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Metastatic Prostate Cancer

Family physicians often provide care for cancer patients with bone metastases. In this challenging clinical situation, the primary focus of management is on maximizing a patient's ability to complete life with dignity and purpose.

Relief of debilitating chronic pain from diffuse bone metastases in prostate, breast and lung cancer (Figure 1) can be difficult to achieve while still allowing patients to be functional and to maintain quality of life. Nonpharmaceutical, nonopioid and opioid approaches to the management of severe, chronic pain in terminal illness have been widely reviewed.[1,2] However, analgesics and narcotics may cause debilitating side effects, including somnolence and depression.

Strontium-89 chloride (Metastron) is a radiopharmaceutical that is widely used in Europe and Canada for the treatment of bone pain in metastatic prostate and breast cancer.[3-7] In the United States,[sup.89]Sr is currently available only in selected medical centers through phase III clinical trials. Once the trials have been completed and Sr has been approved by the U.S. Food and Drug Administration, it should become widely available in this country.

Radiopharmaceuticals and Bone Pain

The therapeutic potential of intravenously administered radioisotopes of strontium and phosphorus was first recognized in the 1940s. These substances, along with radioactive calcium, were shown to localize preferentially in areas of new bone formation. Pecher, in 1942, was the first to report the clinical effectiveness of the beta-emitting radionuclide [sup.89]Sr in the treatment of bone metastases. The therapeutic effectiveness of this radiopharmaceutical has since been well documented.

Other radionuclides that demonstrate preferential localization in areas of active bone formation include strontium-85, strontium-87m, fluorine-18, phosphorus-32 and gallium-72. However, because of their toxicity or their lack of therapeutic effectiveness, none of these radionuclides, except are currently used for therapy, and [sup.32]P is only used in limited circumstances.[5] Newer radiopharmaceuticals, such as rhenium-186-hydroxyethylidene diphosphonate (HEDP) and samarium-153-ethylenediaminetetramethylene phosphonic acid (EDTMP), have shorter half-lives than [sup.89]Sr; these agents are presently undergoing clinical investigation.[8]

Mechanism of Action

The radioisotope [sup.89]Sr serves as a calcium analog. It decays to yttrium-89 principally by radioactive beta-particle emission.[9] This agent is a bone-seeking radionuclide that preferentially localizes to osteoblastic areas, such as metastatic lesions from prostate and breast cancer.

Diagnostic radionuclides such as technetium-99m-methylene diphosphonate (MDP) and technetium-99m-HEDP also localize in osteoblastic new bone, but they emit gamma particles, rather than the higher-energy beta particles emitted by [sup.89]Sr. The less harmful gamma particles are utilized in standard bone scans for the detection of reactive bone lesions. The standard dose of the gamma-emitting [sup.99]Tc-MDP ranges from 15 to 30 mCi, while the typical dose of the beta-emitting [sup.89]Sr is only 2 to 5 mCi.

The preferential localization of [sup.89]Sr in active osteoblastic bone has been demonstrated in several studies that examined strontium uptake in normal fractures and osteoblastic metastatic lesions.[4,5] In one of these studies,[5] approximately 95 percent of malignant bone lesions from various neoplasms were found to have increased uptake of [sup.89]Sr. Not only does significant [sup.89]Sr uptake occur at osteoblastic skeletal metastatic sites, but the [sup.89]Sr remains in these areas for a much longer time than it does in normal bone. Because of its tendency to remain in osteoblastic sites, [sup.89]Sr has a long therapeutic effective half-life, which may nearly equal its physical half-life of 50.5 days.[4]

About 60 percent of unbound [sup.89]Sr is eliminated by the kidneys, while approximately 10 to 12 percent is cleared through the gastrointestinal tract. The elimination rate varies, depending on the condition of the skeleton and the extent of metastatic disease.[5]

As an exclusive beta-particle emitter, [sup.89]Sr demonstrates relative bone marrow sparing, which decreases its potential for toxicity. The long physical half-life of [sup.89]Sr and the small range of the beta particles (which travel only a few millimeters) contribute to the long-lasting effects of this radiopharmaceutical, without causing significant damage to the bone marrow, the bones' nutritive system or the surrounding tissues.

