Joint Program in Nuclear Medicine
Radionuclide Therapy in the Management of Painful Bone Metastases
Najat A. Turief, MD
Milos J. Janicek, MD, PhD
September 14, 1994
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.
Imaging Findings
Bone scintigraphy (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.
Figure 1: Whole body strontium retention.
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.
Figure 2: Local retention.
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.
Figure 3: Response to 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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