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[153Sm]EDTMP: A potential therapy for bone cancer pain
[lS3Sm]EDTMP:
A Potential Therapy for Bone Cancer Pain Richard A. Holmes
Reactor-produced samarium-153 (lS~Sm) is both a beta and gamma emitter with a physical half-life of 46,3 hours. When complexed with EDTMP, more than 50% of the administered dose localizes in bone. Atherapeutic trial on patients with painful bone metastases performed at the University of Missouri produced
relief in 65.4% of the patients who were evaluable. M y e l o t o x i c i t y w a s mild and t r a n s i e n t . For [IS3Sm]EDTMP to attain clinical utility, studies demonstrating its efficacy as an analgesic must be performed to exclude a "ligand analgesic effect." Copyright 9 1992 by W.B. Saunders Company
ORE THAN 50% of patients afflicted with the three most common adult neoplasms-lung, breast, and prostate--will develop skeletal metastases that can lead to progressive pain. Interventional cancer therapy has increased the longevity of cancer patients and the complication of skeletal metastases will certainly become a greater problem. Rarely are skeletal metastases life threatening and their treatment objectives are pain palliation, reduction of narcotic medication, and maintenance of motion. Reduction in tumor mass or growth rate would be an optimistic potential for any mode of therapy. External beam irradiation is a highly effective means of pain relief and may occasionally demonstrate reduction in tumor mass. Unfortunately, skeletal metastases are rarely unifocal and to irradiate multiple lesions generally relies on the systemic administration of a therapeutic agent with a propensity to concentrate in these skeletal metastatic sites. Therapeutic radiopharmaceuticals administered intravenously have been used for several decades to palliate pain from skeletal metastases. 1-6 They have included phosphorus-32 (32p), rhenium-186 (~6 Re), yttrium-90, and iodine131. All emit beta particles during each decay event. Beta particles have short ranges in tissues, depositing all of their energy within a few millimeters from their point of emission to deliver a highly localized radiation dose. Except for 32p and strontium-89, all of the radionuclides have required chelation to a ligand possessing the property to concentrate in malignant bone lesions. Since none of these agents have demonstrated ideal characteristics either clinically or chemically, and earlier studies reported by O'Mara 7 demonstrated that the basic oxide of samarium-153 (1535m) formed a stable complex with hydroxyethylethylenediaminetriacetic acid
and showed good skeletal uptake when injected into rabbits, further work was indicated. For his doctoral thesis Goeckeler, at the University of Missouri Research Reactor, 8 successfully complexed the lanthanide, 153Sm, to several groups of phosphonate ligands. Under strictly controlled and optimum conditions, all of the studied ligands complexed 153Smin high yield. Of the complexes, 153Sm ethylenediaminetetramethylene phosphonic acid (EDTMP) not only produced a stable complex in high yield, but it also demonstrated some of the highest skeletal concentration in test animals. 8 The evolution of [153Sm]EDTMP as a potential therapy for metastatic bone cancer is addressed in this report.
