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Vol. 4, 61-68, January 1998 Clinical Cancer Research 61

Treatment of Metastatic Bone Pain with Tin-117m Stannic

Diethylenetriaminepentaacetic Acid: A Phase 1/1!

Clinical Study”2

Suresh C. Srivastava,3 Harold L. Atkins,

Gerbail T. Krishnamurthy, Italo Zanzi,

Edward B. Silberstein, George Meinken,

Leonard F. Mausner, Fayez Swailem,

Thomas D’Alessandro, Cora J. Cabahug,Yat Lau, Tae Park, and Stefan Madajewicz

Medical Department, Brookhaven National Laboratory, Upton, NewYork 1 1973-5000 [S. C. S., H. L. A., G. M., L. F. M.]; Departments of

Radiology [H. L. A., C. J. C.], Radiation Oncology [Y. L., T. P.], andMedicine [S. M.], State University of New York, Stony Brook. NewYork I 1790; Department of Nuclear Medicine, Veterans AffairsMedical Center, Tucson, Arizona 85723 [G. T. K., F. S.]; Departmentof Medicine, North Shore University Hospital, Manhasset, New York11030 [I. Z.]; Departments of Radiology and Medicine, University of

Cincinnati College of Medicine, Cincinnati, Ohio [E. B. S.]; andDepartment of Nuclear Medicine. Veterans Affairs Medical Center,

Northport, New York 1 1768 [T. D.]

ABSTRACT

The physical characteristics of Sn-117m combined with

the biodistribution of the compound tin-117m (Stannic, 4+)

diethybenetriaminepentaacetic acid (Sn.117m DTPA) suggestthat it should be an excellent agent for the paffiation of painfrom bony metastases. Prior work has established the dosime-try and the safety for the material in human beings. Thepresence of low-energy conversion electrons should result in

the relative sparing ofthe bone marrow while delivering a high

radiation dose to sites of bony metastatic disease. Forty-seven

patients with painful bone metastases from various malignan-

cies were treated with Sn-117m DTPA. The patients were

assigned to five different dose levels ranging from 2.64 to 10.58

MBq (71-286 pCi) per kg of body weight. Follow-up includedreview of pam diaries, performance scores, analgesic require-

ments, blood chemistries, and hematological assessment. Three

Received 4/9/97; revised 9/2/97; accepted 9/29/97.The costs of publication of this article were defrayed in part by the

payment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to

indicate this fact.

I Presented in part at the annual meeting of the Society of Nuclear

Medicine, Minneapolis, MN, June 12-15, 1995, and at the meeting on

Nuclear Oncology: Advances in Diagnostic and Therapeutic Applica-

tions, Key Biscayne. FL, February 1 1-15, 1996.

2 This work was supported by the United States Department of Energy,

Office of Health and Environmental Research, Contract DE-ACO2-76CH00016 and in part by Diatide, Inc., Londonderry, NH.

3 To whom requests for reprints should be addressed, at Medical Dc-partment, Building 801, Brookhaven National Laboratory, Upton. NY

1 1973-5000. Phone: (516) 344-4459; Fax: (516) 344-5962: E-mail:

srivastl @bnl.gov.

patients received a second treatment. There was an overallresponse rate for relief of pain of 75% (range, 60-83%) in the40 treatments that could be evaluated. No correlation was

apparent in this limited series between response rate and thefive dose levels used. The relief was complete in 12 patients

(30%). The time to onset of pain relief was 19 ± 15 days with

doses �S.29 MBq/kg and S ± 3 days with doses �6.61 MBq/kg.

Myebotoxicity was minimal, with only one patient having a

marginal grade 3 ‘NBC toxicity. On the basis of our data,

Sn-117m DTPA should be an effective and safe radiopharma-

ceutical for palliation of painful bony metastases. A large-scale

trial is warranted to evaluate it in comparison to other similar

agents.

INTRODUCTION

A variety of bone-seeking radiopharmaceuticals have been

examined for the relief of painful bony metastases. Among these

are strontium-89 chloride (Refs. 1 and 2; available as Metastron

from Amersham Healthcare, Arlington Heights, IL), samarium-

153 EDTMP (Refs. 3 and 4; Quadramet, CytogenlDuPont),

rhenium-186 HEDP (5, 6), and phosphorus-32 as sodium phos-

phate (7). All are �3-emitting compounds that are taken up by

bone with greater concentration at sites of metastasis. The only

reported significant toxicity is bone marrow depression.

