Radiopharmaceuticals used for Palliative treatment of Bone Pain

1. The use of Beta emitting radiopharmaceuticals for the relief of bone pain is sometimes referred to as palliative therapy.  In situation the patient is being only being treated for pain Pain which is in this situation is for pain caused by painful boney metastatic disease
2. Certain Beta emitting radiopharmaceuticals are used to relieve of bone pain caused by painful bony mets.
3. How does on approach treatment to relieve painful bony metastatic in the clinical setting? There are many ways ...
1. From a therapeutic standpoint metastatic disease is usually treated with either with chemotherapy and external beam radiation
2. One approach in pain management is the use of external beam radiation, however, when this becomes a problem when there are numerous metastatic sites that cause pain.  As the cancer spreads metastatic disease grows and and pain increases
3. Application of external beam therapy has two roles: first it can shrink and/or destroy tumors and second it can be used to target painful bony mets for the relief of bone pain. The later approach can be rather ineffective in treating multiple/painful metastatic sites as those sites continue to multiple
4. Chemotherapy can be used for pain management however, excessive toxicity and multiple metastatic sites makes it difficult to continue this line of approach, because in the end it doesn't improve the patient's outcome.
5. Ultimately, the best course of action, for someone that has multiple metastatic sites that are causing significant discomfort is to treat the pain and not the disease.
6. Pain medication, usually Opioids, is yet another method used to relieve bone pain, yet certain narcotics may have other side effects, which would affect the patient’s quality of life. As an example, constipation, gastrointestinal distress, sedation, nausea and vomiting, and cognitive dysfunction will occur with high levels of morphine.
7. Hence the use of ⁸⁹Sr and ¹⁵³Sm may have a pivotal role in treating bone pain do to painful bony metastasis.
8. ¹⁵³Sm-EDTMP has been approved by the FDA for routine use. The company name is known as Quadramet. This agent was initially discovered at the University of Missouri-Columbia, developed by Cytogen Corporation.

4. Why should one use a beta emitter to treat bone pain do to metastatic bone disease?

1. Ultimately, the best course of action, for someone that has multiple metastatic sites that are causing significant discomfort is to treat the pain and not the disease.
2. There are several options regarding the use of radiopharmaceuticals for the treatment of bone pain.  Let us take a look at it with a slight historical perspective.

1. As early as the 1940s ³²P-Orthophosphate was considered for the administration in patients that have metastatic bone pain. The hope was and is still, not to cure metastatic bone disease, but to relieve pain via a therapeutic injection of a radiotracer. This should result in the relief of bone pain and in the reduction of pain medication, with the end results being an improvement in the patient's quality of life.
2. Although ³²P is rarely, if ever used in today's health care system, let me a make a few brief comments on the use of P-32.

1. This agent has been given to 1000s of patients with over 850 reports in the medical literature.
2. 85% of the dose is incorporated into the hydroxyapatite crystal of the bone; however, 15% is taken up by non-bone tissue. Problems occur with this agent because phosphate involves itself, intracellular with energy storage, cell structure, and in DNA\RNA structure (soft tissue).
3. In turn, the beta radiation can destroy the nucleic acids, because it  incorporates into RNA and DNA structure. Therefore, there maybe additional radiation effects to the body, that would not occur with the newer radiopharmaceuticals being discussed, today

5. Primary cancers, that originate from breast and prostate cancer metastasize to bone are considered blastic lesions.

1. These blastic lesions are lesions, which involve osteoblastic bone cells. When metastatic disease invades the bone an increase in calcium deposits occurs at the site. Performing a routine bone scan in a nuclear medicine department can identify these sites. It is this type of lesion that is most effected by the use of our therapeutic radiopharmaceuticals.
2. On the other hand lesions that are not recommended for radionuclide therapy are those of a lytic nature or lytic lesions. Lytic lesions proliferate from neoblastic plasma precursor cells in bone marrow and bone pain originating from this type of lesion is not effective by our beta producing radiopharmaceuticals.
3. Hence, palliative therapy should only done on those patients in which blastic lesions. The two most common metastatic diseases of this type are breast and prostate and it is these types of metastatic cancers that Sr-89 and Sm-153 should be used for.