M
THE RADIOPHARMACEUTICAL
Radionucfide
Samarium-153 is reactor produced at the University of Missouri Research Reactor by neutron irradiation (flux 1 x 10TM n/cm 2 s) of 99.06% enriched ~5:Sm2O3 for a period of 50 to 60 hours yielding ~'Sm with a specific activity of 1,000 to 1,300 Ci/g. One to four M HC1 is added remotely to dissolve the irradiated Sm203. The solution is then diluted to the appropriate volume with water and transferred by syringe to a clean glass serum vial as stock solution for complexation.9 Samarium-153 is a beta emitter (Ema~+ 640; 710 and 810 Key) with a physical half-life of 46.3 hours and an average penetration range of 0.83 mm in water, s It also emits a 103.2-keV gamma photon with 28% abundance. Radionuclidic purity is practically 100%. From the Medicine Department, King~Drew Medical Center, Los Angeles, CA. Address reprint requests to Richard A. Holmes, MD, Medicine Department, Room 4015, King~Drew Medical Center, 12021 S Wilmington Ave, Los Angeles, CA 90059. Copyright 9 1992 by W.B. Saunders Company 0001-2998/92/2201-0006505.00/0
Seminars in Nuclear Medicine, Vol XXII, No 1 (January), 1992: pp 41-45
41
42
RICHARD A. HOLMES
Ligand EDTMP (Fig 1) was obtained from the Dow Chemical Co, Freeport, TX. Synthesis of EDTMP was by the method of Moedritzer and Irani 1~using commercially available precursors. Because of EDTMP's potential for chelating calcium and magnesium, a new formulation of the chelate was prepared that contained calcium salt (referred to as the Ca/Na formulation). When this preparation was evaluated in mice there was significant improvement in the median lethal dose of the Ca/Na ligand) ~
Complexation Samarium-153 is complexed with EDTMP in a single step by adding 153Smin 0.1 NHCI to a freeze-dried, sterile, pyrogen-free preparation of EDTMP. ~2 Analysis of the [153Sm]EDTMP complex in solution using ion exchange chromatography and high-pressure liquid chromatography confirmed the presence of a single chelate species with a 1:1 metal-to-ligand ratio. ~2'~3The percent of complexed 153Sm always exceeded 99% and showed excellent chemical stability and no measurable decomposition for at least 48 hours postcomplexation. ~2
Biodistribution The biologic distribution of [~S3Sm]EDTMP after intravenous injection has been studied in rodents, rabbits, and dogs. 9'12'14By 2 to 3 hours, 50% to 66% of the administered dose localized in bone with 33% to 50% found in urine. When urinary excretion was experimentally compriraised, a larger fraction of the administered dose was deposited in the skeleton. Less than 2% of the activity was present in nonosseous tissues, with the most prominent organ being the liver. ~4 In normal dogs autoradiographic studies indicated that [153Sm]EDTMP tended to concentrate in trabecular rather than cortical bone.15 Estimates of activity ratios in experimen-
HO~O
j CH2 ~ HO HO~O / ~PCH HO / 2
O .OH
/ N-CH -CH -N 2 2 X
CH2
OH 0 .OH CH P~'~ 2 ~OH
Fig 1. Chemically, EDTMP monohydrate is [CH2N (CH 2 P O 3 H2)v H20 with a molecular weight of 454,15 D.
tal bone lesions compared with normal bone have ranged from 4:1 to 17:1.15'16 Transient myelotoxicitywith complete bone marrow recovery was observed in a series of normal dogs given up to 2.0 mCi/kg (74 MBq/kg) of [153Sm]EDTMP.15 Applebaum et al ~4used much higher doses, up to 30mCi/kg, in normal dogs to determine if it would produce permanent marrow aplasia; however, 11 of the animals unexpectedly demonstrated spontaneous bone marrow recovery that the investigators attributed to the uneven distribution of [~53Sm]EDTMP throughout the skeleton.
ANIMAL AND HUMAN STUDIES Tumor in Dogs Dogs with primary bone sarcomas (osteogenic sarcomas, fibrosarcomas) were studied by Lattimer et al, 17who treated them with either a single (1.0 mCi/kg) or two intravenous doses of [153Sm]EDTMP given 1 week apart. Seventyeight percent of the 40 tumor dogs exhibited pain palliation that was reflected in improved locomotion and deglutition when the tumors were located in an extremity or in the jaw, respectively. Seven dogs became disease free using [153Sm]EDTMP alone (5 dogs) or in conjunction with amputation (2 dogs). Regression of tumor mass was observed in 25 dogs and 8 dogs, generally with larger tumors and advanced disease, showed no response to the radiotherapy. Mean survival of the nonresponding tumor dogs was 0.7 months, whereas mean survival in the responding dogs was 27 months and 5 months in the partial responders. 17
Cancer Patients and Radiopharmacokinetics Singh et al, 18using a 2.0-mCi (74-MBq) dose of [lS3Sm]EDTMP in five metastatic bone cancer patients, showed identical gamma scintigraphic images compared with their technetium-99m (99mTc) hydroxyethylidene disphosphonate (HDP) bone images. Comparing the lesion with normal bone activity, ratios of the two radiopharmaceuticals gave very similar results. Samarium153-EDTMP is excreted through the kidneys with 53% of this amount occurring during the first 8 hours. 18
BONE CANCER PAIN RELIEF AND [~S3Sm]EDTMP
43
Dose Escalation and Myelotoxicity
the higher dose (1.0mCi/kg), although a transient decrease in white cells (leukopenia) was observed in some patients receiving a dose of 0.75 mCi/kg (28 MBq/kg). Like the thrombopenia, the leukopenia returned to pretreatment levels by 6 to 8 weeks. Profiles of the patients exhibiting myelotoxicity indicated that their pretreatment platelet and white cell counts were lower but still within the normal range and that most of them had extensive osteoblastic prostate cancer. Four of the prostate cancer patients developed a transient exacerbation of their pre-[153Sm]EDTMP pain beginning 2 to 3 days posttherapy and lasting 3 to 4 days. This "flare reaction" has only been observed in metastatic prostate cancer patients.