We have investigated the potential of another agent. tin-

il7m (stannic, 4+) DTPA4 (Sn-b l7m DTPA), because of the

premise that the short and discrete range of the emitted conver-

sion electrons from Sn-l 17m should produce much less dam-

aging radiation effects on the bone marrow. We have previously

shown that Sn-l l7m DTPA is an avid bone seeker, and its

biodistribution is nearly identical with that of the routinely used

diagnostic bone imaging radiopharmaceutical Tc-99m MDP in

animals (8) and in humans (9). Our previous dose estimates,

based on the data obtained from the biodistribution study in

humans (9), used the software program MIRDOSE2. A newer

version, MIRDOSE3, is more sophisticated in its treatment of

bone and bone marrow dosimetry ( 10), and we have therefore

recalculated the absorbed dose using the newer program (MIR-

DOSE2 and MIRDOSE3 were kindly supplied by Michael

Stabin of the Radiation Internal Dose Information Center, Oak

Ridge Institute for Science and Education. Oak Ridge. TN).

An earlier publication detailed the results of a pilot study in

15 patients (I 1 assessable) that indicated that pain palliation was

achieved through administration of Sn-ll7m DTPA at 7 1-143

4 The abbreviations used are: DTPA. diethylenetriaminepentaacetic acid:HFIR, high-flux isotope reactor: HFBR, high-flux beam reactor: EDTMP.

ethylenediamine tetramethylene phosphonate: HEDP. hydroxyethylidene

disodium phosphonate: MDP. methylene diphosphonate.

Research. on March 12, 2021. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

http://clincancerres.aacrjournals.org/

62 Treatment of Bone Pain with Sn-ll7m DTPA

Table 1 Primary cancers of patients receivin g Sn-117m (4+) DTPA

Primary site No.

Prostate 30�Breast 7Lung 7

Kidney 1

Pancreas 1

Unknown 1

a Th ree patients were treated twice.

p.Ci/kg levels (ii). Another recent study (12) was aimed at

elucidating the pharmacokinetics and imaging characteristics of

Sn-l 17m DTPA in 17 patients with metastatic bone pain. The

present study was undertaken to evaluate the toxicity, safety,

and efficacy in a total of 47 patients (including 15 patients from

the earlier study) from incremental doses of Sn-i 17m and to

assess pain response, efficacy, and hematological parameters

relative to the administered Sn-i i7m and relative to the calcu-

lated marrow dose.

PATIENTS AND METHODS

A neutron inelastic scattering reaction (n,n’-y) was used to

produce Sn-i 17m from an enriched (84%) Sn-i i7 target in the Oak

Ridge National Laboratory HFLR or in the Brookhaven National

Laboratory I-IFBR. Specific activity at the end of the bombardment

averaged 81.4 MBq/mg (2.2 mCi/mg) from the high-flux beam

reactor and 292.3 MBq/mg (7.9 mCi/mg) from the HFIR.

The irradiated tin metal target was dissolved in concentrated

HC1 with heat and then added to a 20-fold molar excess (over tin)

of the acid salt of DTPA. The pH was adjusted to 6 with NaOH,

and the solution was heated to 100#{176}Cfor 30 mm to ensure complete

complexation of tin. After cooling, a 2-fold equivalent excess of

30% H2O2 (over tin) was added, and the sample was reheated in a

boiling water bath for S mm. An 80% molar equivalent amount of

CaC122H2O (based on DTPA) was added after cooling. The prep-

aration was then sterile filtered and/or autoclaved at 120#{176}Cfor 30

mm. Radiochemical purity was tested using paper chromatography

and high-performance liquid chromatography (13). Twenty-four-h

biodistribution studies in normal mice (n = 5) were performed on

each batch, and sterility and pyrogenicity were checked by standard

methods.

A total of 47 patients (38 male and 9 female) with known

metastatic disease to bone were enrolled in the study. Three patients

(males) were treated twice, resulting in a total of 50 administra-

tions. A variety ofprimary malignancies were studied and are listed

in Table 1. All patients signed an Institutional Review Board-

approved informed consent form. All patients were over the age of

18 years and had histologically documented malignancy with met-

astatic bone involvement and at least one painful lesion. Whole-

body bone scans with Tc-99m MDP had been performed within the

last 30 days. There had been no new systemic chemotherapy or

radiotherapy in the prior month and no new hormonal therapy in

the prior 6 weeks. Other selection criteria included a Karnofsky

performance status (14) of �40%, serum creatinine of �2.0 mg/dl,

a platelet count of �iOO,000/p.l, a granulocyte count �2000/p.i,

and a normal bilinibin level.

Complete blood counts, chemistries, and electrolyte meas-

urements were obtained at time of treatment, 1 week later, and

at intervals following treatment. The Sn-i 17m DTPA was ad-

ministered slowly through an indwelling infusion line within

3-5 mm. Blood samples and urine output were collected for at

least 4 days and sometimes longer for radioactivity assay to

calculate radiation absorbed dose, as described previously (9).