6. Now let us take a closer look on how bone destruction occurs and how these lesions cause bone pain.

1. Although the exact reason for metastatic pain bone is unknown, several possibilities have be theorized.

1. The primary cause of bone pain is thought to be an inflammatory process associated with the metastatic invasion into normal bone tissue. When this occurs it changes the bone metabolism resulting in autocoid production. This occurs with blastic and lytic lesions.
2. Autocoids are heterogeneous group of chemicals released by the body in response to this tumor invasion. Some of these substances include cytokines, potassium, bradykinin, growth factors, and osteoclastic activating factor. Also osteoclastic activity can stimulate the production of prostaglandin.
3. It is theorized that production of autocoids and prostaglandin causes increased stimulus to the nerve ending in the bone, which will also lead to signficant pain.

2. Also through direct tumor invasion to the bone causes extensive bone destruction results in bone fractures and compressions which would also lead to severe pain.So how does Sr-89 and Sm-153 fit into the therapeutic picture?

1. First a general comment about any beta therapy agent. Uptake by the bone depends on the metabolic activity of the bone, the rate of new tissue formation, and tissue vascularity. Hence, with regards to any radiopharmaceutical used in this therapy arena, bone/tumor uptake will depends on bone turnover, vascularity to the area, and the rate of new tissue formation.
2. As for the pathophysiology of these specific agents and how they work in reducing or eliminating bone pain? This is also unknown. However, what is known is that these radiopharmaceuticals do incorporate into the bone matrix and hence allow for direct radiation to sites of high bone turnover. The highly energetic beta particle deposits its radiation close to the metastatic tumor cells. Therefore, the greater the uptake of the specific radiopharmaceutical the greater the radiation to the tumor site, which results in the relief of bone pain.
3. Sr-89, Metastron, is an analog of Ca in the hydroxyapatite molecule. The ratio of strontium up in active bone tissue surrounding a metastatic tumor is between 15 to 3 to 1. The biological T1/2 is 4-5 days, with the body eliminating the excess agent via 80% from the kidneys and 20% via the fecal route. 30 to 35% remains in the bone at 10-14 days post administration with 20% remaining after 3 months. Sr-89 has a physical T1/2 of 50.5 days with maximum beta energy of 1.43 meV and a mean tissue range of 2.4 mm. It also has a 910 keV gamma, however the abundance is only 0.01%. The lack of significant gamma abundance dose not makes Sr a candidate for scintigraphic imaging. Myelosuppression can occur with the use of this agent which usually causes 60 to 70% drop of platelets and WBC's at 5 to 8 weeks post administration, however, the body recovers by 10 to 16 weeks post administration. Data also shows that flare reaction may occur, where the patient will have a temporary increase in bone, which may occur around 2 to 3 days post onset of injection. However, relief of the initial bone pain can occur as little as 3 days post injection, with a more common response to the relief of pain by the second week. In some patient it may take as long as 25 days. The published data indicates that 65 to 80% of all patients receive some relief of pain, while 5 to 20 % have complete relief bone pain. Pain reduction usually lasts about 3 to 6 months. Re-administration of Sr-89 maybe also be done every 3 months, with about half of these patients responding to treatment.



Image obtained from an article in the Indian Journal of Cancer - http://www.indianjcancer.com/article.asp?issn=0019-509X;year=2006;volume=43;issue=2;sp age=86;epa ge=92;au last=Tripartite

