chemotherapy as assessed histologically in the resectedtumor samples (9). In another study, dynamic scintigraphyusing 99mTcMDP was used to quantify blood flow andmapping of plasma clearance rates related to histologicchanges in osteosarcoma specimens, thereby providing apresurgical assessment oftumor response to chemotherapy(10). Quantitative bone scintigraphy has also been used todetect bone metastases from other primary tumors and toassess the response of these metastatic lesions to therapy(11—15).

Quantifiable factors which reliably predict tumor behavior or response to treatment have the potential to play animportant role in cancer therapy. One goal of using prognostic indicators is to identify those patients destined tofail with conventional therapy early in the treatmentperiod. Prognostic variablesfor human osteosarcoma havebeen described and include a combination of several parameters which were indicative of survival (16). Theseinclude the: histologic appearance, primary site, grade andsize, duration of symptoms, weight loss of more than 4.5kg, swelling at the primary site and radiographic appearance (16). In a study ofcanine osteosarcoma, tumor size,site and volume as well as extension into surrounding softtissues were positively related to the presence of pulmonarymetastases at necropsy (1 7). In another study in dogs, thepercent tumor necrosis in osteosarcoma specimens resected as part of limb-sparing surgery was directly relatedto probability oflocal tumor control (18).

To date, the value of quantitative bone scintigraphy inosteosarcoma patients has not been completely assessed.In theory, the biologic aggressiveness of a primary bonetumor may be reflected in bone scan parameters. Additionally, alteration in scintigraphic parameters followingtreatment may also be related to outcome. The purpose ofthis study was to assess the usefulness ofbone scintigraphyas a predictive indicator in canine patients with primary,appendicular osteosarcoma.

MATERIALS AND METhODS

Twenty-fivedogs with spontaneouslyoccurring,primary osteosarcoma of the appendicular skeleton were referred to the

Parameters that predict tumor aggressiveness or responseto therapyare potentiallyusefulin selectingthe most appropilate treatment. In theory, the biologic aggressiveness of anuntreated bone tumor may be reflected in bone scan parameters. The purpose of this study was to assess the usefulnessof bone scintigraphy as a predictive indicator of subsequentmetastasis in 25 dogs with primary osteosarcoma.Dogsreceived radiotherapy and/or intra-arterial cisplatin prior tolimb-sparingsurgery.Quantitativebone sdn@graphyof thetumor was performed prior to treatment (25 dogs) and following treatment but poor to limb-sparing surgery (22 dogs). Alldogs developed metastasis at a median time of 202 days(range, 41—444days) after initiation of treatment. A statistically significantrelationshipwas identifiedbetweentime tometastasis and: (1) the radiographic tumor area, (2) the pretreatment ratio of mean counts per pixel in tumor-to-adjacentnontumor bone (T/NTT), and (3) the pre:post-treatmentT/NTT.Largertumorareaandhighpretreatmenttumoractivity were associated with earlier metastasis. Tumors characterized by greater decreases in scintigraphic uptake aftertreatment were associated with earlier metastasis. These datasuggest that osteosarcomas with high pretreatment meancounts per pixel signify aggressive tumors subject to earlymetastasis.

J NucI Med 1992; 33:1542—1547

one scintigraphy has been used in human and canineosteosarcoma patients as a screening method for detectionof bone metastases and for evaluating primary bone tumors (1-8). More recently, quantitative bone scintigraphyhas been used to evaluate human patients with osteosarcoma. In one study, quantitative bone scintigraphy using67Ga-citrate and @mTc@methylenediphosphonate (MDP)was performed before and after neoadjuvant chemotherapy (9). Changes in tumor-to-nontumor scintigraphic ratios after chemotherapy were associated with response to

ReceivedDec.10.1991;revIsionacceptedMar.19,1992.For reprkfls contact: Donald E. Thrall, DVM, PhD, college of Veterinary

Medicine,NorthCaro@naStateLkilverslty,Raleigh,NC27606.

