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Systemic radiopharmaceutical therapy of painful osteoblastic metastases
Systemic Radiopharmaceutical Therapy of Painful Osteoblastlc Metastases Edward B. Silberstein Bone pain from osteoblastic metastases can be ameliorated 40% to 80% of the time. Although w e can predict nonresponders, w e cannot predict responders; however, patients with a better performance scale may have a better chance of pain relief. Radiopharmaceuticals containing phosphorus 32, strontium 89, samarium 153, rhenium 186, and tin 117m are effective, but w e do not know which is the most efficacious and the safest. Toxicity includes the flare phenOmenon and mild to moderate pancytopenia, but disseminated intravascu-
lar coagulation can cause severe, life-threatening thrombocytopenia. This treatment may be repeated at about 9- to 12-week intervals, perhaps earlier with 1~3Sm lexidronam, lSSRe etidronate, and 117mSn pentetate, with a success rate approaching that of the initial injection. The duration of action of pain reduction ranges from 2 weeks to many months. Tumorical effects are probably not the only mechanism of pain relief. Copyright 9 2000 by W.B. Saunders Company
he lifetime prevalence of cancer in the United States population is 30% to 35% with over 1 million cases per year. About three quarters of patients with advanced cancer have pain, much of this clinically significant, from bone metastases. 1,2 Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used first in the treatment of such pain, followed up by more potent opiates in a stepwise approach recommended by World Health Organization guidelines. 3 Although narcotics are generally effective in relieving pain, the somnolence, nausea, and constipation that result from their use almost inevitably decrease the quality of life in the patient with advanced cancer. 3 The role of treatment with intravenous or oral administration of unsealed boneseeking beta or electron-emitting sources requires greater emphasis because these radiopharmaceuticals can reduce, or even eliminate, an opiate requirement. Whatever modality is used, the goals of therapy must be made clear to the patient. When a cure is not possible, cytoreduction usually is possible, although this tumoricidal effect, often documented by a decrease in the level of serum tumor markers and/or the healing of lesions radiographically on bone scan, does not prolong survival time. 4 However, the radiopharmaceuticals available to us can reduce or eliminate bone pain owing to osteoblastic metastases, thus, decreasing narcotic dose and improving the functional status of the patient. 46 With at least 1 radiopharmaceuticaP the time until more radio-
therapy is required for either new or recurrent painful metastases can be lengthened.
T
From the University of Cincinnati Medical Center, Cincinnati, OH. Address reprint requests to Edward B. Silberstein, MD, University of Cincinnati Medical Center, 234 Goodman, Mont Reid Pavilion, Room G026, Cincinnati, 0H45219. Copyright 9 2000 by W..B. Saunders Company 1053-4296/00/1003-0007510.00/0 doi:l O.lO53/srao.2000.6592
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Mechanisms of Radiopharmaceutical Therapy The administration of beta, electron, or low-energy photon-emitting radiopharmaceuticals that are part of, or attached to, a chemical moiety with an affinity for bone mineral (hydroxyapatite) permits the selective radiation of osteoblastic metastases, with minimal or no radiation of normal tissues. Thus, these internal emitters avoid cutaneous or gastrointestinal side effects and have no other toxicity than minimal to moderate hematologic effects and occasionally a 2to 3-day flare of pain symptoms. These radiopharmaceuticals, called unsealed sources by the Nuclear Regulatory Commission, can be administered intravenously (or, with phosphorus 32, also orally). Wherever osteoblastic activity is increased, these therapeutic radiotracers will react with the newly produced hydrated amorphous calcium phosphate salts and hydroxyapatite there. 7,a The radiopharmaceutical effective half-life (related to both physical and biological half life) must be of sufficient length to cause some death of tumor cells in bone, and probably of mononuclear cytokinesecreting cells near the absorptive surfaces around bony metastases. Table 1 lists the radiotracers that have been shown to have efficacy in humans. (There are only minimal clinical data on yttrium 90 citrate.) These radiopharmaceuticals widely differ in the (1) mechanism of skeletal retention; (2) degree of integration of the chemical moiety carrying the radionuclide throughout the bone or just on the surface; (3) physical half-life (by a factor of 90) and, therefore, in the dose rate at the tumor site; (4) degree of skeletal retention; (5) energy of their emission and, therefore,
Seminars in Radiation Oncology, Vo110, No 3 (July), 2000: pp 240-249
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the effective distance it travels; and (6) presence or absence of a g a m m a emission. With all of these physiological and physical differences, it is still unclear whether there are any significant differences in clinical effectiveness between them. Nevertheless, the emitted energy, in whatever form, is sufficient to reach painful osseous tumor sites with some cytocidal effect. Bone metastases may be radiographically lytic, reducing the adjacent bone mass, or cause production of excessive reactive or woven bone around the tumor, seen as osteoblastic or osteosclerotic lesions on radiograph. The resultant bone density is the result of the balance of osteoclast activity, direct resorptive activity of the tumor, and the response of host osteoblasts. 6 In the vast majority of bone metastases, osteoblasts are stimulated regardless of the net loss or gain of surrounding bone, and hence the technetium 99m methylenediphosphonate (MDP) bone scan will show increased uptake even if the radiographic pattern is osteolytic. An abnormal diagnostic nuclear bone scan indicates truly increased activity of osteoblasts and has been shown invariably to predict the virtually identical bone deposition of all the tracers listed in Table 1. Only with an abnormal bone scan (increased osteoblastic activity) will the radiotracers listed in Table 1 accumulate in a site of osseous metastases to a sufficient extent to have a therapeutic effect. Intravenously (or orally) administered radiotracers promptly diffuse from the intravascular to the extravascular space and come in contact with newly produced calcium phosphates, including hydroxyapatite, with which they may react by incorporation into the hydroxyapatite molecule (32p, strontium 85, and strontium 89), chemisorption on the surface of hy-
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droxyapatite (rhenium 186 and samairum 153), or by oxide formation with hydroxyapatite in a hydrolysis reaction with oxygens donated by hydroxyapatite and water (tin 117m, 153Sm, and la6Re). These radiopharmaceuticals emit beta particles, conversion electrons, or low-energy photons with a mean range between 0.2 and 3 m m (maximum range 0.3 to 11 mm) (Table 1). Emitted higher-energy photons make a minimal contribution to the radiation dose to tumor in bone from the injected radiopharmaceutical. 9 Imageable photons from these radiotracers that react with the g a m m a camera crystal can be used for individual lesion dosimetry, but 99mTc-MDP is a far less expensive way to estimate radiation dose because its biodistribution exactly parallels that of therapeutic bone radiotracers. 1~ The bone scan is thus an essential study before therapy because there can be no analgesic effect if the diagnostic bone scan is normal at the painful site. There is an unexplained but important phenomenon that 89Sr, l~6Re etidronate, 153Sm lexidronam, and ll7mSn pentetate have all been shown to be retained by the woven bone surrounding osteoblastic metastases for a much longer period than they are on normal bone, providing an enhanced target-tonontarget ratio, thus, enhancing therapeutic efficacy.9,1~ These observations have not been sought or published for 32p but probably hold true for this radiotracer as well. A clinical response is not common before the first 5 days after administration of any therapeutic radiotracer but may be seen as late as 4 weeks thereafter; the average response time for these radiopharmaceuticals is between 7 and 14 days. Although cytoreduction may play a role in pain reduction, presumably by decreasing intramedullary pressure from the metas-
Table 1. Beta- or Electron-Emitting Radiopharmadeuticals for Painful Metastases
Radiopharmaceutical
t)/2 (d)
188Re(Sn)HEDP
0.7
~53Sm-EDTMP 90y citrate 186Re(Sn)HEDP H7mSn-DTPA
1.9 2.7 3.8 13.6
32p phosphate 89Sr chloride 85Sr chloride
14.3 50.5 64
*Conversionelectrons.
MaximumEB (MeV)
MeanEB (MeV)
MaximumRange (ram)
MeanRange (ram)
2.12
0.73 0.79
11.0
2.7 3.1
0.81 2.27 1.07 0.127" 0.152" 1.71 1.46 0.025* 0.040*
0.23 0.94 0.33 NA NA 0.70 0.58 NA NA
2.5 11.1 4.5 0.27
0.6 2.5 1.1 0.2 0.3 3.0 2.4 10
7.9 7.0 --
Gamma MeV (%abundance)Half-Life 0.155 (10%) 0.103 (28%) 0.070 (5%) 0.137 (9%) 0.159 (86%) -0.909 (0.10%) 0.514 Plus 10 to 15 keV x-rays
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Edward B. S ilberstein
tases, there is likely to be further analgesic effect from radiation-induced apoptosis of lymphocytes secreting pain-modulating cytokines such as interleukin- 1, interleukin-8, and several interferons.
schema, which incorporates these 3 dimensions of pain reduction (Fig 1), integrates the issues of pain reduction, analgesic drug use, and activities of daily living, 16,17which aids greatly in the determination of whether there has been a true response to treatment with these radiopharmaceuticals.
