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.