1542 TheJournalof NuclearMedicine•Vol.33 •No.8 •August1992

Relationship Between QuantitativeTumorScintigraphyand Time to MetastasisinDogs with OsteosarcomaLisa J. Forrest, Richard K. Dodge, Rodney L. Page, Greta L. Heidner, Margaret C. McEntee,Carol A. Novotney, and Donald E. Thrall

College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina and Duke Comprehensive CancerCenter, Duke University Medical Center, Durham, North Carolina

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College of Veterinary Medicine at North Carolina State University. These dogs were part of a multi-institutional randomizedprospective study assessing the role of radiation and/or cisplatinin limb sparing for osteosarcoma. Criteria for entrance into thistreatment protocol included the following: no evidence of metastasesat presentationand tumor involvementof lessthan 50%ofthe length of the affected bone. Tumors involved the followingsites: distal radius (n = 17), proximal humerus (n = 7) and distalfemur (n = 1). The diagnosis of osteosarcoma was confirmed bybone biopsy in all dogs.

Tumor grade was subjectively assessed in 22 of the 25 dogs;slides were misplaced in 3 dogs. Tumors were classified as highor intermediate grade. Grading criteria were: (1) mitotic rate(high, >10 per 10 400x fields, (2) presence of necrosis (high>15%, assessed subjectively), (3) degree of differentiation, (4)amount of osteoid or cartilage production, and (5) presence orabsence of vascular invasion. Mitotic rate and degree of differentiation were more heavily weighted than other criteria. Tumorswere also classified as being osteoblastic, chondroblastic or fibroblastic based on the predominant histologic feature; this waspossible in the same 22 dogs.

Radiographsof the primary tumor were made prior to treatment. As an estimate of tumor size, the product of proximaldistal and anterior-posteriormeasurementsof the tumor, takenfrom lateral radiographs, was calculated for 24 of the 25 dogs;radiographs from one dog were missing.

As part of the multi-institutional study to assess efficacy ofcisplatin ±radiation in limb-sparing procedures, each dog wasrandomized into one of three treatment protocols:(1) radiationalone (n = 7), (2) intra-arterial cisplatin alone (n = 3), or (3) acombination ofthe two (n = 15). In dogs receiving radiation, theradiation dose was randomly assigned. Total doses for the radiation only group were 36, 40, or 48 Gy. Total radiation doseswhen given with cisplatin ranged from 20 to 40 Gy in 4-Gyincrements. Radiation was given in 10 equally-sized fractions ona M, W, F schedule. Cisplatin was given as a 2-hr infusion directlyinto a major artery supplying the tumor region. Two cisplatindoses (70 mg/m2)were given 3 wk apart, immediatelyprior tothe first and last radiation treatment. Three weeks after completion of treatment, each dog underwent limb-sparing surgerywherein the primary tumor was resected and replaced with acorticalallograft.

Quantitative bone scintigraphy was performed at two times:(1) prior to any treatment (25 dogs) and (2) after treatment butimmediately prior to surgery, approximately 6 wk after the initialscintigraphy(22 dogs). For scintigraphy,the dogs receivedapproximately 740 MBq (20 mCi) of 99mTc@MDP(E.I. duPont deNemours & Co., N. Billerica, MA); this was given intravenously.Alldogswerelarge,and this dosewouldnot be expectedto oversaturate count density in a given pixel in the area of interest.Approximately 1.5—2.5hrlater, lateral views ofthe entire skeletonwere obtained using a large field of view gamma camera with a3/8 in. crystaland a parallel-holegeneralpurposecollimator(ADACMedicalImagingSystems,San Jose,CA).Quantitativeassessment of radionuclide uptake in the primary tumor wasundertaken to determine if the relative activity of the primarytumor before or after treatment was related to patient response.

Quantification of radionuclide uptake was done as follows. Aregion ofinterest (ROl) was placed around the tumor using imagesmoothing and edge detection algorithms to aid in tumor marginidentification (Fig. 1). The center of the edge determined by the

FIGURE1. Edge-enhancementimage,rightlateralforelimbofcaninepatientwith distal radialosteosarcoma.AOl denotingtumor is placedin the centerof the edge.