The Issue of Dosage and Response Tumor and marrow doses given by these radiopharmaceuticals are difficult to calculate for several reasons. The anatomic distribution of bone trabeculae is quite irregular so the greater the thickness of these trabeculae, as in osteoblastic lesions, the less distance an emitted particle or photon can travel. 15 Also, the anatomic relationship and distribution of tumor and marrow vary considerably and are sometimes intermixed. The biological half life of the radiopharmaceuticals is not always predictable, usually being much longer on reactive or woven bone around the tumor than on normal cortical or trabecular bone. 9 The deposition of the radiopharmaceutical is never perfectly uniform and the ratio of activity in the tumor site to normal bone usually ranges from 2 to 5. 4 For example, various investigators have found 32p phosphate bone dosimetry to vary by a factor of 5 depending on the dosimetric assumption; 89Sr chloride doses to bone metastases have been variously estimated with a range of 220 to 2,260 rads/mCi, whereas marrow dosimetry estimates range between 40 and 80-rads/mCi according to different investigators. Individual lesions in the same patient will receive different radiation doses depending on the target-to-nontarget ratio, raising the question of the possible necessity for individual lesion dosimetry. An equally difficult issue is how to measure a subjective response objectively regarding the reduction in pain. 15 Patient diaries, the use of various descriptive adjectives, and a visual analog scale have been used, the latter with a reproducibility of plus or minus 20%. For the visual analog scale the patient indicates on a 10-cm line where his pain falls, with 0 cm representing the pain-free state, and 10 cm representing the worst pain imaginable. In addition, the investigator must know whether any reported pain reduction came at the cost of a change in the activities of daily living. For example, if the patient lies in bed all day, back or leg pain may be reduced, but at the cost of a decrease in functioning. Furthermore the effect of analgesics must be included because if opiate use increases, then the decrease in pain after administration of a beta, electron, or x-ray-emitting radiopharmaceutical cannot be ascribed solely to the radionuclide injected. The Utrecht
Radiopharmaceuticals Used For Bone Pain Therapy All the radiopharmaceuticals active in pain reduction are reactor produced. Painful bone metastases from any primary tumor that show increased tracer uptake on a diagnostic bone scan have a significant chance of responding to radiopharmaceutical therapy, although most of the available data come from the studies on the most comrnon sources of bone metastases: breast, prostate, and lung cancer. The U.S. FDA has approved 32p (as sodium phosphate), 89Sr (as strontium chloride, trade name Metastron, Nycomed-Amersham, Princeton, NJ), and 153Sm lexidronam (trade name Quadramet, Berlex, Richmond, CA) for the treatment of bone pain of osteoblastic metastases. No longer in clinical trials or in the United States are 186Re etidronate and ll7mSn pentetate, although 186Re etidronate is available in Europe. U7n'Snpentetate clinical trials are inactive in the United States at the time of this writing. 85Sr has been used for therapy in France for 20 years.
Sodium Phosphate-a2P Sodium phosphate-S2P is generally administered intravenously. In a few series this radiotracer has been given by the oral route where absorption is 40% to 80% depending on the patient's diet. 32p has been used for over 4 decades, and in the 1950s and 1960s was often given after a week of androgen therapy to stimulate 32p uptake around both metastatic prostate and breast cancer. Is Androgen, however, is no longer recommended in the treatment of prostate carcinoma with 32p because the data on which its use was based were flawed, results without androgen are as good, and androgens will stimulate the growth of malignant prostatic cells. Androgen use has been associated with spinal cord compression. Parathyroid hormone has also been used to enhance 32p uptake, but there is no statistically sound evidence that either parathormone or androgens enhance the efficacy of 32p for reducing bone pain.18 Not only does phosphate enter hydroxyapatite throughout the bone, but, unlike all the other radio-
243
Radiopharmaceutical Pain Therapy
- -
medication increase >25% <25%
~D
ca
constant
PAIN RELIEF > 25% decrease <25% >25%
q3 Cq
(D
0 Cq
4.--.4
V
ca
0 o tt3
tD
ca
r
V
cO 0
tt3
Figure 1. Utrecht tri-dimensional pain therapy evaluation. *Only responses within the gray boxes are counted as showing effectiveness of therapy. (Reprinted by permission of the Society of Nuclear Medicine from: QuirijenJMSP, et al. Efficacyof rhenium- 186 etidronate in prostate cancer patients with metastatic bone pain.J Nucl Med 1996:37:15 i 1-1515.LT)
pharmaceuticals listed in Table 1, phosphate is also incorporated into many intracellular compounds, eg, those responsible for energy storage (adenosine triphosphate [ATP], creatine phosphate) kinases signaling receptor activation, and, most crucially, as part of the structural backbone of DNA and RNA. In fact 32p has been used as a cytocidal agent since 1939 for myeloproliferative, and, less often, lymphoproliferative disease. Only one death from 32P-related myelosuppression has been recorded, but a concern has arisen that the intracellular incorporation of ~2p in marrow cells makes this moiety a dangerous choice. The data do not support this fear. la 32p was first reported as efficacious for pain palliation in 1950.a9 No relationship between administered s2p (dosage) and therapeutic response has been found for prostate or breast cancer. Response rates to oral and intravenous 32p have been in the 60% to 90% range, although the end points of response in older studies have often not been carefully documented because many of the articles on this subject were written before 1990.18 An important study sponsored by the International Atomic Energy Agency was published in 1999 comparing 32p phosphate with agSr chloride. 32p
phosphate was given by the oral route, with 89Sr administered by standard intravenous injection. Enteral administration of 32p permits formulation of a far less expensive radiopharmaceutical because oral 32p does not have to be sterile and pyrogen free. This is an important factor in developing countries because the charge for 89Sr and 153Smlexidronam in the United States exceeds $2,000. The published findings from one of several participating centers have shown equivalence in efficacy for pain reduction for 32p and 89Sr, both in a surprisingly high range of about 90%. 2o There was no difference between 32p and agSr in duration of response. Although 32p did cause National Institute of Health grade 2 marrow toxicity (platelets 50,000 to 74,999//xL; leukocytes 2,000 to 2,999//xL) in a few patients, there were no clinical effects from this. 89Sr caused only grade 1 (platelets 75,000 to 149,999//xL; leukocytes 3,000 to 3,999//xL) myelosuppression in this comparative study, again as expected, without clinical sequelae. 2~ The reduction in pain with 32p maybe seen in 5 to 14 days. A comparative study of 32P with hemibody radiation found equivalent therapeutic responses, but hemibody radiation provided both faster responses and more toxicity. 2]
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Edward B. Sitbe~'stein
89Sr Chloride 89Sr has been in use for many decades, with an increase in interest in its use after reports of successful alleviation of bone pain by several German investigators in the 1970s22 With widely varying doses from less than 1 mCi to about 3 mCi, response rates were reported at an average of almost 60% for complete responses (CR), and close to 30% for partial responses (PR). 22 More recent responses to 898r have shown CR and PR ranging from 40% to 89% depending on the criteria used to measure responses23-29 Response duration has been reported at 6 to 12 weeks. A review by the author of 18 articles describing treatment Of 715 patients treated once solely with 89Sr yielded a CR and PR of 65%, with the range of administered 898r activity varying between 1 to 12 mCi23 In most series using 89Sr there does not appear to be an increasing response with increasing administered activity693 but there are exceptions. In one study, a relationship between increasing dose and CR, but, strangely, not PR was found. 27 Myelotoxicity clearly increases with higher dosage. Some studies have found a higher response rate in patients with a better Karnofsky performance score, a measure of the amount of care a patient requires, 26 whereas other studies have found no such relationship. -93 Two important studies used 89Sr as an adjuvant to teletherapy. 4,3~ The maximum dose of 89Sr in the United States is usually 4 mCi, but in one of these studies, Canadian workers used 10.8 mCi. 4 Compared with a placebo, the 89Sr-treated group was found to have both a longer time interval to treatment of recurrent painful sites and to the appearance of new painful sites requiring radiotherapy. Adjuvant 89Sr also reduced analgesic requirements and improved quality-of-life measurements, bu{ did not prolong life. 4,3~No other radiopharmaceutical has yet been reported to delay the time to the occurrence of new painful sites. This effect might well be related to the long effective half-life of 89Sr at the site of osteoblastic bone metastases. In a British study, at a lower dose of 89Sr comparing local teletherapy, hemibody radiation, and 89Sr, all had a similar response rate (61% to 66%), but only 89Sr reduced the incidence of new painful sites. 95 The placebo effect has been as high as 21% to 34% in controlled studies, with 89Sr yielding, by comparison 59% to 67% (CR and PR) in these studies. 4,6 &s noted earlier, intravenous 89Sr and oral 32p / were reported to have identical response rates in a
study published in 1999 from Bombay2 ~ These response rates, in excess of 90%, are higher than those that most investigators have found, but the evaluation criteria appeared objective. Several groups have found 89Sr therapy to be cost effective, saving patients care costs relative to placebo groups.3~
153Srn Lexidronam 153Sm lexidronam, a samarium tetraphosphonate chelate, binds to hydroxyapatite both through chemisorption and also a hydrolysis reaction in which samarium reacts with oxygen atoms of both water and the hydroxyapatite molecule. 32 153Smlexidronam has been approved for clinical use in the United States. Reported response rates have ranged from 55% to 80%, generally do not improve with dosage escalation, and are independent of the tumor-type treated. 33,34In one placebo-controlled study, patients receiving 1.0 mCi/kg 153Sm lexidronam responded more quickly than a group given 0.5 mCi/kg but the clinical response was equal in the 2 groups by 5 weeks. 35 Response duration has been reported to range from 2 to 17 weeks, with one study noting that 50% of responses lasted 16 weeks. 33,3GThe time to marrow recoveW might be shorter with 153Smlexidronam than with agSr because of the shorter half-life of the former. However, no direct comparative study has been performed to confirm this admittedly anecdotal experience.
