow and blood pool phases, with a further increase in localization in the bone uptake phase. In some cases, the background clearance is not optimum because of vascular insufficiency; a fourth phase bone image may be required, which is usually performed the next day to delineate bone uptake better. Regional bone blood flow rate, bone formation rate, and extraction efficiency are the major factors that influence the bone uptake of phosphonate complexes. In general, the higher the rates of blood flow and bone formation, the greater the bone uptake of radiotracer. There are two hypotheses on the bone uptake mechanism of phosphonate compounds: hydroxyapatite uptake and collagen uptake. In the hydroxyapatite uptake theory, it has been suggested that hydroxyapatite crystal removes the phosphonate component successfully from 99m Tc-phosphate complexes, thus setting the reduced technetium free to bind independently to hydroxyapatite at another binding site. In the collagen uptake theory, it has been suggested that 99mTc-phosphonate complexes localize in both inorganic and organic matrices of bone, the latter uptake depending on the amount of immature collagen present. It has also been found that 99mTcphosphonate complexes localize in soft tissues and tumors to a variable degree.
18
18

F-Sodium Fluoride

F-Sodium Fluoride (18F-NaF) was approved for bone imaging in 1972, but with the introduction of 99mTc-phosphonate compounds, it was discontinued in mid-1970s because of its high-energy photons unsuitable for scintigraphic imaging. With the advent of PET imaging, interest has again grown to use 18FNaF for bone imaging. Studies have shown 18F-NaF to be superior to 99mTcMDP imaging in bone imaging, but its use is somewhat limited by the higher cost of its cyclotron production. Following IV administration of 18F-NaF, 18F rapidly equilibrates in the extracellular space and then is cleared by bone deposition and urinary excretion. It does not appear to bind to plasma proteins and therefore the plasma clearance is very rapid with two components having half-times of 0.4 and 2.6 h. Its urinary excretion is of the order of 20% in 2 h after injection in normal subjects. The bone uptake of fluoride ions is a function of blood flow to the bone and bone extraction efficiency of the 18F ion.

Heart

299

Approximately 4 mCi (148 MBq) 18F-NaF is administered intravenously and imaging is performed 15 30 min later, a shorter waiting time than 99mTc-MDP because of the rapid bone uptake of 18F ion. The patient should void before imaging to reduce the background activity in the body. If PET scanning only is performed, then blank and a patient transmission scans are obtained with a rotating 68Ge source for attenuation correction. In PET/CT imaging, these two scans are obtained with CT for attenuation correction. PET data are acquired for a preset count in different bed positions and corrected for attenuation, and then images are reconstructed by appropriate algorithm in different projections. It is postulated that 18F retention in the bone is a two-phase process. In the first phase, 18F ions exchange with OH ions in the hydroxyapatite matrix of the bone. In the second phase, 18F ions migrate into the crystalline matrix of bone, where it remains there until the bone is remodeled. 18 F-NaF demonstrates higher uptake in malignant tissues than in normal tissues providing better detection of bone metastases. Its diagnostic accuracy is higher than that of 99mTc-MDP.

Diagnosis
Various diseases that are diagnosed by increased uptake of 99mTc-phosphonate compounds or 118F-NaF include metastatic lesion, Pagets disease, fracture, osteomyelitis, bone tumor, rheumatoid arthritis, and any other disorder that results in active bone formation. A normal whole-body bone scan obtained with 99m Tc-MDP is shown in Fig. 13.25. A typical whole-body bone scan obtained with 99mTc-MDP indicating metastatic lesions is presented in Fig. 13.26.