algorithm was defined as the tumor margin. A reference ROl wasplaced on adjacent nontumor bone on the original image (Fig.2). Lateral images ofthe contralateral normal limb were availablein 24 of the dogs. A reference ROI was constructed in thesecontralateral limb images in a location corresponding to the

tumor. For comparative purposes, a reference ROl was alsoconstructed in the contralateral limb in a location identical to thereference ROl in the tumor-bearing limb. Counts per pixel weredetermined for each ROl and the following ratios were calculated:(1) T/NTT, ratio ofcounts per pixel in tumor ROl-to-counts perpixel in reference ROl in tumor-bearinglimb(calculated pretreatment and post-treatment) and (2) T/NTC, ratio of counts perpixel in tumor ROl-to-counts per pixel in contralateral referenceROl correspondingto tumorlocation(calculatedpretreatmentonly). The pretreatment T/NTT, pretreatment T/NTC, posttreatment T/NTT and the ratio of pre:post-treatment T/NTTwere used in the subsequent statistical analysis.

FIGURE2. Originalimage,rightlateralforelimbofsamecaninepatientas inFigure1. ROldenotingdistalradialosteosarcoma(definedfrom Fig. 1) and normaladjacentboneare illustrated.

1543QuantitativeScintigraphyinOsteosarcoma•Forrestet al

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between post-treatment T/NTT and time to metastasis.After adjusting for radiation dose, cisplatin use and site oftumor in a Cox regression, both pretreatment T/NTT andpre:post-treatment T/NTT retained their significant association with time to metastasis (p = 0.04 and 0.003,respectively). Additionally, following this adjustment, therelationship between T/NTC and time to metastasis wasnearly significant (p = 0.08).

The tumor area ranged from 1092 to 9500 cubic mm.There was a significant relationship between tumor areaand time to metastasis (Fig. 5) both without (p = 0.01)and after (p = 0.005) adjustment for radiation dose, cisplatin use and tumor site. In a univariate analysis, therewas not a significant association between tumor area andpretreatment T/NTT or T/NTC. Therefore, larger tumorsdid not have higher count/pixel values.

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FIGURE5. Scatterplotoftimetometastasisasa funCtiOnoftumor area.

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Alldogsunderwentthoracicradiographyat initialpresentationand at all re-checkvisitsto assesspulmonary metastaticdisease.Qualitative whole-body nuclear bone scans were done after limbsparing surgery to assess skeletal metastasis. Any metastatic disease was noted and the time from start of treatment until detection calculated. The limb-sparing site was also assessed clinicallyand radiographically.Any evidenceof local recurrence,such asthe presence of a mass or aggressiveradiographic lesion, wasbiopsied and assessed histopathologically. Postmortem examinations were done on all dogs and any suspected metastatic lesionwasconfirmedhistopathologically.

The endpoint of interest in this study was time to metastasis.The followingindependentvariableswereanalyzedusingthe Coxproportional hazards regression model (19) for relationship totime to metastasis:pretreatment T/NTT, pretreatment T/NTC,post-treatment T/NTT, pre:post-treatment T/NTT, tumor area,tumor gradeand histologicsubtype.MultivariateCox regressionanalysis of: (1) pretreatment T/NTT, (2) pretreatment T/NTC,(3) pre:post-treatmentT/NTT and (4) tumor areato time tometastasis was performed by adjusting for radiation dose, cisplatin use and site of tumor. Scatter plots of: (1) pretreatmentT/NTT, (2) pretreatment:post-treatmentT/NTT and (3) tumorarea with respectto time to metastasisweredrawn.

RESULTS

Metastasis was documented in all 25 dogs at a mediantime of 202 days (range, 41—444days) after initiation oftreatment. Local tumor recurrence was documented in sixdogs at a median time of 213 days (range, 87—590days)after initiation of treatment.

There was a statistically significant relationship betweenboth: (1) pretreatment T/NTT (p = 0.03, Fig. 3) and (2)pre:post-treatment T/NTT (p = 0.02, Fig. 4) and timeto metastasis. The higher the pretreatment T/NTT, orpre:post-treatment T/NTT, the shorter the time to metastasis (Figs. 3 and 4). The univariate relationship betweenT/NTC and time to metastasis was not statistically significant (p = 0. 14). There was not a significant relationship

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1544 TheJournalof NuclearMedicine•Vol.33 •No.8 •August1992

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Histologic subtype was osteoblastic in 13 dogs, chondroblastic in 8 dogs and fibroblastic in 1 dog. Tumor gradewas high in 20 dogs and intermediate in 2 dogs. There wasno significant relationship between either tumor subtypeor tumor grade and time to metastasis.