186Re Etidronate 186Re etidronate was synthesized to use the therapeutic possibilities of the beta-emitting 186Re. Chelation with etidronate was attempted because this bisphosphonate, labeled with 99~Tc, was one of the first bone-imaging agents labeled with 99mTc.37,38 Rhenium and technetium are in the same chemical family (VIIA) of the Periodic Table, and their chemical properties are quite similar, although rhenium is more easily reoxidized and, therefore, tends to dissociate from bone to a greater extent than some other radiotracers used for pain relief, so it is excreted for a longer period in the urine than, for example, samarium. 37,3a 186Re etidronate both chemisorbs to bone and probably forms an oxide with hydroxyapatite in a hydrolysis reaction. This material has not been approved in the United States for clinical use, although it is widely used in Europe. Careful evaluations of 186Re etidronate by the Utrecht group has
245
Radiopharmaceutical Pain Therapy
found about 54% effectiveness in both breast and prostate cancer, 1~,17 whereas earlier data reported response rates up to 80%. I~ The group from Utrecht showed the efficacy of this radiopharmaceutical in both breast and prostate cancer using the approach shown in Fig 1 that integrates pain relief, changes of actMties of daily living, and analgesic use. With this careful tridimensional analysis the response rate with lS6Re etidronate, was 6 of 18 at 35 mCi, 7 of 9 at 50 to 60 mCi, and 7 of 10 at 80 to 95 mCi. There was no statistically significant dose-response relationship detected. Pain reduction was attributed to therapy only if it lasted 2 weeks and 54% met this criterion. Only 35% of.responses lasted 4 weeks. The range of reported flare phenomena has been greatest for 186Re etidronate of any radiopharmaceutical, ranging from 5% to 63%. Hematologic toxicity has been quantitatively related to the extent of skeletal involvement and is rarely clinically significant. 39-41 lS6Re etidronate has a very short half-life (0.7 days) and there are minimal clinical data available.4s
ll7mSn Pentetate The diethylenetriaminepentaacetic acid (pentetate) carrier brings llTmSn to the hydroxyapatite surface, where a hydrolysis reaction is again believed to bind tin with oxygen from both hydroxyapatite and water. This radiotracer differs from the other radiopharmacenticals involved in the treatment of bone pain because its emission is not a beta particle but rather 2 conversion electrons with discrete low energies and very short paths in tissue (Table 1). Because of this short path it is likely that there is less marrow irradiated from nTmSn pentetate unless, as some suggest, stem cells are primarily located adjacent to trabecular bone (where all of these radiotracers localize). Preliminary data do suggest less myelotoxicity with llTmSn pentetate. 43,44 In the largest study
published to date on the efficacy of ll7mSn pentetate (47 patients), there was no evidence of an increasing response with increased dosage. However, the time to onset of pain relief was decreased at a threshold of approximately 12 mCi/70 kg body weight. 44 In this same study, dosimetry estimates for 4 of the radiopharmaceuticals discussed earlier were recalculated, with the ratio of dose to bone surfaces to red marrow favoring ll7mSn pentetate (Table 2). 44
Other Radiopharmaceuticals For Treatment of Osteoblastic Metastases Several other tracers have been reported to have therapeutic efficacy. 90y citrate has been reported from an Italian medical center to give dramatic pain relief. 188Re etidronate yielded a response in 5 of 8 patients treated, also in a single study. These 2 radiotracers are both beta emitters. 85Sr, an agent used 30 years ago for bone imaging, produces x-rays of 10 to 15 keV, and was found by a French group to give almost 50% complete responses in breast and prostate cancer, with 75% to 80% PR and CR. Pain relief was less likely with poorer performance status, reminiscent of 2 SgSr studies discussed earlier.
Adverse Reactions From Radiopharmaceuticals Used to Relieve Bone Pain Myelotoxicity is the prima~T adverse event, which can rarely lead to life-threatening thrombocytopenia or leukopenia. In fact, several deaths have been reported from thrombocytopenic bleeding caused by both SgSr chloride and 153Sm-lexidronam.3~,45 There are a number of causes of thrombocytopenia besides radiation-induced marrow toxicity, which must also be considered. Low platelet (and leukocyte) counts
Table 2. Dosimetry Estimates for Various Pain PalIiation Agents (Average Dose, rad/mCi) Agent
Sex
n
ll7mSn pentetate SgSrchloride 153Smlexidronam
M F M/F M
3 4 * 7
186Reetidronate
M/F
27
Bone Susfaces
Red Marrow
Ratio of Bone Surfaces" to Red Marrow
65.1 63.2 63.0 25.0 15.4t 7.0
9.8 12.6 40.7 5.7 2.8t 3.0
6.6 5.0 1.6 4.4 5.5t 2.3
*Data from brochure ofAmershamHealth Care, ArlingtonHeights,IL 1995,p. 11. tRecalculated with MIRDOSE3. Reprinted with permissionof the AmericanAssociationfor Cancer Research.44
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Edward B. Silberstein
may also be produced by recent or current chemotherapy or radiotherapy, from metastatic disease replacing bone marrow, or from disseminated intravascular coagulation (platelets only).45 The flare phenomenon, a transient increase in bone pain beginning 48 to 72 hours after radiopharmaceutical therapy for painful metastases, usually lasting 2 to 3 days, has been described in 5% to 60% of patients and may predict a reduction in bone pain, ie, a therapeutic response. The wide range of flare phenomena reported relate to both varying levels of surveillance for worsening bone pain and to the definition of flare used.
Combination Radiation and Chemotherapy There are several clinical trials under way, primarily using agSr plus a variety of chemotherapeutic agents that have shown efficacy in cytotoxicity and pain reduction. Effectiveness, as measured by prostatespecific antigen decrements (in patients with prostate cancer) and by pain reduction, has been shown for 89Sr, to which has been added in various studies: estramustine plus vinblastine, estramustine alone, cisplatin plus dexamethasone, cisplatin alone, doxorubicin, mitoxantrone plus hydrocortisone, and carboplatin, agSr plus carboplatin has been reported to yield a better response than agSr alone,46 but there was no survival rate difference. However placebocontrolled trials have not been published at the time of this writing. There may be synergistic effects in both analgesia and cytotoxicity of the chemotherapeutic drug and the beta-emitter, agSr plus cisplatin or carboplatin appear particularly promising. 46 Presumably these chemotherapeutic agents, as well as doxorubicin, mitoxantrone, and paclitaxal, provide a "degree of radiosensitization tO enhance the efficacy of a9Sr in the trials in which these combinations are being used.
Alpha-Emitters An alpha-emitter radiotracer has been developed at Pacific Northwest National Laboratory that is a chelate of radium 223 with a very high binding affinity. 223Ra emits 4 alpha particles as 95% of its energy, with a range of 40 to 60/xm, about 25% of the rangd of the conversion electron coming from l l7mSn. TwO fairly energetic beta particles are also emitted by 223Ra, which is a natural bone seeker without a
radon decay product. Another alpha-emitting bisphosphonate using astatine 211 is under development. No clinical trials have yet been reported with alphaemitters.
