Radionuclide Therapy In The Management Of Painful Bone Metastases
Najat A. Turief, MD
Milos J. Janicek, MD
September 14, 1994
Case Presentation:
A 67 year old male was diagnosed with stage IV prostate cancer 6 years prior to presentation. At that time he had a metastasis in the right pubic bone. He was treated with surgery and pelvic irradiation including the right pubis. One year prior to presentation he had an orchiectomy with prompt relief of pain and a decrease in his prostate specific antigen (PSA). He presented for management of increasing bone pain.
Findings:
Bone scan (68k bytes) showed several regions of focal increased uptake. It was decided to treated the patient with 35 mCi of Rhenium-186 HEDP. There was a flare in pain symptoms 3 days post injection, but he became asymptomatic 5-6 weeks after therapy. Treatment was repeated every 5 weeks for a total of 15 injections. The CBC and platelet count remained stable. Serial Re-186 bone scintigraphy showed local progression of disease with right sided hydroureter and hydronephrosis.
Discussion:
Due to effective therapy and longer life expectancy of cancer patients, an important part of the practice of oncology is pain palliation in patients with advanced disease. It is estimated that each year at least 100,000 people in the United States are afflicted with painful skeletal metastases, most commonly from primary tumors of breast, prostate and lung. Patients with predominantly skeletal metastases frequently survive longer than those with soft tissue involvement and hence issues of pain palliation and improvement in those patients' quality of life becomes an important consideration.
It is necessary to understand the different etiologies of pain in patients with skeletal metastases in order to tailor treatment to individual needs. Etiologies such as nerve root compression, pathological fractures and vertebral body collapse need a different approach to pain management than skeletal pain that is related to osteoclast proliferation and release of a variety of pain mediators.
Conventional Methods:
Conventional methods used to control bone pain include analgesics, hormonal manipulation, chemotherapy and radiation. Most prostate cancer patients experience relief of pain after orchiectomy. However the duration of pain relief is typically short with most patients experiencing a recurrence of their symptoms, after an average response time of about a year, possibly because of the natural selection and growth of malignant cells that are not hormone sensitive. Similarly, therapy with estrogen and it's analog tamoxifen in breast cancer patients can control symptoms in 25-50% of patients temporarily. Chemotherapy has a limited role in the treatment of skeletal pain in patients with advanced disease. External beam local radiation therapy is the treatment of choice for the patient with an isolated site of pain with a reported response rate of more than 80%. A common problem in this group of patients, however, is development of pain in multiple sites. Wide field (hemibody) irradiation, though a highly effective treatment for diffuse bone pain, has an unacceptable high toxicity in up to 60% of patients, the most serious of which is permanent myelosuppression.
Systemic Radionuclide Therapy:
Systemic radionuclide therapy represents a very promising alternative, Phosphorous-32 (P-32) has been used to manage bone pain for many years but it's use was limited by high marrow toxicity. Strontium-89 (Sr-89) was first studied in the early 1940s, and despite encouraging early results, these were not applied to human studies until late 1970s. Sr-89 has recently been approved by the FDA to be used as a palliative agent for bone metastases. Other compounds that are currently in phase II and III clinical trials are Rhenium-186 HEDP and Samarium-153 EDTMP. These compounds have a significantly shorter half life than Sr-89 and are able to deliver a higher dose rate. Both have an imagable gamma photon that allows direct measurement of biodistribution and assessment of suitability for therapy.
Optimal Characteristics of a Therapeutic Radionuclide:
The optimum characteristics of a radionuclide to be considered as an effective radiopharmaceutical for palliative pain relief include a particulate emission of an appropriate energy and range, a physical half life that approaches the biological T1/2 of the radiopharmaceutical in the tumor, selective concentration in bone lesions, rapid blood clearance and low extraosseous uptake. Furthermore it should be available in a chemical form suitable for complexing to produce a stable radiopharmaceutical in vivo.
Sr-89 is an analog of calcium that concentrates at sites of increased bone mineral turnover. It decays by beta emission with a maximum energy of 1.5 MeV, to yttrium-89. When injected intravenously, it clears rapidly from the blood with more than 50% of the injected dose localizing in the skeleton and the remainder excreted by glomerular filtration. Retention of Strontium within the body highly correlates with the extent of metastatic involvement, with up to 88% of injected dose retained at 100 days in patients with extensive disease as opposed to about 20% in normal individuals.