Farhangi et al ~9evaluated the dose response in cancer patients with painful metastases by performing a dose escalation study in consenting patients with histologically documented cancer. Doses of [lS3Sm]EDTMP ranged from 0.2 to 1.0 mCi/kg with groups of approximately 5 patients receiving intravenous injections at 0.35, 0.5, and 0.75 mCi/kg. Twenty-nine doses were administered to 22 patients with 2 of the patients receiving two doses and 1 patient receiving four doses. Bony lesions in the study patients did not exceed seven and, although pain palliation was not a primary objective of the study, 17 of the 26 evaluable patients (65.4%) experienced relief and their treatment courses were recorded. A graphic example from the pain diary of one of these patients showing the decrease in painful metastases is shown in Fig 2. Decrease in pain averaged from 1 to 11 months, with a mean of 3.8 months. Myelotoxicity was mild and transient (returned to baseline in 6 to 8 weeks) and was generally confined to a decrease in platelet counts. Surprisingly, the transient thrombocytopenia occurred at the midrange doses (0.35 to 0.5mCi/kg) and not at
Dosimetry The radiation-absorbed dose of [~538m]EDTMP to red marrow was calculated using formulations developed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Logan et al 2~and Turner et al2~employed the biologic distribution of []53Sm]EDTMP in experimental animals and the calculation of terms describing the radiation
PATIENT: EAR 0.2 mCi/kg 10 ,! 0--0
SITE A SITE B A - - - " , SITE C
9-
e--o
Z
I 6.,
5-
(.~
II II
~o~ O, z
Fig 2. Following the intravenous administration of 0.2 mCi/kg of [~S3Sm]EDTMP, all three pain sites decreased and codeine replaced Tylenol (acetaminophen; McNeil, Spring House, PA). This patient received four escalating dose levels, each with good results. (Motrin, ibuprofin; Upjohn, Kalamazoo, MI.)
0
:E
4000. 2000, O.
4000. ,,z, .J >-
~ :~ u
O,
-!0
0
tO
~n
DAYS POST TREATMENT
40
m
44
dose in various target organs as a function of the cumulated activity or "S" factor, which includes the emission properties of Samarium and the absorption and attenuation characteristics of its emissions in a model of the adult body developed by MIRD. 22This allows skeletal absorbed dose to be calculated from the injected dose, but does not permit the absolute quantification of normal bone or skeletal metastatic activity. Since the metastases, relative to the total marrow-bearing skeleton, contributes very little to the total bone marrow, except in extensive disease, accurate dosimetry is very improbable. This is demonstrated in Fig 3, which shows a 9-month-old child with a large, inoperable intrathoracic neuroblastoma that concentrated [99mTc]methylene diphosphonate (MDP) and subsequently was treated with [153Sm]EDTMP (1.14 mCi/kg; total dose, 9.12 mCi) for palliation. Although approximately 28% of the injected dose concentrated in the tumor mass and the patient experienced some temporary clinical relief, the estimated radiation absorbed dose to the tumor was less than 100 rad, One would
RICHARD A, HOLMES
not anticipate any clinical response to this mass of tumor if the authors' calculations were correct.
