internal radionuclide therapy of primary osteosarcoma in dogs,...

3148s Vol. 5, 3148s-3152s, October 1999 (Suppl.) Clinical Cancer Research

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

M a g n e Aas , 2 Lars M o e , H a n s G a m l e m ,

A r n e Skret t ing , N ina Ottesen , and

O y v i n d S. B r u l a n d

Norwegian Radimn Hospital [M. A., A. S., 0. S. B.]; Norwegian School of Veterinary Science [L.M., N. O.]; and National Veterinary Laboratory [H. G.], Oslo, Norway

Abstract

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 com- bination with surgery, lS3Sm-EDTMP may prolong life sig-

nificantly 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 10.7- 11.5%, 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 rea- sons, 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 he- moglobin, 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.

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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. injec-

tions of 153Sm-EDTMP (a gift from MAP Medical Technolo-

gies 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. Some- times a mixture of the two was present.



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.

Results The total WBC and RBC counts as well as PLT counts in

most cases showed a moderate and transient decrease followed by a complete recovery of hematological parameters within 5 weeks. The lowest WBC and PLT counts were recorded 21-23 days after injection in three of the dogs (cases 12, 13, and 14) that received the highest dose of 153Sm-EDTMP per kg. The

nadir values for WBC counts were 1.9 • 109/liter to 3.4 •

109/liter; the nadir values for PLT counts were 28 • 109/liter,

37 • 109/liter, and 41 • 109/liter. Other biochemistry and

hematology values were within the normal range. No infection,

bleeding, or any other toxicity was observed.

All tumors showed rapid and similar uptake of both of the bone-seeking radiopharmaceuticals, 99mTc-methylene-diamino-



Clinical Cancer Research 3 1 5 1 s

Table 3 Outcome of 15 dogs with spontaneous OS treated with 153Sm-EDTMP

No. of Time from first Pain Case no. treatments Outcome treatment to death relief a Pattern of metastasis revealed postmortem

1 2 Relap-Eu b 7 months + + + Lungs micro, reg. 1. n. 2 1 Path fract-Eu 4 weeks + Lungs 3 1 Path fract-Eu 4 weeks + + No 4 1 PR-Eu 2.5 months 0 Reg. 1. n. 5 1 Progr-Eu 3 weeks + + + Femur and lungs micro 6 C 2 DF (48 mo)-met-Eu 50 months + + + Lung with growth into the left atrium

after 4 years; kidney arteries micro 7 2 Remis-Relap-Eu 23 months + + + Lungs 3-ram nodule and micro 8 4 SD-Eu 9 months + +(+) Liver, reg. 1. n. (seminoma mets?) 9 2 Progr-Eu 2 months + + Lungs 3-mm nodule and micro

10 1 SD-Eu 4 weeks + + No 11 c 2 Remis-Dead 5 months ND Multiple in liver, spleen, peritoneum

(hemangioma?) 12 1 Progr-Eu 6 weeks + No 13 2 Remis-Relap-Eu 11.5 months + Multiple in lungs 14 C 3 Remis-Relap-Path fract-Eu 6 months + + Multiple in lungs, in muscle of hindleg,

kidney, ileofemoral lymph node 15 1 Progr-Eu 3 weeks 0 No

Pain relief graded from 0 to + + +: 0, no effect; +, improvement of limb function and slightly reduced pain on tumor palpation; + +, markedly improved limb function and markedly reduced pain on tumor palpation; + + +, normal weightbearing and no pain sensation on palpation of the tumor.

h Relap, relapse; Eu, euthanasia; micro, microscopic; reg. 1. n., regional lymph nodes; Path fract, pathological fracture; PR, poor response; Progr, progressive disease; DF, disease free; met, metastases; Remis, remission; SD, stable disease; ND, not determined.

c In cases 6, 11, and 14, surgical removal of the primary tumor was performed.

phosphonate and 153Sm-EDTMP (Fig. 1). The osteoblastic tu-

mors showed the highest uptake. In most of the dogs, some liver uptake of the radioactive samarium was observed.

Tumor size varied from 20 to 351 cm 3, the median size

being 54 cm 3 (Table 2). Tumor dose estimates were made in

three dogs. Average tumor doses after a single injection were --20 Gy but were considerably higher in some areas because of inhomogeneous uptake.

The outcomes of the treatment are shown in Table 3. The palliative effect of the samarium treatment was usually observed in

the second week after the first injection, and the improvement continued for the next 2-3 weeks in those dogs that responded favorably. In case 11, the primary tumor was removed 2 days after

the radionuclide treatment; hence, it was impossible to evaluate the full palliative effect of the samarium treatment. This dog died

suddenly from bleeding into the peritoneal cavity from liver and

spleen metastases. Nine of the dogs were euthanized and necrop- sied 3 weeks to 7 months after the first treatment because of poor

response, progression of the disease, or pathological fracture. Six of these, however, had obvious pain relief, and two of them seemed free of pain for some time (one for several months). In two of the

six dogs (cases 2 and 3) the leg fractured because of weight-bearing stress after relief of pain. One dog (case 8) was euthanized because of other diseases (urine retention, prostatic hypertrophy, dermatitis) after 9 months of stable OS disease. Metastases to the liver and to

regional lymph nodes in this case were diagnosed histologically as possible seminoma metastases. One dog (case 7) who had a 20- month remission, was euthanized after 23 months because of relapse but had no signs (radiography and scintigraphy) of lung metastases. The dog that underwent the hemimaxillectomy (case 6)

was free of disease for 4 years after the first treatment (15). It then presented with hypertrophic osteopathy that severely affected all four legs. Lung lesions were suspected as the cause of the osteopathy, and a solitary lung/heart mass was disclosed on radiography.