DISCUSSION

Canine osteosarcoma is similar in its biological behavior, radiographic appearance and histology to human osteosarcoma (20,21). Tumors in both species are locallyinvasive, highly metastatic to the lung and other skeletalsites and commonly occur in the metaphyseal region ofthe appendicular skeleton (20—22).Based on the manysimilarities of canine and human osteosarcoma, canineosteosarcoma is a valuable model for the study of thehuman disease (18,20,23).

Both adjuvant and neoadjuvant therapies for osteosarcoma have improved survival rates and increased thenumber ofpatients eligible for limb-sparing procedures (1,24—27).However, a question still remains regarding theoptimal treatment for osteosarcoma patients and how toidentify those patients destined to fail early in treatment.

Although the mechanism for @mTc@MDPlocalizationin bone is not completely understood, it is thought to berelated to parameters such as osteoblastic activity, rate ofbone remodeling and increases in blood flow to bone (28,29). Bone tracers will concentrate in osteosarcoma becauseof the presence of excess immature osteoid. An aggressivetumor will be more likely to be rapidly growing with highosteoblastic activity and increased vascularity (30). Therefore, an aggressive, rapidly proliferating bone tumor, witha high likelihood of metastasis, may concentrate moreradionuclide than a less aggressive tumor (31).

In this study, we identified a relationship between: (1)pretreatment T/NTT and (2) pre:post-treatment T/NTTand time to metastasis (Figs. 3 and 4). The relationshipbetween T/NTC and time to metastasis was nearly significant after adjusting for radiation dose and cisplatin use (p= 0.08). These scintigraphic findings suggest that more

aggressive osteosarcomas accumulate greater amounts of99mTc-MDPand metastasize sooner than tumors whichaccumulate less 99mTcMDP Although the exact mechanism for the relationship between pretreatment bone scanparameters and time to metastasis remains unknown, tumors with high pretreatment T/NTT may indeed signifya more aggressive, rapidly growing, well perfused tumor,and one prone to early distant metastasis.

We used both radiographically normal bone in theipsilateral limb and bone in the contralateral limb corresponding to the tumor location as reference ROIs. It is notclear which is most appropriate. Convention would suggestthat contralateral bone tumor location be used as thereference ROI. However, altered weight bearing in thecontralateral normal limb, due to pain in the tumorbearinglimb, may alter bone activity therein. Additionally,the tumor may have altered scintigraphic parameters in

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FIGURE6. Counts/pixel/unittimeinnormalboneinthenontumor-bearinglimb as a functionof counts/pixel/unittime inradiograph@ly normalbone in the tumor-bearinglimb.The ROlwasdrawninthecontralaterallimbinthesamelocationusedfordeterminationof normalboneROl in the tumor-bearinglimb.Although counts/pixel in the tumor-bearing limb are generallyhigherthan in the contralaterallimb,there is a statisticallysignificantrelationshipbetweenlimbs.Thissuggeststhat anyalterationof ipsilateralboneactivityby the tumorwas uniformbetweendogs and supports the use of the ipsilateralbone AOl for reference.

the radiographically normal portion of the tumor-bearingbone, e.g., by an increase in bone blood flow. However, incomparing normal bone counts/pixel/time in the tumorbearing limb to normal bone counts/pixel/time in a comparable location in the contralateral limb, there was asignificant correlation (Fig. 6). This suggests the tumoreffect on alteration ofbone uptake of radiopharmaceuticalin the ipsilateral limb was uniform between dogs.

In a univariate Cox analysis, a ratio of counts per pixelin the tumor ROl-to-counts per pixel in the contralaterallimb ROl corresponding to the tumor location (T/NTC)was not statistically related to time to metastasis (p =0. 14). After correcting for radiation dose and cisplatin use,however, the relationship between T/NTC and time tometastasis was nearly significant (p = 0.08). Therefore,there is a trend for tumor counts per pixel expressedrelative to both ipsilateral normal bone, and contralateralnormal bone in the location corresponding to the tumor,to be related to time to metastasis. Both T/NTT and TINTC show a relationship to time to metastasis and additional assessment of this method would appear to beindicated.