The Clinical Use of Beta- or Electron-Emitting Radiotracers There are clinical conditions in which apparent bone pain will not be reduced with these radiotracers. Epidural metastases with pressure on the spinal cord, or soft-tissue tumors elsewhere pressing on nerves, will not be affected by a tracer that irradiates bone but not the soft-tissue lesion responsible for the pain. Pathological fracture must be examined and eliminated before any of these radiopharmaceuticals are used because the resultant pain will not be reduced. 23 It is essential that a bone scan be performed before administration of these radiotracers because there will not be selective localization of these unsealed sources in the absence of increased uptake on bone scan at the painful site. A normal bone scan suggests another cause for the patient's bone pain. It is difficult to predict responders to these therapeutic radiopharmaceuticals once one has eliminated the causes of nonresponse noted earlier. A higher Karnofsky (performance) scale in some 2~ (but not all23) series has suggested a greater chance of a response. There have been, however, impressive responses in bedridden terminal patients, and the author does not believe these radiopharmaceuticals should be withheld unless the patient is moribUnd. EveW day of improved quality of life is precious to the patient and his/her family. The occurrence and severity of cytopenia caused by the radiotracer does not correlate well with pain relief.23 The presence of narcotic tolerance does not give any indication as to whether the radiotracer will have a therapeutic effect.23 With most radiotracer studies there has been no significant dosage-activity response to suggest that higher dosage of these radiopharmaceuticals will be more efficacious.6 Teletherapy is recommended: when there are 1 or 2 painful metastases, in the presence of impending spinal cord compression, as prophylaxis or treatment of pathological fracture, and to treat pain resulting from soft-tissue tumor extending to bone. In all of these instances the therapeutic radiopharmaceuticals will not be helpful. These radiotracers should not be given within 4 weeks of most myelosuppressive chemotherapy or wide-field teletherapy. Beta, electron, or low-energy photon-emitting ra-
RadiopharmaceutiealPain Therapy
diopharmaceuticals are contraindicated when there is a nonosseous cause for the pain as described earlier; if the bone scan is negative at the painful site; if there is significant leukopenia or thrombocytopenia; if a pathological fracture is present; in the presence of disseminated intravascular coagulation when platelet turnover is already high and a reduction in megakaryocytes can lead to a rapid and severe thrombocytopenia. These radiotracers are most useful in the presence of multiple painful metastatic osseous sites when increased radiotracer uptake on bone scan correlates with the sites of pain. They will also be useful when there is recurrent pain in local or wide-field teletherapy sites and further teletherapy is contraindicated.
Practical Aspects of Therapy These agents should be injected through a running intravenous line; a plastic syringe shield should be used because it reduces bremsstrahlung, unlike a lead shield. This policy avoids subcutaneous infiltration and reduces the radiation dose to the hands of the administering physician who then does not have to spend time attempting a venipuncture. Infusion should be slow, over 1 to 2 minutes because a9Sr can mimic the cardiovascular effects of calcium if given rapidly, whereas chelates such as lexidronam can bind intravascular free calcium and magnesium, acutely lowering these blood levels. Current Nuclear Regulatory Commission guidelines permit release of these patients to their homes after treatment. Careful handwashing and avoidance of urinary contamination are required. Table 3 summarizes guidelines for administration of these unsealed beta-electron emitters. 47
Future Study Considerable research will be required to answer many outstanding questions and concerns about Table 3. Administering Unsealed Beta Emitters The painful site must correspond to an area positive on a bone scan performed within 3 to 4 weeks Platelet and leukocyte counts must be adequate Informed consent form should be signed Inject through a running intravenous line Use a finger dosimeter when injecting Inject slowly over 1 to 2 minutes A plastic syringe shield, not a lead shield, should be used
247
therapy of bone pain with unsealed sources. We do not yet know if life can be prolonged, although data from several studies suggest that this does not occur. 4,48 We do not know how to predict who will respond to these injected radiopharmaceuticals, with conflicting data regarding whether better performance scale scores translate into higher response rates. Which radiopharmaceutical provides the optimal response? Meaningful comparative studies will require hundreds of patients per study arm to avoid the type II error of assuming no difference in response when one exists. What is the optimum administered activity of each of these radiotracers? With higher administered activity myelotoxicity is increased, and only a minority of studies show improved response rates with the higher dosage. Dose rate effects and the efficacy of split doses have not yet been studied. The combinations of these radiotracers with chemotherapeutic agents and with bisphosphonates must be examined. There could be a role for alpha-emitting radiotracers in this field. In asymptomatic patients with bone metastases there may be an important adjuvant role for beta, electron, or low-energy photon-emitting radiopharmaceuticals, but such studies have not yet been published. The equivalence found for oral 32p and ~gSr; with only minimally more, and clinically insignificant, 32p toxicity, 2~ requires a reexamination of this far less expensive radiopharmaceutical and route. The techniques of tumor and marrow dosimetry with these agents have still not been completely worked out. The mechanisms of action of the radiotracers is not understood. We do not even know the optimum tool to measure outcome.
Conclusion Radiopharmaceuticals with affinity for reactive bone and that emit electron, beta particles, or low-energy photons will reduce or eliminate the pain ofosteoblastic metastases with 55% to 80% effectiveness. The variability in measurement techniques for partial responses causes this wide variation in response rate. Side effects include a brief flare of pain about 10% to 20% of the time and mild to moderate pancytopenia. This therapy may be repeated 2 or more times (every 9 to 12 weeks) because the effect on pain reduction lasts only weeks to months.
References 1. McEwanAJ:Unsealed sourcetherapy ofpainful bone metastases. SeminNucl Med 27:165-182,1997
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2. Garrett IR: Bone destruction in cancer. Semin Onco120(Suppl 2):4-9, 1993 3. World Health Organization: Cancer pain relief and palliative care. Report of a WHO expert committee. World Health Organization Technical Report Series 804. World Health Organization, Geneva, Switzerland, pp. 1-75, 1990 4. Porter AT, McEwan AJB, Powe JE, e t al: Results of a randomized phase-HI trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. IntJ Radiat Oncol Biol Phys 25:805-813, 1993 5. Atkins HL: Radiopharmaceuticals for bone malignancy.J Nucl Med Techno126:80-83, 1998 6. McEwan AJ: Palliation therapy with bone seeking radiopharmaceuticals. Cancer Biother Radiopharm 13:413-426, 1998 7. Hosain F, Spencer RP: Radiopharmaceuticals for palliation of metastatic osseous lesions: Biologic and physicai background. Semin Nucl Med 22:11-19, 1992 8. Ben-Josef E, Lucas Dr, Vasan S, et al: Selective accumulation of strontium-89 in metastatic deposits in bone; Radiohistological correlation. Nucl Med Commun 16:457-463, 1995 9. Blake GM, Zivanovic MA, McEwan AJ, et al: Sr-89 therapy: Strontium kinetics in disseminated carcinoma of the prostate. EurJ Nucl Med 12:447-454, i986 10. Maxon HR, Thomas SR, Herzberg VS, et al: Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases. Semin Nucl Med 22:33-40, 1992 11. KetringAR: 153Sm-EDTMPand 186Re-HEDP as bone therapeutic radiopharmaceuticals. Nucl Med Biol 14:223-232, 1987 12. Logan KW, Volkert WA, Holmes RA: Radiation dose calculations in persons receiving injections of samarium-153 EDTMP. J Nucl Med 28:505-509, 1987 13. Krishnamurthy GT, Swailen FM, Srivastava SC, et al: Tin117m(4+) DTPA: Pharmacokinetics and imaging characteristics in patients with metastatic bone pain. J Nucl Med 38:230-237, 1997 14. EaryJF, Collins C, Stabin M, et al: Samarium-153-EDTMP biodistribution and dosimetry estimation.J Nucl Med 34:1031 1 0 3 6 , 1993 15. Samartunga RC, Thomas SR, Hinnefeld JD, et ah A Monte Carlo simulation model for radiation dose to metastatic skeletal tumor from rhenium-186(Sn)-HEDP. J Nucl Med 36:336-350, 1995 16. deKlerkJMH, van het Schip AD, Zonnenberg BA, et al: Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer. E u r J Nucl Med 21:1114-1120, 1994 17. Quirijen JMSP, Han SH, Zonnenberg BA, et al: Efficacy of rhenium-186 etidronate in prostate cancer patients with metastatic bone pain.J Nuci Med 37:15 ! 