Future Developments Samarium-153-EDTMP is one of three betaemitting radiopharmaceuticals under commercial development to palliate bone cancer pain. Strontium-89, discussed elsewhere in this issue, has been effective in palliating skeletal cancer pain, 3'23 but its long physical half-life of 50.6 days, slower blood clearance, and lack of an imageable photon makes is less than ideal. [186Re]HEDP and its clinical acceptance will be decided by the time of its Food and Drug Administration approval, its commercial availability, and the simplicity of its administration. For [153Sm]EDTMP to attain clinical utility, studies demonstrating its efficacy as an analgesic must be performed to exclude a "ligand analgesic effect." Ligand analgesia can be determined in a controlled double-blind cross-over study using [~53Sm]EDTMP and a nontherapeu-
Fig 3. (Left) A 9-month-old child with proliferating intrathoracic neuroblastoma detected on diagnostic [99mTc]MDP image, (Right) Identical scintigram following therapeutic dose (1.14mCi/kg) of [153Sm]EDTMP.
BONE CANCER PAIN RELIEF AND [lS3Sm]EDTMP
45
tic radiolabeled EDTMP complex, eg, [99"~Tc]EDTMP, indium-ll3m-EDTMP). The dose escalation studies have shown a broad degree of safety and 0.75 to 1.0 mCi/kg appears to be an optimum dose range. The results of the tumor dog studies demonstrated a decrease in the number of pulmonary metastases following the administration of [~53Sm]EDTMp?r This sug-
gests that childhood osteogenic sarcoma might benefit from the administration of [153Sm]EDTMP; however, these studies await the clinical development and approval of this therapeutic radiopharmaceutical. It appears that [153Sm]EDTMP may hold the greatest clinical potential as an alternative to present methods of therapy.
REFERENCES 1. Kaplan E: Historical development of P-32 in bony therapy, in Spencer RP (ed): Therapy in Nuclear Medicine. Philadelphia, PA, Saunders, 1978, 237-249 2. Johnson DE, Haynie TP: Phosphorus-32 for untreatable pain in carcinoma of prostate. Analysis and androgen primary, parathormone, rebound and combination therapy. J Urol 9:137-139, 1977 3. Robinson RG, Spicer JA, Preston DF, et al: Treatment of metastatic bone pain with strontium-89. Nucl Med Biol 14:219-222, 1987 4. Maxon HR, Deutsch EA, Thomas SR, et al: J86Re (Sn)-HEDP for treatment of multiple metastatic foci in bone: Human biodistribution and dosimetric studies. Radiology 155:501-507, 1988 5. Kutzner J, Dahnert W, Schreyer T, et al: Yttrium-90 zur schmerztherapie von knockenmetasten. J Nucl Med 20:229-235, 1981 6. Eisenkut M, Berberich R, 'Kimmig B, et al: lodine-131labeled diphosphonate for palliative treatment of bone metastases. II. Preliminary clinical results with iodine-131 BDP 3. J Nucl Med 27:1255-1261, 1986 7. O'Mara RE, McAfee JG, Subramanian G: Rare earth nuclides as potential agents for skeletal imaging. J Nucl Med 1:49-5I, 1969 8. Goeckeler WF: The preparation and characterization of several acetate and phosphonate complexes of Sm-153 for use as radiotherapeutic bone agents. Doctoral Dissertation, University of Missouri-Columbia, MO, i984 9. Ketring A: ~S3Sm-EDTMP and ~86Re-HEDP as bone therapeutic radiopharmaceuticals. Nucl Med Biol 14:223232, 1987 10. Moedritzer K, Irani RR: The direct synthesis of x-aminomethyl phonphonic acids. Mannich-type reactions with orthophosphorus acid. J Organic Chem 31:1603-1607, 1966 11. Gerbig C, Chandler AD, Dillberger JE: Sm-EDTMP: Comparative intravenous median lethal dose (LDs0) determination of he sodium and calcium salts. Merrill Dow Report NBX 914, 1987 12. Goeckeler WF, Edwards B, Bokert WA, et al: Skeletal localization of Sm-153 chelates: Potential therapeutic bone agents. J Nucl Med 28:495-504, 1987