It was also shown by serial quantitative gamma camera imaging (by adding a tracer amounts of the gamma emitter Sr-85) that turn-over of strontium in bone adjacent to a metastatic deposit is much slower compared to that of normal bone enhancing the radiation dose absorbed by the lesions.
Efficacy:
Efficacy and toxicity of strontium therapy were studied in several open and controlled studies. In a multicenter efficacy study, Sr-89 was administered at a dose of at least 1.5 mCi / kg to patients with metastatic prostate cancer who had failed other modes of therapy, 75% of 83 patients had benefited clinically, and 22% were essentially pain free. A placebo controlled trial in which 32 prostate cancer patients were randomized to treatment with either Sr-89 or non radioactive strontium clearly demonstrated a therapeutic response of radioactive strontium.
Adverse effects:
The primary adverse effect of Sr-89 therapy is hematological depression, generally maximum about the fifth week after strontium administration, with an average of 15-20% decrease in total platelet and WBC count. This depression is however transient and return to normal level is expected by 10 to 12 weeks.
Indications:
The primary indication for treatment is bone pain and the physician should confirm that the patient's pain is indeed due to his bone metastases and not due to other causes. A primary physician that will take on follow up of the patient for the duration of the treatment should be clearly identified. The patient's platelet count should be at least 60,000/ml, and his WBC count of at least 2,400/ml. Complete blood and platelet counts should be obtained on a 2 weeks basis. Patients should be alerted to the occurrence of a brief exacerbation of pain for 2-3 days after injection (flare pain 20%). Most patients note pain relief in 2-3 (maximum 6) weeks and the average response time is 4-15 months. Strontium injection can be repeated safely to selected patients who responded to their initial injection.
Mechanism of Pain Relief:
The exact mechanism of pain relief caused by radionuclide targeted therapy is not known. It is unlikely related to tumor cell kill since the absorbed radiation dose effective in pain palliation is much lower than that necessary to achieve a tumoricidal effect. It is possible that pain relief is caused by a cytotoxic effect on normal bone cells, thereby inhibiting the release of pain mediators. This would explain why bone metastases that invoke more osteoblastic reaction are more responsive to palliative radionuclide therapy.
Conclusions:
Targeted radiotherapy with unsealed sources offers several advantages over conventional radiotherapy. By being more tumor specific there should be no limit to the absorbed dose that can be delivered to the tumor or the number of administrations. Another advantage is that this form of therapy allows the opportunity to manage these patients on an out patient basis, reducing medical costs and preserving the integrity of patients in the terminal stages of their disease. It also is generally well tolerated and repeatable.
References:
1) Laing AH, et al: Strontium-89 Chloride for Pain Palliation in Prostatic Skeletal Malignancy. Br J Radiol 64:816-822, 1991.
2) Robinson RG, et al: Strontium-89 for Bone Pain Due to Blastic Metastatic Disease. App Radiol Aug 1993.
3) Holmes RA: Radiopharmaceuticals in Clinical Trials. Sem in Oncol 20, No3, Supp 2:22-26, 1993.
4) Merters WC: Radionuclide Therapy of Bone Metastases: Prospects for Enhancement of Therapeutic Efficiency. Sem in Oncol 20,No 3, Supp 2:49-55, 1993.
5) Porter AT, et al: Results of a Randomized Phase III Trial to Evaluate the Efficacy of Strontium-89 Adjuvant to Local Field External Beam Irradiation in the Management of Endocrine Resistant Metastatic Prostate Cancer. J Rad Oncol Biol Phys 25:5:805-813 1993.
6) Robinson RG, et al: Radionuclide Therapy of Intractable Bone Pain: Emphasis on Strontium-89. Sem Nuc Med vol XXII, No 1:28-32 1992.
7) Maxon HR, et al: Rhenium-186 Hydroxyethylidene Diphosphonate for the Treatment of Painful Osseous Metastases. Sem Nuc Med vol XXII, No 1:33-40 1992.
8) Robinson RG, et al: Strontium-89 Treatment Results and Kinetics in Patients with Painful Metastatic Prostate and Breast Cancer in Bone. Radiographics vol IX, No 2:271-281 1989.
9) Lewington VJ, et al: A Prospective Randomized 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 27:954-958 1991.
10) Maxon HR, et al: Re-186(Sn)HEDP for Treatment of Multiple Metastatic Foci in Bone: Human Biodistribution and Dosimetric Studies. Radiology 166:501-507 1988.
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J. Anthony Parker, MD PhD, Tony_Parker@bih.harvard.edu