1-1515, 1996 18. Silberstein EB: The treatment of painful osseous metastases with phosphorus-32-1abeled phosphates. Semin Onco120(suppl 2):10-21, 1993 19. Friedell HL, StoraasliJP: The use of radioactive phosphorus in the treatment of carcinoma of the breast with widespread metastas~s to bone. AJR AmJ Roentgeno164:559-575, 1950 20. NairN: Relative efficacyof32P and S%r in palliation in skeletal metastases.J Nucl Med 40:256-261, 1999 21. Aziz'H, Choi K, Sohn C, et al: Comparison ofa2P therapy and sequential hemibody irradiation (HBI) for bony metastases as methods of whole body irradiation. AmJ Clin Oncol 9:264-268, 1986
22. Schmidt CG, Firusian N: 89Sr for the treatment of incurable pain in patients with neoplastic osseous infiltration. IntJ Clin Pharmacul 9:199-205, 1974 23. Silberstein EB, Williams C: Strontium-89 therapy for the pain of osseous metastases.J Nuci Med 26:345-348, 1985 24. Robinson RG, Preston DF, Spicer JA, et ai: Radionuclide therapy of intractable bone pain. Emphasis on strontium-89. Semin Nucl Med 22:28-30, 1992 25. Quilty PM, Kirk D, Bolger JJ, et al: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31:3340, 1994 26. Schmeler K, Bastin K: Strontium-89 for symptomatic metastatic prostate cancer to bone: Recommendations for hospice patients. HospiceJ 11:1-10, 1996 27. Mertens WC, Stitt L, Porter AT: Strontium-89 therapy and relief of pain in patients with prostate carcinoma metastatic to bone: A dose response relationship? A m J Clin Oncol 16:238242, 1993 28. Berna L, Carrio I, Alonso C, et al: Bone pain palliation with strontium-89 in breast cancer patients with bone metastases and refractory bone pain. Eur J Nucl Med 22:1101-1104, 1995 29. Pine F, Herranz R, Garcia A, et al: Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer. EurJ Nucl Med 24:1210-1214, 1997 30. Malmberg I, Persson U, Ask A, et al: Painful bone metastases in hormone-refractory prostate cancer: Economic costs of strontium-89 and/or external radiotherapy. Urology 50:747753, 1997 31. McEwan AJ, Amyotte GA, McGowan DG, et al: A retrospective analysis of the cost effectiveness of treatment with Metastron in patients with prostate cancer metastatic to bone. Eur Uro126(suppi 1):26-31, 1994 32. Goeckeler WF, Trontner DE, Volkert WA, et al: 153Sm radiotherapeutic bone agents. Nucl Med Biol 13:479-482, 1986 33. Collins C, Eary JF, Donaldson G, et al: Samarium-153EDTMP in bone metastases of hormone refractory prostate carcinoma: A phase I/II trial.J Nucl Med 34:1839-1844, 1993 34. Resche I, ChatalJF, Pecking A, et al: A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 33:1583-1591, 1997 35. Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled clinical trial.J Clin Oncol 16:1574-1581, 1998 36. Sandeman TF, Bndd RS, Martin .IJ: Samarium-153-1abeled EDTMP for bone metastases from cancer of the prostate. Clin Oncoi 4:160-164, 1992 37. Mathieu L, Chevalier P, Galy G, et al: Preparation of rhenium186 labeled HEDP and its possible use in the treatment of osseous neoplasms. IntJ Appl Rad Isotopes 20:725-727, 1979 38. Deutsch E, Libson K, VanderheydenJL, et al: The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine. Nucl Med Biol 13:465-477, 1986 39. deKierkJMH, van Dieren EB, van het Schip AD, et al: Bone marrow absorbed dose ofrhenium-i 86-HEDP and the relationship with decreased platelet counts.J Nucl Med 37:38-41, 1996 40. deKierk JMH, van bet Schip AD, Zonnenberg BA, et al:
RadiopharmaceuticalPain Therapy
Evaluation of thrombocytopenia in patients treated with rhenium-186-HEDP. Guidelines for individual dosage recommendations.J Nucl Med 35:1423-1428, 1994
45.
41. deKlerkJMH, van bet Schip AD, Zonnenberg BA, et al: Phase I study of rhenium-186-HEDP in patients with bone metastases originating from breast cancer. J Nucl Med 37:244-249, 1996
46.
42. Maxon HI{, Schroder IX', Washburn LC, et al: Rhenium188(Sn)-HEDP for treatment of osseous metastases. J Nucl Med 39:659-663, 1998 43. Atkins HL, Mausner LF, Srivastava SC, et al: Tin-117m(4+) for palliation of pain from osseous metastases: A pilot study.J Nucl Med 36:725-729, 1995 44. Srivastava SC, Atkins HL, Krishnamurthy GT, et al: Treatment of metastatic bone pain with tin-117m stannic diethyl
47. 48.
249
enetriaminepentaacetic acid. A phase I/II clinical study. Clin Cancer Res 4:61-68, 1998 Leong C, McKenzie MR, Coupland DB, et al: Disseminated intravascular coagulation in patients with metastatic prostate cancer: Fatal outcome following strontium-89 therapy.J Nucl Med 35:1662-1664, 1994 Scioto R, Maini CL, Tofani A, et al: Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. Nucl Med Commun 17:799-804, 1996 Silberstein EB, Taylor Air: Procedure guideline for bone pain treatment: 1.0J Nucl Med 37:881-884, 1995 Brundage IVfD, Crook JM, Lukka H: Use of strontium-89 in endocrine-refractory prostate cancer metastatic to bone. Provincial Genitourinary Cancer Disease Site Group. Cancer Prev Control 2:79-87, 1998
lar coagulation can cause severe, life-threatening thrombocytopenia. This treatment may be repeated at about 9- to 12-week intervals, perhaps earlier with 1~3Sm lexidronam, lSSRe etidronate, and 117mSn pentetate, with a success rate approaching that of the initial injection. The duration of action of pain reduction ranges from 2 weeks to many months. Tumorical effects are probably not the only mechanism of pain relief. Copyright 9 2000 by W.B. Saunders Company
he lifetime prevalence of cancer in the United States population is 30% to 35% with over 1 million cases per year. About three quarters of patients with advanced cancer have pain, much of this clinically significant, from bone metastases. 1,2 Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used first in the treatment of such pain, followed up by more potent opiates in a stepwise approach recommended by World Health Organization guidelines. 3 Although narcotics are generally effective in relieving pain, the somnolence, nausea, and constipation that result from their use almost inevitably decrease the quality of life in the patient with advanced cancer. 3 The role of treatment with intravenous or oral administration of unsealed boneseeking beta or electron-emitting sources requires greater emphasis because these radiopharmaceuticals can reduce, or even eliminate, an opiate requirement. Whatever modality is used, the goals of therapy must be made clear to the patient. When a cure is not possible, cytoreduction usually is possible, although this tumoricidal effect, often documented by a decrease in the level of serum tumor markers and/or the healing of lesions radiographically on bone scan, does not prolong survival time. 4 However, the radiopharmaceuticals available to us can reduce or eliminate bone pain owing to osteoblastic metastases, thus, decreasing narcotic dose and improving the functional status of the patient. 46 With at least 1 radiopharmaceuticaP the time until more radio-
therapy is required for either new or recurrent painful metastases can be lengthened.
