Internal Radionuclide Therapy of Primary Osteosarcoma in Dogs, Using lS3Sm-Ethylene-diamino-tetramethylene- phosphonate (EDTMP)

Fifteen dogs were referred because of a spontaneous bone tumor, lameness, and local pain. The osteosarcoma diagnosis was established by clinical examination, X-ray, bone scintigraphy, and histological examination of biopsy material. The tumors were located in the extremities (n = 12), scapula (n = 1), maxilla (n = 1), and the frontal bone (n = 1). The dogs were given one to four i.v. injections of ~S3Sm-labeled ethylene-diamino-tetramethylene-phosphonate (~S3Sm-EDTMP; 36-57 MBq/kg body weight). Three dogs had surgery in addition to the radionuclide treatment. Platelet and WBC counts showed a moderate and transient decrease. No other toxicity was observed. Average tumor doses after a single injection were --20 Gy, considerably higher in some areas because of inhomogeneous uptake. Macroscopically distant metastases were detected in seven dogs at autopsy. One dog died from an intercurrent disease, free of cancer, 5 months after the radionuclide treatment. None of the dogs was cured. The median and mean survival times from the first treatment to death or euthanasia were 150 and 252 days, respectively. Nine of the dogs had obvious pain relief, and five of them seemed pain-free: one for 20 months and one for 48 months. It is concluded that high tumor doses may be deposited in dog osteosarcomas by ~S3Sm-EDTMP, and the ratio between tumor dose and the dose to surrounding tissues is favorable. The treatment gives pain relief and in some cases tumor growth delay. In combination with surgery, lS3Sm-EDTMP may prolong life significantly and possibly cure the disease because the development of metastases are seemingly postponed. No serious side effects were observed. Presented at the "Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer," October 15-17, 1998, Princeton, NJ. Supported by grants from Astri and Birger Torsted's legacy, Ase Marie and Hans Peter Petersen's legacy, and the Norwegian Cancer Society. 2 To whom requests for reprints should be addressed, at Department of Nuclear Medicine, Norwegian Radium Hospital, N-0310 Montebello, Oslo, Norway. Phone: 47-22935835; Fax 47-22934607; E-mail: magne.aas @ klinmed.uio.no. Introduction OS 3 is the most common canine primary bone tumor (>85%) and represents a good model for the same disease in humans (1, 2). The appendicular skeleton is commonly affected, with the distal radius as the single most frequent site in dogs. The prognosis of canine OS is poor because of rapid growth of the primary tumor and a very high frequency of metastasis, predominantly to the lungs. After amputation, the median survival time is 18-19 weeks, the 1-year survival rate is 10.711.5%, and the 2-year survival rate is 2% (3, 4). Improved survival has been reported after the combined use of amputation and postoperative adjuvant chemotherapy (5-7). External radiotherapy as the sole treatment has shown a palliative effect (8), whereas radiotherapy prior to cortical allograft limb sparing in dogs with OS does not seem to influence the prognosis (9). In Scandinavia, amputation has not been accepted for ethical reasons, and the treatment has been analgesics followed by euthanasia, usually after 3-6 weeks. Among new therapeutic approaches in OS is the use of bone-seeking radiopharmaceuticals that are distributed through the blood stream and have bone-producing tissue as targets. A promising bone targeting agent is 153Sm-EDTMP (10, 11); its therapeutic effect is produced by short-range f3-irradiation, and ~-photons enable visualization of the lesions on bone scans. Within minutes after the injection of 153Sm-EDTMP, most OS primaries and metastases are targeted and seen as intense radionuclide accumulation on the bone scintigrams (Fig. 1). The aims of the study were to evaluate the toxicity and the palliative and therapeutic effects of IS3Sm-EDTMP on primary OS tumors and to gain information on the possible effects on the metastases. Materials and Methods Fifteen dogs of various breeds, weighing fi'om 20 to 80 kg, were referred because of lameness, local pain, and a diagnosed bone tumor (Table 1). The OS diagnosis was established by clinical examination, radiography, and histopathological examination of core biopsy material. The histological classification of OS subtypes was performed according to Pool (12). On arrival, all of the dogs received a general physical examination, and blood samples for hematology and clinical chemistry were collected. The parameters measured included total number of RBCs, WBCs, and PLTs; measurement of hematocrit and hemoglobin, and the determination of serum concentrations of alanine aminotransferase, aspartate aminotransferase, alkaline 3The abbreviations used are: OS, osteosarcoma; J53Sm-EDTMP, 153Sm-labeled ethylene-diamino-tetramethylene-phosphonate; PLT, platelet; 99mTc-MDP, 99mTc-labeled methylene-diamino-phosphonate. Research. on July 14, 2017. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 3149s Table 1 Clinical and pathological characteristics of 15 dogs with spontaneous OS Case no. Breed Sex Age (years) Body weight (kg) 1 St. Bernard F 7 80 Tibia 2 Golden retriever F 10 31 Frontal bone 3 Mixed F 12 30 Humerus 4 Alaskan malamute M 4 20 Femur 5 Rottweiler M 10.5 50.5 Humerus 6 Bearded collie F 8 19 Maxilla 7 Rottweiler F 2.2 34 Radius 8 Bullmastiff M 5.9 56 Radius 9 Doberman F 6.1 34 Ulna 10 Deerhound M 6 46.5 Femur 11 Podenco ibicenco M 7.5 27.5 Ulna 12 Bernese mountain dog M 6.5 47 Radius 13 Rottweiler M 7.5 34 Scapula 14 Leonberger M 7 55 Radius 15 Shorthaired pointer M 10 33.5 Radius Site Histopathology (OS subtype) Osteoblastic Multilobular Fibroblastic Poorly differentiated Combined Chondroblastic Osteoblastic Combined Combined Osteoblastic Combined Osteoblastic Osteoblastic Combined Fibroblastic phosphatase, creatine kinase, total bilirubin, cholesterol, plasma proteins, urea, creatinine, calcium, inorganic phosphate, sodium, chloride, potassium, glucose, carbon dioxide amylase, lipase, and bile acids. In nine cases, urine samples were collected by the owner several times every week following treatment for analysis of specific gravity and urinary enzymes ('y-glutamyl transferase and alkaline phosphatase) and creatinine. Dynamic and static bone scintigraphy were performed with a dual-head gamma camera (ADAC Genesys) after a bolus injection of 99mTc-MDP (20 MBq/kg body weight). Twelve of the tumors were localized in the legs, 1 in the scapula, 1 in the maxilla, and 1 in the frontal bone. Lung metastases were not detected in any of the dogs before treatment. In all of the dogs, the diagnosis of OS was confirmed by necropsy. Treatment. The dogs were given one to four i.v. injections of 153Sm-EDTMP (a gift from MAP Medical Technologies Oy, Tikkakoski, Finland), which emits electrons with Eoa v -0.29 MeV and a physical half-life of 46.75 h. Therapeutic injections were given 5-7 weeks apart, except in cases 8 and 13, where the first two injections were given with a 1-and 19-week interval, respectively. The amount of radioactivity varied from 36 to 57 MBq/kg body weight. The dogs were given 0.5 to 1 liter of Ringer-acetate solution as an i.v. infusion, one-third before and two-thirds after the injection of the therapeutic radionuclide. Dynamic and static scintigraphy measured the 103 keV y-photons of 153Sm. The dog with the maxillary tumor (case 6), one dog with a tumor in ulna (case 11), and one with a tumor in radius (case 4; limb-sparing, allograft) had surgical removal of the primary tumor 9 weeks, 2 days, and 4 weeks, respectively, after the first injection of 153Sm-EDTMP. The remaining dogs received the radiopharmaceutical as the sole treatment. In selected cases, the tumor doses were calculated by a technique described earlier (13). Clinical Follow-Up. The dogs were followed to euthanasia or death by regular contact with the owner, clinical examination, blood samples for measuring hematological and clinical chemistry parameters, and X-ray of the thorax. The animals were examined weekly for the first 5 -8 weeks after treatment and then monthly. Lameness, local pain of the tumor upon manual pressure, and the general condition were recorded. In Table 2 Pretreatment radiographic findings in 15 dogs with OS Case no. Dominant X-ray finding Tumor volume (cm 3) 1 Sclerotic 102 2 Not determined 26 3 Lytic 35 4 Lytic 346 5 Sclerotic 351 6 Sclerotic 79 7 Sclerotic 47 8 Mixed 20 9 Mixed 46 10 Lyric 64 11 Lyric 51 12 Lyric 21 13 Sclerotic 80 14 Mixed 59 15 Lyric 54 addition, information from the owners about food and water intake and appearance at home were recorded. Lameness Grading and Scoring for Pain Relief. Lameness was graded from 0 to 5, where 0 meant normal walking and 5 meant that the animal did not touch the ground with the affected limb. Most dogs had grade 5 at remit tance. Pain rel ief was evaluated on the basis of the lameness grading and the pain react ion on local palpation and was graded f rom 0 to + + + , where 0 was no pain rel ief and + + + was no signs of pain. Radiographs. The pretreatment radiographs were read by a radiologist, and the parameters length, width, and depth of the visible bone and tissue changes were measured to allow an estimation of the tumor volumes (Table 2). The tumor volumes were calculated according to Bieling et al. (14), using the ellipsoid formula. The tumors were classified radiographically according to the dominant pretreatment radiographic pattern in mainly sclerotic or blastic type when new bone formation and calcification of the tumor was the dominant feature and in lytic type when bone destruction was the predominant finding. Sometimes a mixture of the two was present. Research. on July 14, 2017. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 3150s 153Sm-EDTMP Treatment of Canine OS Fig. 1 Scintigraphic examination of case 12. Dynamic scintigraphy with a time-activity curve using 99mTc-MDP (A) or 153Sm-EDTMP (B), and static scintigraphy 5 h after the injection of 99mTc-MDP (C) and 18 h after the injection of ~S3Sm-EDTMP (D). Tumor in the right radius. Remaining activity in the injected vein is seen on the left side in the dynamic studies.