13. Volkert WA, Simon J, Ketring AR, et al: Radiolabeled phosphonic acid chelates: Potential therapeutic agents for treatment of skeletal metastases. Drug Future 14:799811, 1989 14. Appelbaum FR, Sandmaier B, Brown P, et al: Myelosuppression and mechanism of recovery following administration of J53Sm-EDTMP. Antibody immunoconj Radiopharmacol 1:263-270, 1980 15. Lattimer JC, Corwin LA, Stapleton J, et al: Clinical and clinicophathologic effects of samaruim-153-EDTMP administered intravenously in normal dogs. J Nucl Med 31:586-593, 1990 16. Ghiron J, Volkert WA, Garlich J, et al: Determination of lesion to normal bone uptake ratios of skeletal radiopharmaceuticals by QARG. Nucl Med Biol 18:235240, 1991 17; Lattimer JC, Corwin LA, Stapleton J, et al: Clinical and clinicopathological response of canine primary bone tumor patients to treatment with ~S3Sm-EDTMP. J Nucl Med 31:1316-1325, 1990 18. Singh A, Holmes RA, Farhangi M, et al: Human pharmacokinetics of ~53Sm-EDTMP in metastic cancer, J Nucl Med 30:1814-1818, 1989 19. Farhangi M, Holmes RA, Volkert WA, et al: ~53SmEDTMP, a radio therapeutic agent for palliative treatment of metastatic bone cancer pain. J Nucl Meal (in press) 20. Logan KW, Volkert WA, Holmes RA: Radiation dose calculations in person receiving injection of samarium153 EDTMP. J Nucl Med 28:505-509, 1987 21. Turner JH, Martindale AA, Sorby P, et al: Samaruim153 EDTMP therapy of disseminated skeletal metastasis. Eur J Nucl Med 15:784-795, 1989 22. Synder WS, Ford MR, Warner GG: Estimates of specific absorbed fractions for photon scources uniformly distributed in various organs of a heterogeneous phantom. MIRD Pamphlet No. 5. New York, NY, Society of Nuclear Medicine, 1978 23. Reddy EK, Robinson RG, Mansfield CM: Strontuim-89 for palliation of bone metastes. J Natl Med Assoc 78:27-32, 1986
A Potential Therapy for Bone Cancer Pain Richard A. Holmes
Reactor-produced samarium-153 (lS~Sm) is both a beta and gamma emitter with a physical half-life of 46,3 hours. When complexed with EDTMP, more than 50% of the administered dose localizes in bone. Atherapeutic trial on patients with painful bone metastases performed at the University of Missouri produced
relief in 65.4% of the patients who were evaluable. M y e l o t o x i c i t y w a s mild and t r a n s i e n t . For [IS3Sm]EDTMP to attain clinical utility, studies demonstrating its efficacy as an analgesic must be performed to exclude a "ligand analgesic effect." Copyright 9 1992 by W.B. Saunders Company
ORE THAN 50% of patients afflicted with the three most common adult neoplasms-lung, breast, and prostate--will develop skeletal metastases that can lead to progressive pain. Interventional cancer therapy has increased the longevity of cancer patients and the complication of skeletal metastases will certainly become a greater problem. Rarely are skeletal metastases life threatening and their treatment objectives are pain palliation, reduction of narcotic medication, and maintenance of motion. Reduction in tumor mass or growth rate would be an optimistic potential for any mode of therapy. External beam irradiation is a highly effective means of pain relief and may occasionally demonstrate reduction in tumor mass. Unfortunately, skeletal metastases are rarely unifocal and to irradiate multiple lesions generally relies on the systemic administration of a therapeutic agent with a propensity to concentrate in these skeletal metastatic sites. Therapeutic radiopharmaceuticals administered intravenously have been used for several decades to palliate pain from skeletal metastases. 1-6 They have included phosphorus-32 (32p), rhenium-186 (~6 Re), yttrium-90, and iodine131. All emit beta particles during each decay event. Beta particles have short ranges in tissues, depositing all of their energy within a few millimeters from their point of emission to deliver a highly localized radiation dose. Except for 32p and strontium-89, all of the radionuclides have required chelation to a ligand possessing the property to concentrate in malignant bone lesions. Since none of these agents have demonstrated ideal characteristics either clinically or chemically, and earlier studies reported by O'Mara 7 demonstrated that the basic oxide of samarium-153 (1535m) formed a stable complex with hydroxyethylethylenediaminetriacetic acid
and showed good skeletal uptake when injected into rabbits, further work was indicated. For his doctoral thesis Goeckeler, at the University of Missouri Research Reactor, 8 successfully complexed the lanthanide, 153Sm, to several groups of phosphonate ligands. Under strictly controlled and optimum conditions, all of the studied ligands complexed 153Smin high yield. Of the complexes, 153Sm ethylenediaminetetramethylene phosphonic acid (EDTMP) not only produced a stable complex in high yield, but it also demonstrated some of the highest skeletal concentration in test animals. 8 The evolution of [153Sm]EDTMP as a potential therapy for metastatic bone cancer is addressed in this report.