T
From the University of Cincinnati Medical Center, Cincinnati, OH. Address reprint requests to Edward B. Silberstein, MD, University of Cincinnati Medical Center, 234 Goodman, Mont Reid Pavilion, Room G026, Cincinnati, 0H45219. Copyright 9 2000 by W..B. Saunders Company 1053-4296/00/1003-0007510.00/0 doi:l O.lO53/srao.2000.6592
240
Mechanisms of Radiopharmaceutical Therapy The administration of beta, electron, or low-energy photon-emitting radiopharmaceuticals that are part of, or attached to, a chemical moiety with an affinity for bone mineral (hydroxyapatite) permits the selective radiation of osteoblastic metastases, with minimal or no radiation of normal tissues. Thus, these internal emitters avoid cutaneous or gastrointestinal side effects and have no other toxicity than minimal to moderate hematologic effects and occasionally a 2to 3-day flare of pain symptoms. These radiopharmaceuticals, called unsealed sources by the Nuclear Regulatory Commission, can be administered intravenously (or, with phosphorus 32, also orally). Wherever osteoblastic activity is increased, these therapeutic radiotracers will react with the newly produced hydrated amorphous calcium phosphate salts and hydroxyapatite there. 7,a The radiopharmaceutical effective half-life (related to both physical and biological half life) must be of sufficient length to cause some death of tumor cells in bone, and probably of mononuclear cytokinesecreting cells near the absorptive surfaces around bony metastases. Table 1 lists the radiotracers that have been shown to have efficacy in humans. (There are only minimal clinical data on yttrium 90 citrate.) These radiopharmaceuticals widely differ in the (1) mechanism of skeletal retention; (2) degree of integration of the chemical moiety carrying the radionuclide throughout the bone or just on the surface; (3) physical half-life (by a factor of 90) and, therefore, in the dose rate at the tumor site; (4) degree of skeletal retention; (5) energy of their emission and, therefore,
Seminars in Radiation Oncology, Vo110, No 3 (July), 2000: pp 240-249
RadiopharmaceuticalPain Therapy
the effective distance it travels; and (6) presence or absence of a g a m m a emission. With all of these physiological and physical differences, it is still unclear whether there are any significant differences in clinical effectiveness between them. Nevertheless, the emitted energy, in whatever form, is sufficient to reach painful osseous tumor sites with some cytocidal effect. Bone metastases may be radiographically lytic, reducing the adjacent bone mass, or cause production of excessive reactive or woven bone around the tumor, seen as osteoblastic or osteosclerotic lesions on radiograph. The resultant bone density is the result of the balance of osteoclast activity, direct resorptive activity of the tumor, and the response of host osteoblasts. 6 In the vast majority of bone metastases, osteoblasts are stimulated regardless of the net loss or gain of surrounding bone, and hence the technetium 99m methylenediphosphonate (MDP) bone scan will show increased uptake even if the radiographic pattern is osteolytic. An abnormal diagnostic nuclear bone scan indicates truly increased activity of osteoblasts and has been shown invariably to predict the virtually identical bone deposition of all the tracers listed in Table 1. Only with an abnormal bone scan (increased osteoblastic activity) will the radiotracers listed in Table 1 accumulate in a site of osseous metastases to a sufficient extent to have a therapeutic effect. Intravenously (or orally) administered radiotracers promptly diffuse from the intravascular to the extravascular space and come in contact with newly produced calcium phosphates, including hydroxyapatite, with which they may react by incorporation into the hydroxyapatite molecule (32p, strontium 85, and strontium 89), chemisorption on the surface of hy-
241
droxyapatite (rhenium 186 and samairum 153), or by oxide formation with hydroxyapatite in a hydrolysis reaction with oxygens donated by hydroxyapatite and water (tin 117m, 153Sm, and la6Re). These radiopharmaceuticals emit beta particles, conversion electrons, or low-energy photons with a mean range between 0.2 and 3 m m (maximum range 0.3 to 11 mm) (Table 1). Emitted higher-energy photons make a minimal contribution to the radiation dose to tumor in bone from the injected radiopharmaceutical. 9 Imageable photons from these radiotracers that react with the g a m m a camera crystal can be used for individual lesion dosimetry, but 99mTc-MDP is a far less expensive way to estimate radiation dose because its biodistribution exactly parallels that of therapeutic bone radiotracers. 1~ The bone scan is thus an essential study before therapy because there can be no analgesic effect if the diagnostic bone scan is normal at the painful site. There is an unexplained but important phenomenon that 89Sr, l~6Re etidronate, 153Sm lexidronam, and ll7mSn pentetate have all been shown to be retained by the woven bone surrounding osteoblastic metastases for a much longer period than they are on normal bone, providing an enhanced target-tonontarget ratio, thus, enhancing therapeutic efficacy.9,1~ These observations have not been sought or published for 32p but probably hold true for this radiotracer as well. A clinical response is not common before the first 5 days after administration of any therapeutic radiotracer but may be seen as late as 4 weeks thereafter; the average response time for these radiopharmaceuticals is between 7 and 14 days. Although cytoreduction may play a role in pain reduction, presumably by decreasing intramedullary pressure from the metas-
Table 1. Beta- or Electron-Emitting Radiopharmadeuticals for Painful Metastases
Radiopharmaceutical
t)/2 (d)
188Re(Sn)HEDP
0.7
~53Sm-EDTMP 90y citrate 186Re(Sn)HEDP H7mSn-DTPA
1.9 2.7 3.8 13.6
32p phosphate 89Sr chloride 85Sr chloride
14.3 50.5 64
*Conversionelectrons.
MaximumEB (MeV)
MeanEB (MeV)
MaximumRange (ram)
MeanRange (ram)
2.12
0.73 0.79
11.0
2.7 3.1
0.81 2.27 1.07 0.127" 0.152" 1.71 1.46 0.025* 0.040*
0.23 0.94 0.33 NA NA 0.70 0.58 NA NA
2.5 11.1 4.5 0.27
0.6 2.5 1.1 0.2 0.3 3.0 2.4 10
7.9 7.0 --
Gamma MeV (%abundance)Half-Life 0.155 (10%) 0.103 (28%) 0.070 (5%) 0.137 (9%) 0.159 (86%) -0.909 (0.10%) 0.514 Plus 10 to 15 keV x-rays
242
Edward B. S ilberstein
tases, there is likely to be further analgesic effect from radiation-induced apoptosis of lymphocytes secreting pain-modulating cytokines such as interleukin- 1, interleukin-8, and several interferons.
schema, which incorporates these 3 dimensions of pain reduction (Fig 1), integrates the issues of pain reduction, analgesic drug use, and activities of daily living, 16,17which aids greatly in the determination of whether there has been a true response to treatment with these radiopharmaceuticals.
The Issue of Dosage and Response Tumor and marrow doses given by these radiopharmaceuticals are difficult to calculate for several reasons. The anatomic distribution of bone trabeculae is quite irregular so the greater the thickness of these trabeculae, as in osteoblastic lesions, the less distance an emitted particle or photon can travel. 15 Also, the anatomic relationship and distribution of tumor and marrow vary considerably and are sometimes intermixed. The biological half life of the radiopharmaceuticals is not always predictable, usually being much longer on reactive or woven bone around the tumor than on normal cortical or trabecular bone. 9 The deposition of the radiopharmaceutical is never perfectly uniform and the ratio of activity in the tumor site to normal bone usually ranges from 2 to 5. 4 For example, various investigators have found 32p phosphate bone dosimetry to vary by a factor of 5 depending on the dosimetric assumption; 89Sr chloride doses to bone metastases have been variously estimated with a range of 220 to 2,260 rads/mCi, whereas marrow dosimetry estimates range between 40 and 80-rads/mCi according to different investigators. Individual lesions in the same patient will receive different radiation doses depending on the target-to-nontarget ratio, raising the question of the possible necessity for individual lesion dosimetry. An equally difficult issue is how to measure a subjective response objectively regarding the reduction in pain. 15 Patient diaries, the use of various descriptive adjectives, and a visual analog scale have been used, the latter with a reproducibility of plus or minus 20%. For the visual analog scale the patient indicates on a 10-cm line where his pain falls, with 0 cm representing the pain-free state, and 10 cm representing the worst pain imaginable. In addition, the investigator must know whether any reported pain reduction came at the cost of a change in the activities of daily living. For example, if the patient lies in bed all day, back or leg pain may be reduced, but at the cost of a decrease in functioning. Furthermore the effect of analgesics must be included because if opiate use increases, then the decrease in pain after administration of a beta, electron, or x-ray-emitting radiopharmaceutical cannot be ascribed solely to the radionuclide injected. The Utrecht
Radiopharmaceuticals Used For Bone Pain Therapy All the radiopharmaceuticals active in pain reduction are reactor produced. Painful bone metastases from any primary tumor that show increased tracer uptake on a diagnostic bone scan have a significant chance of responding to radiopharmaceutical therapy, although most of the available data come from the studies on the most comrnon sources of bone metastases: breast, prostate, and lung cancer. The U.S. FDA has approved 32p (as sodium phosphate), 89Sr (as strontium chloride, trade name Metastron, Nycomed-Amersham, Princeton, NJ), and 153Sm lexidronam (trade name Quadramet, Berlex, Richmond, CA) for the treatment of bone pain of osteoblastic metastases. No longer in clinical trials or in the United States are 186Re etidronate and ll7mSn pentetate, although 186Re etidronate is available in Europe. U7n'Snpentetate clinical trials are inactive in the United States at the time of this writing. 85Sr has been used for therapy in France for 20 years.