4. Sm-153EDTMP ... Sm-153is chelated to EDTMP and it is the EDTMP that forms an insoluble oxide on the hydroxyapatite surface. It behaves much like Tc99mMDP; however, EDTMP clears even faster than MDP, with renal excretion completed at 8 hrs post dose. Likewise, it clears quickly from the blood with less than 1% of the dose remaining at 5 hours. Animal studies indicate that less than 0.5% binds to serum protein. 65% +/- 15% of the total dose goes to the bone, with greater percentages when there is an increase of metastatic bone involvement. Sm has a 1.9-day T1/2 and emits 3 different energy beta particles with the average beta energy at 233 keV. These beta particles travel 1.7 mm in bone and 3.1 in soft tissue. Also there are 2 gamma energies admitted at 103 and 41 keV, allowing it to be imaged with a gamma camera. In addition, the patient should be well hydrated, which helps in the renal excretion and will result in a decreased of the radiation burden to the kidneys and bladder. Flare reaction occurs in approximately 7% of the patients treated at 2 to 3 days post administration. 75% of the radiation doses to the effected sites are delivered in 4 days post administration. And Myelosuppression does occur. Specifically, platelet and WBCs drop at their lowest value in 3 to 5 weeks and then return to normal at 8 weeks post administration.
5. The efficacy of Sm-153 EDTMP or Quadramet was determined from two clinical trials in which a total of 270 patients were given either Quadramet or a placebo. Both clinical trials were randomized, double blind. Another words, no one new what he/she was getting. Patients were also graded on his/her pain level twice a day with a ranged of 0 meaning no pain up to 10 which was identified as excruciating pain. The level of oral morphine was monitored in its mg value and the weekly average dose was determined. The morphine intake was then calculated with patients that received Quadramet and the placebo. In both clinical trials the relief of bone pain was greater with those individuals that received Quadramet, with the reduction in pain and a reduction of morphine administration occurring 1-week post administration of Sm. However, the greatest relief of pain occurred between 2 to 5 weeks post administration. Also interesting to note is a concern with adverse reaction. In analyzing 399 patients that received Quadramet, 23 deaths occurred with there average occurring on day 67-post administration of Sm-153. Serious events occurred with 46 patients post administration of Sm-153. However, the question as to weather or not this was truly a reaction to the therapeutic agent must be discussed. The reaction maybe more directly related to the underlining disease and therefore probably has no association with Quadramet administration.

Other bone agents that have not been approved for routine use

8. Rhenium – 186 hydroxyethylene Disphosphonate (186Re HEDP)
1. Is in the technetium family and allows for similar labeling properties (HEDP)
2. Properties
1. Production: 185Re(no,γ)186Re
2. 186Re is oxidized to perrhenate ion and reacts/combines with SnCl2 and Na2H2HEDP to form 186Re HEDP
3. This is the same process used to form 99mTc-HEDP
4. In addition, heat (100oC) must be applied for 10 minutes to complete the 186Re HEDP reaction
5. Beta particles maximum energy is 1.07 MeV
6. Gamma ray energy is 137 keV and 9% abundant
7. Physical T1/2 is 90 hours
3. Mechanism of uptake
1. Phosphate portion of the molecule is chemabsorbed to the hydroxyapatite crystal structure of the bone matrix (same as 99mTc-HEDP)
2. Portion of the 186Re HEDP is released into the urine
4. Has not been approved by the FDA and is in Phase III clinical trials sponsored by  Mallinckrodt Medical
5. Literature Review of 186Re HEDP
1. Pain relief occurs in 77% of patients treated
2. Mostly prostate and breast metastases to bony tissue where analyzed
3. Dose was 35 mCi per patient (Maxon)
4. Attempt to define the correct dose
1. 35 to 90 mCi had a maximum tolerated dose of 80 mCi (Klerk)
2. 35 to 95 mCi range with the following having the palliative response (Quirijnen)
1. 35 mCi received a 33% response
2. 50 – 65 mCi received a 78% response
3. 80 – 95 mCi received a 70% response
3. 50 – 65 mCi dose range of 186Re HEDP is similar to Quadramet® in pain relief causing the fewest side effects
5. (Klerk) 186Re HEDP was tolerated up to 80 mCi with patients having metastatic disease from prostate cancer, where metastatic breast could only tolerate 65 mCi (breast cancer chemotherapy lowers bone marrow production)
6. Transient drop of marrow production occurs around 4 – 5 weeks and rebounds at 8 weeks
7. Stomach uptake has also been reported during imaging (similar to 99mTc labeled bone compounds)
8. Following the completion of a large clinical trial in Europe, Mallinckrodt Medical may soon apply for an NDA
9. Alumina-Based Tungsten-188/Rhenium-188 Generator
1. Oak Ridge National Laboratories (ORNL) has developed a generator for providing a therapeutic radionuclide, 188Rh
2. 188Rh is analogous to the chemical form of 99mTc
3. 188Rh may react with a variety of “cold” kits used with pertechnetate
4. Properties
1. 188W (parent) has a 69 day T1/2
2. 188Rh T1/2 is 16.9 hours
3. 188Rh maximum beta energy is 2.2 MeV with a 155 keV gamma at 15% abundance (allowing for gamma camera imaging)
4. Generator uses an ion exchange column and its elute is 188ReO4 (eluted with normal saline)
5. Review of the literature 188Rh
1. Three different radiopharmaceuticals have been prepared with this agent
2. 188Rh-HEDP had similar results 186Re HEDP (small patient population)
1. Dose range 35 – 50 mCi
2. One patient with a 50 mCi dose experienced a “flare” response
3. Hematopoietic toxicity reported in 50% of the patients
4. Overall palliation response rate was 63%
3. 188Rh(V)-DMSA was compared with 99mTc-HDP
1. 188Rh(V)-DMSA concentrated in metastatic sites and not in normal bone
2. Radiopharmaceutical can be made from a DMSA cold kit
3. Images where obtained 3 and 24 hours post injection with negligible hematopoietic toxicity
4. Kidneys may receive a relatively large radiation dose
4. 188Rh-Octreotide was also prepared, but is not used for palliation of bone pain
6. Lack information on effectiveness, side effects, and cost
10. Tin-117m (Stannic, 4+) Diethylenetriaminepentaacetic Acid (Tin-117m (4+) DTPA)
1. Brookheaven National Laboratory (BNL) developed this product
2. Develop a palliative agent for osseous bone metastases with ideal characteristics for therapy with little to no side effects
3. Properties
1. Sn-117 T1/2 = 14 days
2. Decays by conversion electron at 127 – 129 keV and gamma ray energy of 152 keV (86% abundance)
3. Production:  117Sn(no,γ)117mSn
4. Sn is produced as an oxide, converted to a pure metal via heating prior to irradiation, and the process is evolved
5. Specific activity varies, however, does not seem to effect its uptake
6. Does not emit beta radiation and the conversion electrons may improve the radiation dose to the bone marrow (active component for therapy is the conversion electron)
4. Literature review of Tin-117m (4+) DTPA
1. Pilot study
1. Group one was dosed with 33 – 84 uCi/kg of body weight
2. Group two was dosed with 131 – 156 uCi/kg of body weight
3. Group one, 4 of 7 patients received some form of pain relief
4. Group two, 7 of 8 patients received some form of pain relief
5. Only one patient had decreased WBC counts and no decrease platelet counts were observed
2. Krishnamurthy studied pharmacokinetics of (Tin-117m (4+) DTPA) using three different dose ranges
1. 77% of the injected dose remained in the bone at 14 days post injection
2. All ranges gave partial or total pain relief
3. 85% received partial or total pain relief
4. No observable marrow toxicity
3.  Srivastava completed two separate studies evaluating different dose levels of (Tin-117m (4+) DTPA)
1. Partial or complete pain relief was noted in 75% of patients in both studies
2. No significant platelet or WBC suppression was noted
3. No correlation was noted between the dose ranges and pain relief