Table 4 Biodistribution of radioactivity in dogs with spontaneous OS after i.v. injection of 153Sm-EDTMP

Case no. 9 8 15

Hours postinjection 42 h 20 h 48 h

Organ Organ/blood ratio ~'

Central part of tumor 5232 Peripheral part of tumor 910 Normal bone 465 Skin 25 Subcutaneous tissue 2 Liver 930 Lung tissue 80 Lung metastasis 985 Thyroid gland 2609 Lymph node unaffected side 117 Lymph node affected side 197

223 35

1

0.3

800 2754

820 10

"The radioactivity is expressed as the ratio of cpm per gram of tissue versus cpm per gram of whole blood. The blood sample was taken at the time of euthanasia (case 9) or at the time of surgery or biopsy.

The diagnosis was confirmed by necropsy after euthanasia. There was a single OS metastasis in the lung close to the heart. The metastasis had grown from the lung tissue via a vein into the left atrium of the heart, a very rare location for a tumor in dogs. The

part of the metastasis that was in the atrium measured 3 - 4 cm in diameter. Thus, it must have compromised the cardiopulmonary circulation significantly. Microscopic examination of vessels in the

lung and renal tissue revealed aggregation of tumor cells similar to those found in the gross metastasis. The surgically treated dog with tumor in the ulna (case 11) was li'ee of disease until it died suddenly

5 months after the radionuclide treatment. The necropsy showed metastasis to several organs, mainly the liver, peritoneum, and spleen. Macroscopic metastases from OS were detected in distant



3152s ~53Sm-EDTMP Treatment of Canine OS

organs in seven of the dogs. One of these, case 11, which died

suddenly, was frozen before necropsy. The histological evaluation

was difficult, and the metastases were diagnosed as possible he-

mangiosarcoma.

The median and mean survival times f rom the first treat-

ment to death were 150 and 252 days, respectively.

The distribution of radioactivity in some tissues is shown in

Table 4. The radioactivity was cleared rapidly from the blood. The

highest organ/blood ratios were found in tumor tissue with osteoid

production, often in the central part of the tumor, and in the

spongiosa of normal bone. A very heterogeneous activity pattern

was seen, however, throughout the tumor. The lowest tumor con-

centrations were higher than the highest normal bone concentra-

tions. A rather high level of radioactivity was found in the fiver and

sometimes in the thyroid gland, whereas the concentration in skin,

s.c. tissue, and normal lung tissue was low.

Lung metastases and liver tissue showed the same concentra-

tion as the lower bone tumor concentration. Lung metastases with

a diameter of 6 - 1 0 m m (case 13) were not seen in whole-body

scintigrams immediately before euthanasia. No in vitro measure-

ments of the radioactivity in these metastases were done.

Discussion The long-term clinical benefit of radiotherapy is usually

dependent on the radiation dose deposited in the tumor. The

targeting ability of 153Sm-EDTMP depends on the neovascular-

ization and the calcification of the tumor. Hence, the OS cases

that will benefit most f rom this type of radionuclide treatment

are probably the osteoblastic/sclerotic subtype, where the tumor

cells produce abundant osteoid without larger necrotic or fi-

brotic parts. Despite that, several of the dogs in this series that

were classified as having mainly osteolytic OS had at least some

pain relief. The failure to induce complete remission without

surgery, except in two dogs, may be explained by the large size

of the primary tumors, the heterogeneity within the tumor tissue,

and the uneven distribution of radioactivity in the different parts

of the tumor. An increased radiation dose to the tumor would

probably improve the results. This can be achieved in several

ways. Because the toxicity seems very low, the injected amount

of radioactivity can be increased, and/or a local injection of the

radiopharmaceutical , either directly into the tumor or via the

local artery, would increase the tumor uptake.

Because --80% of OS cases have metastases in the lungs

detectable by radiography at 6 months after amputation alone (3, 4),

it is likely that 153Sm-EDTMP treatment prevented or at least

slowed the growth of OS metastases in some of the dogs that

survived more than 4 months after radionuclide treatment. A pos-

sible explanation for the liver uptake is colloid formation, whereas

the thyroid uptake is more likely due to free radioactivity.

Conclusion. High tumor doses may be deposited in OS lesions by 153Sm-EDTMP, and the ratio between tumor dose

and the dose to surrounding tissues is favorable. The treatment

gives pain relief and in some cases significant tumor growth

delay. In combinat ion with surgery, ~53Sm-EDTMP may pro-

long life significantly and possibly cure the disease because the

development of metastases is seemingly postponed.

Acknowledgments The ~5~Sm-EDTMP was a gift from MAP Medical Technologies

OY, Espoo, Finland.

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1999;5:3148s-3152s. Clin Cancer Res Magne Aas, Lars Moe, Hans Gamlem, et al. Sm-Ethylene-diamino-tetramethylene-phosphonate (EDTMP)

153Dogs, Using Internal Radionuclide Therapy of Primary Osteosarcoma in

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