Bone uptake was calculated by whole-body retention (total

injected-urinary excretion) and corrected for extraceilular con-

tent of Sn-i 17m (9). The latest available MIRDOSE3 software

was used for the calculations (10). Imaging of Sn-ii7m distri-

bution with a gamma camera was carried out twice within the

first 8 days. In a few patients, imaging of Sn-i i7m was also

carried out at approximately 1 month and 3 months.

Patients were given forms that depicted an anatomical

drawing of 13 body areas, checkpoints to describe the degree

and the location of pain, space to provide information regarding

sleep, descriptions of ability to sleep with or without analgesics,

and doses of medications taken. Pain was recorded on a scale of

0-4 (15). This scale has been used in other evaluations of bone

pain palliation (4, 16, 17). Patients were asked to complete these

forms on a daily basis for at least 2 weeks and biweekly

thereafter. Total pain score was obtained by adding the individ-

ual pain scores (i 8) recorded for each of the 1 3 sites. Patients

were followed until they died (24 patients), or required other

therapy, for a minimum of 2 months. Thirteen subjects could be

followed for 6 months or more.

Five different levels of Sn-i 17m radioactivity were admin-

istered. These (per kg body weight; n number of administra-

tions) were as follows: 2.64 MBq (71 �j,Ci), n = 9; 5.29 MBq

(143 p�Ci), n = 1 1 ; 6.61 MBq (179 p.Ci), n 8; 8.46 MBq (229

p,Ci), n = 9; and 10.58 MBq (286 p,Ci), n 13. These levels

corresponded to nominal dose groups of 5, 10, 12.5, 16, and 20

mCi, respectively, for 70-kg men or 50-kg women.

RESULTS

Only one patient experienced any untoward reaction to the

administration of the Sn-i i7m DTPA. She had generalized

itching the day following the administration, readily relieved by

antihistamine medication. Ten of 47 patients could not be eval-

uated for various reasons. These included the unanticipated need

for chemotherapy for treatment of soft tissue disease, refusal to

make follow-up visits, or intervening death from disease pro-

gression. Of the 10 patients who were nonassessable, four had

lung, three had prostate, and three had breast primary cancer

sites. Four patients died within two weeks of progressive disease

(two lung cancer cases and two prostate cancer cases), two

refused further follow-up (one breast cancer case and one lung

cancer case), and four required other treatment for progressive

soft tissue disease (two breast cancer cases, one lung cancer

case, and one prostate cancer case).

The results of pain relief related to the dose level of

administered Sn-i 17m DTPA are summarized in Table 2. A

total of 12 treatments (30%) resulted in complete relief of pain

for 2 weeks or more. An additional 18 treatments (45%) evi-

denced a drop in the pain index of at least 50% for 2 weeks or

more. Ten treatment doses (25%) provided some (<50%) or no

relief of pain. The mean duration of response (n = 30) past time

to onset was 98 days, with a range of 20-402 days. There was



>�

�.25

4-

w

1I�0

0Cl)

0

Dose Group (mCiIlO kg)

Clinical Cancer Research 63

Table 2 Results of pain relief with Sn-b l7m (4 +) DTPA in 47 patients”

Normalized dosegroup, p.Ci/kg

No. of administrations Degree of pain reliefTotal %responseComplete Partial None

(mean ± SD) Total Assessable (100%) (>50%) (0-50%) (50-100%)

71(78±6) 9 5 0 3 2 60143(150 ± 12) 11 9 3 4 2 78

179 (186 ± 8) 8 5 3 1 1 80

229(217 ± 13) 9 9 2 4 3 67

286 (287 ± 6) 13 12 4 6 2 83

All doses 50 40 12 18 10 75

a Forty-four patients received a single administration, and 3 received two doses each.

Fig. 1 Time to onset of pain relief in patients atvarious administered doses (mCi/70 kg) of Sn-117m (4+) DTPA. The number of patients studiedand the error bars (± I SD) for the various dosesare included.

no clear trend of the duration of response versus the adminis-

tered radioactivity. Responses for the most part were long last-

ing, particularly in those patients who had complete relief of

pain. The 12 complete responses have lasted as foilows (dura-

tion past onset): 6 weeks, 9 weeks, 12 weeks, 12 weeks, 12

weeks, 3 months, 3.6 months, S months, 6 months, 1 1 months,

1 i months, and 13 months. The onset of pain relief was noted at

5 ± 3 days with doses � 12.5 mCi/70 kg (n 20), and at 19 ±

is days with doses �iO mCi/70 kg (n = 10); P < 0.05 (Fig. 1).

Three of the patients with prostate primary cancer received

a second dose of Sn-i i7m DTPA when symptoms recurred.