M
THE RADIOPHARMACEUTICAL
Radionucfide
Samarium-153 is reactor produced at the University of Missouri Research Reactor by neutron irradiation (flux 1 x 10TM n/cm 2 s) of 99.06% enriched ~5:Sm2O3 for a period of 50 to 60 hours yielding ~'Sm with a specific activity of 1,000 to 1,300 Ci/g. One to four M HC1 is added remotely to dissolve the irradiated Sm203. The solution is then diluted to the appropriate volume with water and transferred by syringe to a clean glass serum vial as stock solution for complexation.9 Samarium-153 is a beta emitter (Ema~+ 640; 710 and 810 Key) with a physical half-life of 46.3 hours and an average penetration range of 0.83 mm in water, s It also emits a 103.2-keV gamma photon with 28% abundance. Radionuclidic purity is practically 100%. From the Medicine Department, King~Drew Medical Center, Los Angeles, CA. Address reprint requests to Richard A. Holmes, MD, Medicine Department, Room 4015, King~Drew Medical Center, 12021 S Wilmington Ave, Los Angeles, CA 90059. Copyright 9 1992 by W.B. Saunders Company 0001-2998/92/2201-0006505.00/0
Seminars in Nuclear Medicine, Vol XXII, No 1 (January), 1992: pp 41-45
41
42
RICHARD A. HOLMES
Ligand EDTMP (Fig 1) was obtained from the Dow Chemical Co, Freeport, TX. Synthesis of EDTMP was by the method of Moedritzer and Irani 1~using commercially available precursors. Because of EDTMP's potential for chelating calcium and magnesium, a new formulation of the chelate was prepared that contained calcium salt (referred to as the Ca/Na formulation). When this preparation was evaluated in mice there was significant improvement in the median lethal dose of the Ca/Na ligand) ~
Complexation Samarium-153 is complexed with EDTMP in a single step by adding 153Smin 0.1 NHCI to a freeze-dried, sterile, pyrogen-free preparation of EDTMP. ~2 Analysis of the [153Sm]EDTMP complex in solution using ion exchange chromatography and high-pressure liquid chromatography confirmed the presence of a single chelate species with a 1:1 metal-to-ligand ratio. ~2'~3The percent of complexed 153Sm always exceeded 99% and showed excellent chemical stability and no measurable decomposition for at least 48 hours postcomplexation. ~2
Biodistribution The biologic distribution of [~S3Sm]EDTMP after intravenous injection has been studied in rodents, rabbits, and dogs. 9'12'14By 2 to 3 hours, 50% to 66% of the administered dose localized in bone with 33% to 50% found in urine. When urinary excretion was experimentally compriraised, a larger fraction of the administered dose was deposited in the skeleton. Less than 2% of the activity was present in nonosseous tissues, with the most prominent organ being the liver. ~4 In normal dogs autoradiographic studies indicated that [153Sm]EDTMP tended to concentrate in trabecular rather than cortical bone.15 Estimates of activity ratios in experimen-
HO~O
j CH2 ~ HO HO~O / ~PCH HO / 2
O .OH
/ N-CH -CH -N 2 2 X
CH2
OH 0 .OH CH P~'~ 2 ~OH
Fig 1. Chemically, EDTMP monohydrate is [CH2N (CH 2 P O 3 H2)v H20 with a molecular weight of 454,15 D.