Now let us discuss the procedure for administering either Sr-89 or Sm-153.

Patient Preparation

Obtain a recent complete blood count:

1. A white blood cell count should be greater than < 3,000.
2. Discuss the procedure with the patient and identify appropriate radiation safety techniques for the reduction of radiation exposure to the general public. Note the greater concern if Sm-153 is administered, since the dose is significantly greater.
3. After explaining the procedure to the patient, they should sign a consent form.
4. A platelet count should be greater than < 60,000.
5. Patient should not be hypersensitive to phosphonate (for Sm-153 EDTMP).

1. If the patient is incontinent, he/she should be catheterized.
2. Setup an indwelling catheter with saline flush.

Radiopharmaceutical Dose

1. For Sr-89 the average dose is is 4.0 mCi, however, a 40 to 60 uCi/kg dose of body weight can be calculated.
2. For Sm-153 EDTMP the dose should be calculated at 1.0 mCi/kg of body weight.
3. Use a syringe shield, however, a large plastic syringe shield will not be very effective with the gamma energies being procedure from the decaying Sm-153.

Administration Technique

1.         After setting the indwelling catheter attach a three-way stopcock to the IV line.

1. Insure that the needle is properly in the vein prior to injecting the radiopharmaceutical.
2. Administer the radiopharmaceutical over a 1-minute period of time.
3. Then flush the syringe with a saline bolus and turn up the IV to further flush the line.

Additional Comments

1. Discuss with the patient concerns on radiation exposure to other individuals in an attempt to reduce the total effective dose equivalent to other individual that the patient may come in contact with. It is further suggested that you develop written policy that can be given to the patient. Regulation Guide 8.39 allows the patient to be discharged, even if the dose is greater than 30 mCi.
2. You may want to follow the patient platelet and WBC counts.

Comparison of Sr-89 and Sm-153EDTMP

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