Sodium Phosphate-a2P Sodium phosphate-S2P is generally administered intravenously. In a few series this radiotracer has been given by the oral route where absorption is 40% to 80% depending on the patient's diet. 32p has been used for over 4 decades, and in the 1950s and 1960s was often given after a week of androgen therapy to stimulate 32p uptake around both metastatic prostate and breast cancer. Is Androgen, however, is no longer recommended in the treatment of prostate carcinoma with 32p because the data on which its use was based were flawed, results without androgen are as good, and androgens will stimulate the growth of malignant prostatic cells. Androgen use has been associated with spinal cord compression. Parathyroid hormone has also been used to enhance 32p uptake, but there is no statistically sound evidence that either parathormone or androgens enhance the efficacy of 32p for reducing bone pain.18 Not only does phosphate enter hydroxyapatite throughout the bone, but, unlike all the other radio-
243
Radiopharmaceutical Pain Therapy
- -
medication increase >25% <25%
~D
ca
constant
PAIN RELIEF > 25% decrease <25% >25%
q3 Cq
(D
0 Cq
4.--.4
V
ca
0 o tt3
tD
ca
r
V
cO 0
tt3
Figure 1. Utrecht tri-dimensional pain therapy evaluation. *Only responses within the gray boxes are counted as showing effectiveness of therapy. (Reprinted by permission of the Society of Nuclear Medicine from: QuirijenJMSP, et al. Efficacyof rhenium- 186 etidronate in prostate cancer patients with metastatic bone pain.J Nucl Med 1996:37:15 i 1-1515.LT)
pharmaceuticals listed in Table 1, phosphate is also incorporated into many intracellular compounds, eg, those responsible for energy storage (adenosine triphosphate [ATP], creatine phosphate) kinases signaling receptor activation, and, most crucially, as part of the structural backbone of DNA and RNA. In fact 32p has been used as a cytocidal agent since 1939 for myeloproliferative, and, less often, lymphoproliferative disease. Only one death from 32P-related myelosuppression has been recorded, but a concern has arisen that the intracellular incorporation of ~2p in marrow cells makes this moiety a dangerous choice. The data do not support this fear. la 32p was first reported as efficacious for pain palliation in 1950.a9 No relationship between administered s2p (dosage) and therapeutic response has been found for prostate or breast cancer. Response rates to oral and intravenous 32p have been in the 60% to 90% range, although the end points of response in older studies have often not been carefully documented because many of the articles on this subject were written before 1990.18 An important study sponsored by the International Atomic Energy Agency was published in 1999 comparing 32p phosphate with agSr chloride. 32p
phosphate was given by the oral route, with 89Sr administered by standard intravenous injection. Enteral administration of 32p permits formulation of a far less expensive radiopharmaceutical because oral 32p does not have to be sterile and pyrogen free. This is an important factor in developing countries because the charge for 89Sr and 153Smlexidronam in the United States exceeds $2,000. The published findings from one of several participating centers have shown equivalence in efficacy for pain reduction for 32p and 89Sr, both in a surprisingly high range of about 90%. 2o There was no difference between 32p and agSr in duration of response. Although 32p did cause National Institute of Health grade 2 marrow toxicity (platelets 50,000 to 74,999//xL; leukocytes 2,000 to 2,999//xL) in a few patients, there were no clinical effects from this. 89Sr caused only grade 1 (platelets 75,000 to 149,999//xL; leukocytes 3,000 to 3,999//xL) myelosuppression in this comparative study, again as expected, without clinical sequelae. 2~ The reduction in pain with 32p maybe seen in 5 to 14 days. A comparative study of 32P with hemibody radiation found equivalent therapeutic responses, but hemibody radiation provided both faster responses and more toxicity. 2]
244
Edward B. Sitbe~'stein
89Sr Chloride 89Sr has been in use for many decades, with an increase in interest in its use after reports of successful alleviation of bone pain by several German investigators in the 1970s22 With widely varying doses from less than 1 mCi to about 3 mCi, response rates were reported at an average of almost 60% for complete responses (CR), and close to 30% for partial responses (PR). 22 More recent responses to 898r have shown CR and PR ranging from 40% to 89% depending on the criteria used to measure responses23-29 Response duration has been reported at 6 to 12 weeks. A review by the author of 18 articles describing treatment Of 715 patients treated once solely with 89Sr yielded a CR and PR of 65%, with the range of administered 898r activity varying between 1 to 12 mCi23 In most series using 89Sr there does not appear to be an increasing response with increasing administered activity693 but there are exceptions. In one study, a relationship between increasing dose and CR, but, strangely, not PR was found. 27 Myelotoxicity clearly increases with higher dosage. Some studies have found a higher response rate in patients with a better Karnofsky performance score, a measure of the amount of care a patient requires, 26 whereas other studies have found no such relationship. -93 Two important studies used 89Sr as an adjuvant to teletherapy. 4,3~ The maximum dose of 89Sr in the United States is usually 4 mCi, but in one of these studies, Canadian workers used 10.8 mCi. 4 Compared with a placebo, the 89Sr-treated group was found to have both a longer time interval to treatment of recurrent painful sites and to the appearance of new painful sites requiring radiotherapy. Adjuvant 89Sr also reduced analgesic requirements and improved quality-of-life measurements, bu{ did not prolong life. 4,3~No other radiopharmaceutical has yet been reported to delay the time to the occurrence of new painful sites. This effect might well be related to the long effective half-life of 89Sr at the site of osteoblastic bone metastases. In a British study, at a lower dose of 89Sr comparing local teletherapy, hemibody radiation, and 89Sr, all had a similar response rate (61% to 66%), but only 89Sr reduced the incidence of new painful sites. 95 The placebo effect has been as high as 21% to 34% in controlled studies, with 89Sr yielding, by comparison 59% to 67% (CR and PR) in these studies. 4,6 &s noted earlier, intravenous 89Sr and oral 32p / were reported to have identical response rates in a
study published in 1999 from Bombay2 ~ These response rates, in excess of 90%, are higher than those that most investigators have found, but the evaluation criteria appeared objective. Several groups have found 89Sr therapy to be cost effective, saving patients care costs relative to placebo groups.3~
153Srn Lexidronam 153Sm lexidronam, a samarium tetraphosphonate chelate, binds to hydroxyapatite both through chemisorption and also a hydrolysis reaction in which samarium reacts with oxygen atoms of both water and the hydroxyapatite molecule. 32 153Smlexidronam has been approved for clinical use in the United States. Reported response rates have ranged from 55% to 80%, generally do not improve with dosage escalation, and are independent of the tumor-type treated. 33,34In one placebo-controlled study, patients receiving 1.0 mCi/kg 153Sm lexidronam responded more quickly than a group given 0.5 mCi/kg but the clinical response was equal in the 2 groups by 5 weeks. 35 Response duration has been reported to range from 2 to 17 weeks, with one study noting that 50% of responses lasted 16 weeks. 33,3GThe time to marrow recoveW might be shorter with 153Smlexidronam than with agSr because of the shorter half-life of the former. However, no direct comparative study has been performed to confirm this admittedly anecdotal experience.
186Re Etidronate 186Re etidronate was synthesized to use the therapeutic possibilities of the beta-emitting 186Re. Chelation with etidronate was attempted because this bisphosphonate, labeled with 99~Tc, was one of the first bone-imaging agents labeled with 99mTc.37,38 Rhenium and technetium are in the same chemical family (VIIA) of the Periodic Table, and their chemical properties are quite similar, although rhenium is more easily reoxidized and, therefore, tends to dissociate from bone to a greater extent than some other radiotracers used for pain relief, so it is excreted for a longer period in the urine than, for example, samarium. 37,3a 186Re etidronate both chemisorbs to bone and probably forms an oxide with hydroxyapatite in a hydrolysis reaction. This material has not been approved in the United States for clinical use, although it is widely used in Europe. Careful evaluations of 186Re etidronate by the Utrecht group has
245
Radiopharmaceutical Pain Therapy
found about 54% effectiveness in both breast and prostate cancer, 1~,17 whereas earlier data reported response rates up to 80%. I~ The group from Utrecht showed the efficacy of this radiopharmaceutical in both breast and prostate cancer using the approach shown in Fig 1 that integrates pain relief, changes of actMties of daily living, and analgesic use. With this careful tridimensional analysis the response rate with lS6Re etidronate, was 6 of 18 at 35 mCi, 7 of 9 at 50 to 60 mCi, and 7 of 10 at 80 to 95 mCi. There was no statistically significant dose-response relationship detected. Pain reduction was attributed to therapy only if it lasted 2 weeks and 54% met this criterion. Only 35% of.responses lasted 4 weeks. The range of reported flare phenomena has been greatest for 186Re etidronate of any radiopharmaceutical, ranging from 5% to 63%. Hematologic toxicity has been quantitatively related to the extent of skeletal involvement and is rarely clinically significant. 39-41 lS6Re etidronate has a very short half-life (0.7 days) and there are minimal clinical data available.4s
ll7mSn Pentetate The diethylenetriaminepentaacetic acid (pentetate) carrier brings llTmSn to the hydroxyapatite surface, where a hydrolysis reaction is again believed to bind tin with oxygen from both hydroxyapatite and water. This radiotracer differs from the other radiopharmacenticals involved in the treatment of bone pain because its emission is not a beta particle but rather 2 conversion electrons with discrete low energies and very short paths in tissue (Table 1). Because of this short path it is likely that there is less marrow irradiated from nTmSn pentetate unless, as some suggest, stem cells are primarily located adjacent to trabecular bone (where all of these radiotracers localize). Preliminary data do suggest less myelotoxicity with llTmSn pentetate. 43,44 In the largest study
published to date on the efficacy of ll7mSn pentetate (47 patients), there was no evidence of an increasing response with increased dosage. However, the time to onset of pain relief was decreased at a threshold of approximately 12 mCi/70 kg body weight. 44 In this same study, dosimetry estimates for 4 of the radiopharmaceuticals discussed earlier were recalculated, with the ratio of dose to bone surfaces to red marrow favoring ll7mSn pentetate (Table 2). 44
Other Radiopharmaceuticals For Treatment of Osteoblastic Metastases Several other tracers have been reported to have therapeutic efficacy. 90y citrate has been reported from an Italian medical center to give dramatic pain relief. 188Re etidronate yielded a response in 5 of 8 patients treated, also in a single study. These 2 radiotracers are both beta emitters. 85Sr, an agent used 30 years ago for bone imaging, produces x-rays of 10 to 15 keV, and was found by a French group to give almost 50% complete responses in breast and prostate cancer, with 75% to 80% PR and CR. Pain relief was less likely with poorer performance status, reminiscent of 2 SgSr studies discussed earlier.