Because [sup.89]Sr has such strong localizing properties, it has the potential to deliver safe, effective systemic skeletal radiation therapy. Many studies have failed to demonstrate significant hematologic toxicity or myelosuppression due to [sup.89]Sr therapy.[10] This is true even in patients who have received multiple doses of [sup.89]Sr. The mechanism of action by which locally administered irradiation produces pain relief is not well understood. Various studies have shown that the pain relief achieved with [sup.89]Sr therapy is not due to a placebo effect.[7] The irradiation may stop the tumor from producing certain enzymes that cause pain, or it may simply slow expansion of the tumor, thereby reducing pain. Some patients show a reduction in alkaline and acid phosphatase levels after [sup.89]Sr therapy, which suggests a physiologic basis for clinical improvement.[11] The results of one small study[5] suggest that [sup.89]Sr therapy does not prevent disease progression at initially uninvolved sites, but that higher-dose therapy may suppress tumor growth by radioactive beta-particle emission. Consequently, [sup.89]Sr therapy may be useful much earlier in the treatment of metastatic cancer.[5,11]

Patient Selection

Patients who are currently selected for inclusion in the phase Ill [sup.89]Sr clinical trials must have disseminated painful skeletal metastases that are associated with reactive bone changes from any primary cancer. Robinson and associates[12] recently published guidelines for [sup.89]Sr therapy, including patient selection, follow-up, management of treatment-related problems and concurrent use of analgesics (Table 1). [TABULAR DATA 1 OMITTED] For a patient to be eligible for [sup.89]Sr therapy, it must be determined that the pain is caused by metastatic osseous lesions, rather than by osteoarthritis, nerve root compression, or another medical or musculoskeletal condition. The patient must also have demonstrated an unsatisfactory response to other therapies, such as radiotherapy, chemotherapy, hormone therapy and analgesics. If these therapeutic modalities are deemed necessary and beneficial, they do not need to be discontinued during [sup.89]Sr therapy.

The patient should be informed that [sup.89]Sr therapy is not curative, but is palliative for bone pain. The goal of this therapy is to allow a patient to function with as little pain as possible, to decrease the need for narcotics and to improve sleep and mobility.

Administration and Side Effects

Strontium-89 can be given as a single intravenous injection in an outpatient setting, either a nuclear medicine department or a radiation oncology department. Currently, [sup.89]Sr may be obtained only under the terms of an Investigational New Drug (IND) research protocol.

No significant side effects of [sup.89]Sr have been reported. Occasionally, patients experience mild, brief "flushing" for several seconds after the injection, similar to the flushing that may occur with calcium injections.[4] This side effect can be avoided by injecting [sup.89]Sr slowly over one to two minutes. In our experience with 51 patient doses, flushing has occurred in only two patients.

Most clinicians use a dose of 55 [Mu]Ci of [sup.89]Sr per kg of body weight. This dose has not been shown to cause significant hematologic depression, and it may have a higher response rate than the previously used dose of 40 [Mu]Ci per kg. Use of doses higher than 55 [Mu]Ci per kg is currently under investigation. Under the protocol guidelines, may be readministered after a minimum of three months if the patient demonstrates a beneficial response to the initial dose and continues to meet the criteria for acceptance into the study protocol.

Since [sup.89]Sr is a pure beta-particle emitter, there are no significant environmental concerns and no direct radiation risks to other people.[6]

Clinical Results

At least 75 percent of patients who receive [sup.89]Sr therapy experience a reduction in pain, a decreased need for analgesics and an improved quality of life.[3-7,11] About 25 to 30 percent of patients experience complete or very significant pain reduction for a variable period.

Evaluation of pain and the response to therapy is always difficult. However, a clinical assessment of the effectiveness of a patient's response to [sup.89]Sr therapy can be made, based on a reduction in analgesic usage, improved sleep patterns and the patient's own assessment of functional improvement and degree of pain reduction. A patient diary can be useful in the assessment process.