The finding ofan inverse relationship between pre:posttreatment T/NTT and time to metastasis suggests thatgreater decreases in scintigraphic activity following cytotoxic treatment of osteosarcoma does not necessarily reflect a favorable prognosis. The relationship between highpre:post-treatment T/NTT values and time to metastasisis probably a reflection of the high pretreatment traceruptake in tumors prone to metastasis and the likelihood

1545Quantitative Scintigraphy in Osteosarcoma •Forrest et al

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that undetected metastasis had occurred and was moreadvanced in such tumors before treatment was initiated.The finding of a lack of relationship between post-treatment T/NTT and time to metastasis suggests that thesignificant pre:post-treatment T/NTT value was essentially a manifestation of the pretreatment value.

In this study, we also identified an inverse relationshipbetween tumor area and time to metastasis (Fig. 5). Anassociation between tumor size and metastasis in human(16) and canine (17) osteosarcoma has been reportedpreviously. In the human study, tumor size was found tobe a predictor of survival, with largertumors being associated with more patient deaths and more rapid tumorprogression and/or recurrence (16). In the canine study, alarger tumor size was associated with an increased mcidence of pulmonary metastasis (1 7). In this study, tumorsize was shown to be related to time from treatment todetection of metastasis. It is not surprising that larger, andpresumably more advanced, osteosarcomas would be associated with a greater incidence, and earlier detection, ofmetastasis. However, there was not a significant univariate relationship between tumor area and pretreatmentT/NTT. Therefore, large tumors did not have significantlyhigher mean counts per pixel and the relationship betweenthe scintigraphic findings and time to metastasis is notsimply another manifestation of tumor size.

Most predictive factors in osteosarcoma that have beenshown to have a bearing on response to treatment, such aspercent necrosis (18,24,25,32—39)or change in tumorvascularity (40), are predictors that have been measuredafter surgery. The availability of a pretreatment or presurgical predictor of tumor response may allow earlieridentification of patients destined for failure and implementation ofalternative modes oftreatment. For example,

FIGURE7. Kaplan-Melercurvesdepictingtimeto metastasisfor dogsgroupedby pretreatmentT/NTTvalues<11.0 versus?:11.0. lime to metastasis is significantlyshorter in dogs withthehigherT/NTTvalues.Thecutpointof I 1.0y@ldedthemaximalseparationof timeto metastasisbetweenany two T/NTTgroups.

in this study when time to metastasis was compared indogs with pretreatment T:NTT ratios <1 1 versus 11,a significant difference was found with time to metastasis being shorter in dogs with the higher T/NTT value(Fig. 7).

The effect of chemotherapy on development of metastasis in this study must be addressed because seven dogsdid not receive cisplatin. In the 18 dogs that receivedcisplatin, the dose intensity was relatively low, i.e., onlytwo intra-arterial injections at 70 mg/rn2. In addition, in aCox modelwherecisplatinuse wasconsidered,therewasstill a significant relationship between both pretreatmentT/NTT and pre:post-treatment T/NTT and time to metastasis. However, the absolute effect of chemotherapy inthis study is not known with certainty. Additionally, intreatment of human osteosarcoma patients where chemotherapy dose intensity will be much higher, the relationshipof pretreatment bone scan parameters and time to metastasis may be different. Nevertheless, data reported herein

suggest that assessment of human osteosarcoma aggressiveness by quantitative bone scintigraphy may have value,either alone or in concert with other assessments of tumorresponse, in predicting the development of metastatic disease.

ACKNOWLEDGMENT

Supportedby grant number CA29582fromthe NationalCancer Institute.

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1547Quantitative Scintigraphy in Osteosarcoma •Forrest et al

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1992;33:1542-1547.J Nucl Med.   Donald E. ThrallLisa J. Forrest, Richard K. Dodge, Rodney L. Page, Greta L. Heidner, Margaret C. McEntee, Carol A. Novotney and  with OsteosarcomaRelationship Between Quantitative Tumor Scintigraphy and Time to Metastasis in Dogs

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