tal bone lesions compared with normal bone have ranged from 4:1 to 17:1.15'16 Transient myelotoxicitywith complete bone marrow recovery was observed in a series of normal dogs given up to 2.0 mCi/kg (74 MBq/kg) of [153Sm]EDTMP.15 Applebaum et al ~4used much higher doses, up to 30mCi/kg, in normal dogs to determine if it would produce permanent marrow aplasia; however, 11 of the animals unexpectedly demonstrated spontaneous bone marrow recovery that the investigators attributed to the uneven distribution of [~53Sm]EDTMP throughout the skeleton.
ANIMAL AND HUMAN STUDIES Tumor in Dogs Dogs with primary bone sarcomas (osteogenic sarcomas, fibrosarcomas) were studied by Lattimer et al, 17who treated them with either a single (1.0 mCi/kg) or two intravenous doses of [153Sm]EDTMP given 1 week apart. Seventyeight percent of the 40 tumor dogs exhibited pain palliation that was reflected in improved locomotion and deglutition when the tumors were located in an extremity or in the jaw, respectively. Seven dogs became disease free using [153Sm]EDTMP alone (5 dogs) or in conjunction with amputation (2 dogs). Regression of tumor mass was observed in 25 dogs and 8 dogs, generally with larger tumors and advanced disease, showed no response to the radiotherapy. Mean survival of the nonresponding tumor dogs was 0.7 months, whereas mean survival in the responding dogs was 27 months and 5 months in the partial responders. 17
Cancer Patients and Radiopharmacokinetics Singh et al, 18using a 2.0-mCi (74-MBq) dose of [lS3Sm]EDTMP in five metastatic bone cancer patients, showed identical gamma scintigraphic images compared with their technetium-99m (99mTc) hydroxyethylidene disphosphonate (HDP) bone images. Comparing the lesion with normal bone activity, ratios of the two radiopharmaceuticals gave very similar results. Samarium153-EDTMP is excreted through the kidneys with 53% of this amount occurring during the first 8 hours. 18
BONE CANCER PAIN RELIEF AND [~S3Sm]EDTMP
43
Dose Escalation and Myelotoxicity
the higher dose (1.0mCi/kg), although a transient decrease in white cells (leukopenia) was observed in some patients receiving a dose of 0.75 mCi/kg (28 MBq/kg). Like the thrombopenia, the leukopenia returned to pretreatment levels by 6 to 8 weeks. Profiles of the patients exhibiting myelotoxicity indicated that their pretreatment platelet and white cell counts were lower but still within the normal range and that most of them had extensive osteoblastic prostate cancer. Four of the prostate cancer patients developed a transient exacerbation of their pre-[153Sm]EDTMP pain beginning 2 to 3 days posttherapy and lasting 3 to 4 days. This "flare reaction" has only been observed in metastatic prostate cancer patients.