Adverse Reactions From Radiopharmaceuticals Used to Relieve Bone Pain Myelotoxicity is the prima~T adverse event, which can rarely lead to life-threatening thrombocytopenia or leukopenia. In fact, several deaths have been reported from thrombocytopenic bleeding caused by both SgSr chloride and 153Sm-lexidronam.3~,45 There are a number of causes of thrombocytopenia besides radiation-induced marrow toxicity, which must also be considered. Low platelet (and leukocyte) counts
Table 2. Dosimetry Estimates for Various Pain PalIiation Agents (Average Dose, rad/mCi) Agent
Sex
n
ll7mSn pentetate SgSrchloride 153Smlexidronam
M F M/F M
3 4 * 7
186Reetidronate
M/F
27
Bone Susfaces
Red Marrow
Ratio of Bone Surfaces" to Red Marrow
65.1 63.2 63.0 25.0 15.4t 7.0
9.8 12.6 40.7 5.7 2.8t 3.0
6.6 5.0 1.6 4.4 5.5t 2.3
*Data from brochure ofAmershamHealth Care, ArlingtonHeights,IL 1995,p. 11. tRecalculated with MIRDOSE3. Reprinted with permissionof the AmericanAssociationfor Cancer Research.44
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may also be produced by recent or current chemotherapy or radiotherapy, from metastatic disease replacing bone marrow, or from disseminated intravascular coagulation (platelets only).45 The flare phenomenon, a transient increase in bone pain beginning 48 to 72 hours after radiopharmaceutical therapy for painful metastases, usually lasting 2 to 3 days, has been described in 5% to 60% of patients and may predict a reduction in bone pain, ie, a therapeutic response. The wide range of flare phenomena reported relate to both varying levels of surveillance for worsening bone pain and to the definition of flare used.
Combination Radiation and Chemotherapy There are several clinical trials under way, primarily using agSr plus a variety of chemotherapeutic agents that have shown efficacy in cytotoxicity and pain reduction. Effectiveness, as measured by prostatespecific antigen decrements (in patients with prostate cancer) and by pain reduction, has been shown for 89Sr, to which has been added in various studies: estramustine plus vinblastine, estramustine alone, cisplatin plus dexamethasone, cisplatin alone, doxorubicin, mitoxantrone plus hydrocortisone, and carboplatin, agSr plus carboplatin has been reported to yield a better response than agSr alone,46 but there was no survival rate difference. However placebocontrolled trials have not been published at the time of this writing. There may be synergistic effects in both analgesia and cytotoxicity of the chemotherapeutic drug and the beta-emitter, agSr plus cisplatin or carboplatin appear particularly promising. 46 Presumably these chemotherapeutic agents, as well as doxorubicin, mitoxantrone, and paclitaxal, provide a "degree of radiosensitization tO enhance the efficacy of a9Sr in the trials in which these combinations are being used.
Alpha-Emitters An alpha-emitter radiotracer has been developed at Pacific Northwest National Laboratory that is a chelate of radium 223 with a very high binding affinity. 223Ra emits 4 alpha particles as 95% of its energy, with a range of 40 to 60/xm, about 25% of the rangd of the conversion electron coming from l l7mSn. TwO fairly energetic beta particles are also emitted by 223Ra, which is a natural bone seeker without a
radon decay product. Another alpha-emitting bisphosphonate using astatine 211 is under development. No clinical trials have yet been reported with alphaemitters.
The Clinical Use of Beta- or Electron-Emitting Radiotracers There are clinical conditions in which apparent bone pain will not be reduced with these radiotracers. Epidural metastases with pressure on the spinal cord, or soft-tissue tumors elsewhere pressing on nerves, will not be affected by a tracer that irradiates bone but not the soft-tissue lesion responsible for the pain. Pathological fracture must be examined and eliminated before any of these radiopharmaceuticals are used because the resultant pain will not be reduced. 23 It is essential that a bone scan be performed before administration of these radiotracers because there will not be selective localization of these unsealed sources in the absence of increased uptake on bone scan at the painful site. A normal bone scan suggests another cause for the patient's bone pain. It is difficult to predict responders to these therapeutic radiopharmaceuticals once one has eliminated the causes of nonresponse noted earlier. A higher Karnofsky (performance) scale in some 2~ (but not all23) series has suggested a greater chance of a response. There have been, however, impressive responses in bedridden terminal patients, and the author does not believe these radiopharmaceuticals should be withheld unless the patient is moribUnd. EveW day of improved quality of life is precious to the patient and his/her family. The occurrence and severity of cytopenia caused by the radiotracer does not correlate well with pain relief.23 The presence of narcotic tolerance does not give any indication as to whether the radiotracer will have a therapeutic effect.23 With most radiotracer studies there has been no significant dosage-activity response to suggest that higher dosage of these radiopharmaceuticals will be more efficacious.6 Teletherapy is recommended: when there are 1 or 2 painful metastases, in the presence of impending spinal cord compression, as prophylaxis or treatment of pathological fracture, and to treat pain resulting from soft-tissue tumor extending to bone. In all of these instances the therapeutic radiopharmaceuticals will not be helpful. These radiotracers should not be given within 4 weeks of most myelosuppressive chemotherapy or wide-field teletherapy. Beta, electron, or low-energy photon-emitting ra-
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diopharmaceuticals are contraindicated when there is a nonosseous cause for the pain as described earlier; if the bone scan is negative at the painful site; if there is significant leukopenia or thrombocytopenia; if a pathological fracture is present; in the presence of disseminated intravascular coagulation when platelet turnover is already high and a reduction in megakaryocytes can lead to a rapid and severe thrombocytopenia. These radiotracers are most useful in the presence of multiple painful metastatic osseous sites when increased radiotracer uptake on bone scan correlates with the sites of pain. They will also be useful when there is recurrent pain in local or wide-field teletherapy sites and further teletherapy is contraindicated.
Practical Aspects of Therapy These agents should be injected through a running intravenous line; a plastic syringe shield should be used because it reduces bremsstrahlung, unlike a lead shield. This policy avoids subcutaneous infiltration and reduces the radiation dose to the hands of the administering physician who then does not have to spend time attempting a venipuncture. Infusion should be slow, over 1 to 2 minutes because a9Sr can mimic the cardiovascular effects of calcium if given rapidly, whereas chelates such as lexidronam can bind intravascular free calcium and magnesium, acutely lowering these blood levels. Current Nuclear Regulatory Commission guidelines permit release of these patients to their homes after treatment. Careful handwashing and avoidance of urinary contamination are required. Table 3 summarizes guidelines for administration of these unsealed beta-electron emitters. 47
Future Study Considerable research will be required to answer many outstanding questions and concerns about Table 3. Administering Unsealed Beta Emitters The painful site must correspond to an area positive on a bone scan performed within 3 to 4 weeks Platelet and leukocyte counts must be adequate Informed consent form should be signed Inject through a running intravenous line Use a finger dosimeter when injecting Inject slowly over 1 to 2 minutes A plastic syringe shield, not a lead shield, should be used
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therapy of bone pain with unsealed sources. We do not yet know if life can be prolonged, although data from several studies suggest that this does not occur. 4,48 We do not know how to predict who will respond to these injected radiopharmaceuticals, with conflicting data regarding whether better performance scale scores translate into higher response rates. Which radiopharmaceutical provides the optimal response? Meaningful comparative studies will require hundreds of patients per study arm to avoid the type II error of assuming no difference in response when one exists. What is the optimum administered activity of each of these radiotracers? With higher administered activity myelotoxicity is increased, and only a minority of studies show improved response rates with the higher dosage. Dose rate effects and the efficacy of split doses have not yet been studied. The combinations of these radiotracers with chemotherapeutic agents and with bisphosphonates must be examined. There could be a role for alpha-emitting radiotracers in this field. In asymptomatic patients with bone metastases there may be an important adjuvant role for beta, electron, or low-energy photon-emitting radiopharmaceuticals, but such studies have not yet been published. The equivalence found for oral 32p and ~gSr; with only minimally more, and clinically insignificant, 32p toxicity, 2~ requires a reexamination of this far less expensive radiopharmaceutical and route. The techniques of tumor and marrow dosimetry with these agents have still not been completely worked out. The mechanisms of action of the radiotracers is not understood. We do not even know the optimum tool to measure outcome.
Conclusion Radiopharmaceuticals with affinity for reactive bone and that emit electron, beta particles, or low-energy photons will reduce or eliminate the pain ofosteoblastic metastases with 55% to 80% effectiveness. The variability in measurement techniques for partial responses causes this wide variation in response rate. Side effects include a brief flare of pain about 10% to 20% of the time and mild to moderate pancytopenia. This therapy may be repeated 2 or more times (every 9 to 12 weeks) because the effect on pain reduction lasts only weeks to months.
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