Several studies have shown that the best responses to [sup.89]Sr therapy occur in patients with pain from bone lesions in metastatic breast and prostate cancer. One health care provider at our center reported that two women with breast cancer, previously immobilized because of bone pain, were able to travel within two weeks of receiving [sup.89]Sr therapy. Furthermore, cost analysis of [sup.89]Sr therapy may demonstrate financial benefits as a result of decreased dependence on analgesics.

Clinical results from several published studies on [sup.89]Sr therapy are summarized in Table 2,[3-6] and the clinical results from our ongoing study of patients with prostate or breast cancer are given in Table 3. Some studies suggest that the positive response rates for [sup.89]Sr therapy are higher than those shown in Table 2 if patients are referred earlier in the course of their disease; these better response rates may be due to a higher absorbed radiation dose to the metastatic deposits.[3] [TABULAR DATA 2&3 OMITTED]

Strontium-89 therapy cannot relieve pain that is caused by pathologic fractures or by tumor invasion of the spinal cord or adjacent peripheral nerves near involved bone.[11] In addition, [sup.89]Sr therapy does not relieve pain in soft tissue tumor sites.

The authors thank Sherry Bucholz and Lou Carver for their assistance in the preparation of this manuscript.

REFERENCES

[1.] Creagan ET, Wilkinson JM. Pain relief in terminally ill patients. Am Fam Physician 1989;40(6): 133-40. [2.] McGivney WT, Crooks GM. The care of patients with severe chronic pain in terminal illness. JAMA 1984;251:1182-8. [3.] Robinson RG, Blake GM, Preston DF, et al. Strontium-89: treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. Radiographics 1989;9:271-81. [4.] Robinson RG, Spicer JA, Preston DF, Wegst AV, Martin NL. Treatment of metastatic bone pain with strontium-89. Int J Rad Appl Instrum [B] 1987;14:219-22. [5.] Firusian N, Mellin P, Schmidt CG. Results of 89 strontium therapy in patients with carcinoma of the prostate and incurable pain from bone metastases: a preliminary report. J Urol 1976; 116:764-8. [6.] Laing AH, Ackery DM, Bayly RJ, et al. Strontium-89 chloride for pain palliation in prostatic skeletal malignancy. Br J Radiol 1991; 64:816-22. [7.] Lewington VJ, McEwan AJ, Ackery DM, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991;27:954-8. [8.] Ketring AR. 153Sm-EDTMP and 186Re-HEDP as bone therapeutic radiopharmaceuticals. Int J Rad Appl Instrum [B] 1987;14:223-32. [9.] Blake GM, Zivanovic MA, McEwan AJ, Condon BR, Ackery DM. Strontium-89 therapy: strontium kinetics and dosimetry in two patients treated for metastasising osteosarcoma. Br J Radiol 1987;60:253-9. [10.] Silberstein EB, Williams C. Strontium-89 therapy for the pain of osseous metastases. J Nucl Med 1985;26:345-8. [11.] Kloiber R, Molnar CP, Barnes M. Sr-89 therapy for metastatic bone disease: scintigraphic and radiographic follow-up. Radiology 1987;163:719-23. [12.] Robinson RG, Preston DF, Spicer JA, Baxter KG. Radionuclide therapy of intractable bone pain: emphasis on strontium-89. Semin Nucl Med 1992;22:28-32.

The Authors

DAVID V. HANSEN, M.D. is chief of diagnostic radiology at the U.S. Air Force Hospital, Mountain Home Air Force Base, Idaho. Dr. Hansen completed a residency in family practice at the U.S. Air Force Medical Center, Scott Air Force Base, Ill., and a residency in diagnostic radiology at Sacred Heart Medical Center, Spokane, Wash.

EDWIN R. HOLMES, M.D. is director of nuclear medicine at Sacred Heart Medical Center.

GERI CATTON is the protocol nurse and data manager for the cancer center associated with Sacred Heart Medical Center.

DAVID A. THORNE, M.D. is a staff radiologist at Sacred Heart Medical Center.

DAN H. CHADWICK is supervisor and chief technician for the Department of Nuclear Medicine at Sacred Heart Medical Center.

DONALD A. SCHMUTZ, M.D. is director of the Department of Radiation Oncology at Sacred Heart Medical Center.

COPYRIGHT 1993 American Academy of Family Physicians
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