Farhangi et al ~9evaluated the dose response in cancer patients with painful metastases by performing a dose escalation study in consenting patients with histologically documented cancer. Doses of [lS3Sm]EDTMP ranged from 0.2 to 1.0 mCi/kg with groups of approximately 5 patients receiving intravenous injections at 0.35, 0.5, and 0.75 mCi/kg. Twenty-nine doses were administered to 22 patients with 2 of the patients receiving two doses and 1 patient receiving four doses. Bony lesions in the study patients did not exceed seven and, although pain palliation was not a primary objective of the study, 17 of the 26 evaluable patients (65.4%) experienced relief and their treatment courses were recorded. A graphic example from the pain diary of one of these patients showing the decrease in painful metastases is shown in Fig 2. Decrease in pain averaged from 1 to 11 months, with a mean of 3.8 months. Myelotoxicity was mild and transient (returned to baseline in 6 to 8 weeks) and was generally confined to a decrease in platelet counts. Surprisingly, the transient thrombocytopenia occurred at the midrange doses (0.35 to 0.5mCi/kg) and not at
Dosimetry The radiation-absorbed dose of [~538m]EDTMP to red marrow was calculated using formulations developed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Logan et al 2~and Turner et al2~employed the biologic distribution of []53Sm]EDTMP in experimental animals and the calculation of terms describing the radiation
PATIENT: EAR 0.2 mCi/kg 10 ,! 0--0
SITE A SITE B A - - - " , SITE C
9-
e--o
Z
I 6.,
5-
(.~
II II
~o~ O, z
Fig 2. Following the intravenous administration of 0.2 mCi/kg of [~S3Sm]EDTMP, all three pain sites decreased and codeine replaced Tylenol (acetaminophen; McNeil, Spring House, PA). This patient received four escalating dose levels, each with good results. (Motrin, ibuprofin; Upjohn, Kalamazoo, MI.)
0
:E
4000. 2000, O.
4000. ,,z, .J >-
~ :~ u
O,
-!0
0
tO
~n
DAYS POST TREATMENT
40
m
44
dose in various target organs as a function of the cumulated activity or "S" factor, which includes the emission properties of Samarium and the absorption and attenuation characteristics of its emissions in a model of the adult body developed by MIRD. 22This allows skeletal absorbed dose to be calculated from the injected dose, but does not permit the absolute quantification of normal bone or skeletal metastatic activity. Since the metastases, relative to the total marrow-bearing skeleton, contributes very little to the total bone marrow, except in extensive disease, accurate dosimetry is very improbable. This is demonstrated in Fig 3, which shows a 9-month-old child with a large, inoperable intrathoracic neuroblastoma that concentrated [99mTc]methylene diphosphonate (MDP) and subsequently was treated with [153Sm]EDTMP (1.14 mCi/kg; total dose, 9.12 mCi) for palliation. Although approximately 28% of the injected dose concentrated in the tumor mass and the patient experienced some temporary clinical relief, the estimated radiation absorbed dose to the tumor was less than 100 rad, One would
RICHARD A, HOLMES
not anticipate any clinical response to this mass of tumor if the authors' calculations were correct.
Future Developments Samarium-153-EDTMP is one of three betaemitting radiopharmaceuticals under commercial development to palliate bone cancer pain. Strontium-89, discussed elsewhere in this issue, has been effective in palliating skeletal cancer pain, 3'23 but its long physical half-life of 50.6 days, slower blood clearance, and lack of an imageable photon makes is less than ideal. [186Re]HEDP and its clinical acceptance will be decided by the time of its Food and Drug Administration approval, its commercial availability, and the simplicity of its administration. For [153Sm]EDTMP to attain clinical utility, studies demonstrating its efficacy as an analgesic must be performed to exclude a "ligand analgesic effect." Ligand analgesia can be determined in a controlled double-blind cross-over study using [~53Sm]EDTMP and a nontherapeu-
Fig 3. (Left) A 9-month-old child with proliferating intrathoracic neuroblastoma detected on diagnostic [99mTc]MDP image, (Right) Identical scintigram following therapeutic dose (1.14mCi/kg) of [153Sm]EDTMP.
BONE CANCER PAIN RELIEF AND [lS3Sm]EDTMP
45
tic radiolabeled EDTMP complex, eg, [99"~Tc]EDTMP, indium-ll3m-EDTMP). The dose escalation studies have shown a broad degree of safety and 0.75 to 1.0 mCi/kg appears to be an optimum dose range. The results of the tumor dog studies demonstrated a decrease in the number of pulmonary metastases following the administration of [~53Sm]EDTMp?r This sug-
gests that childhood osteogenic sarcoma might benefit from the administration of [153Sm]EDTMP; however, these studies await the clinical development and approval of this therapeutic radiopharmaceutical. It appears that [153Sm]EDTMP may hold the greatest clinical potential as an alternative to present methods of therapy.
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