Two of these patients had had a partial response from the first

treatment. One of these two experienced a complete response

with the second treatment, and the other again had a partial

response. The third patient had a complete response lasting i

year after the prior treatment. He experienced complete relief of

pain for 5 months following the second therapy dose.

The uptake of Sn-ii7m DTPA (mean % injected dose) into

bone calculated as described earlier (9), in the present series of

patients (n = 43), was 69.7 ± 14.7 at 1-90 days after injection.

Broken down by category, this uptake in prostate cancer patients

(n = 29) was 75.8 ± 12.0, and in breast cancer patients (n = 7) it

was 54.8 ± 15.7. Comparable values from the literature are an

average of 52% (range, 20-84) for Sr-89 chloride (n = 6) at 90

days after injection (1) and 63% (range, 47-76) for Sm-i53

EDTMP, 0.5-2 days after injection (19). It should be noted that

these uptakes can be highly variable, depending upon metastatic

bone involvement, and due to patient variation. Therefore, inter-

study comparisons always have to be interpreted with caution.

All patients had normal levels of WBCs and platelets prior to

treatment. Although most patients experienced reductions in cell

counts, these were not of a serious nature. There was not a signif-

icant correlation between the administered doses of tin-ii7m

DTPA that were used in this study and the drop in blood cell

counts. The average maximum drop for all combined doses (n =

39) was 26.1 ± 15.9% (1870 ± 1450 absolute) for WBCs and

23.4 ± 18.3% (66,900 ± 64,600 absolute) for platelets. The nadir

was observed at 34 ± 16 days (n 35) for WBCs and at 4i ± 26

days (n = 34) for platelets. These results are compared with those

recently reported for other bone pain palliation agents (Table 3).

One of our patients (MaHa) with metastatic breast cancer had

completed a course of chemotherapy approximately 6 weeks prior



r-.-- MaHa-5-- EIDu-.‘-. PaKI -�

64 Treatment of Bone Pain with Sn-I 17m DTPA

Table 3 Average percentage of drop in blood cell counts f rom various bone pain palliation agents

- �-- Agent No. of administrations

Maximum % drop

WBCs Platelets

Sr-89 Chloride” 17 37.4 ± 13.3 39.2 ± 23.7

(50 p.Cilkg)

Srn-l53 EDTMP” 9 45.1 ± 20.7 56.3 ± 15.2

(I mCi/kg)

Re-l86 HEDP” 12 36.0 ± 23.3 43.3 ± 35.0

(31-79 mCi/l.73m)

Sn-I l7rn DTPA 39 26.1 ± 15.9 23.4 ± 18.3

(71-286 pCi/kg)

C’ Ref. 22.

F, Ref. 23.

C This study.

8

-J

c�)

0

0

6

2

0 20 40 60 80 100 120 140

Fig. 2 Response of total WBC count to Sn-b 17m

DTPA therapy in three women who had metastaticbreast cancer. Patient MaHa received 296 MBq (8

mCi). She had been receiving chemotherapy until

6 weeks prior to treatment. Patient ElDu received

703 MBq ( l9mCi). and patient PaK1 received 3 1 1

Mbq (8.4 mCi).

Days Following Sn-117m Administration

to Sn-I l7m administration and experienced a reduction in WBC

count from 4500/pb prior to treatment to between 1900 and 2000/

p.1. which persisted for several months. Her response is shown in

Fig. 2 along with two other women with breast cancer who also had

received chemotherapy prior to their treatment with Sn-l b7m. The

remaining breast cancer patients could not be evaluated because all

required other therapy within a few weeks of the radiopharmaceu-

tical administration.

Levels of myebotoxicity were judged by the NIH criteria. As

seen from the data in Tables 4-6, radiation toxicity from Sn-l 17m

DTPA was minimal. Of the 40 patients with complete data sets, 29

patients experienced no toxicity. 8 experienced level 1 toxicity, 2

experienced level 2 toxicity, and 1 (the breast cancer patient men-

tioned above) experienced bevel 3 toxicity (Table 5). It is notewor-

thy that all toxicities were related to reduction in WBC count and

none to reduction in platelet count. Recently reported typical data

on �grade 2 myelotoxicity from the various bone pain palliation

agents are summarized in Table 6.

Recalculation of radiation absorbed dose (data from Ref. 9)

has resulted in a considerably lower value per unit activity when

MIRDOSE3 is used (e.g. , in males, 17.6 mGyfMBq to bone and

2.6 mGyIMBq to red marrow). The results are shown in Table

7. Additional calculations were performed on 26 patients in-

cbuded in this paper, and calculations were performed by a

consultant, as well, on 18 patients from this group. There was no

substantial difference from the original data when using MIR-

DOSE3, although the variation from patient to patient was large

because of the variation in extent of disease. A comparison with

dosimetry data available on other pain palliation agents is also

included in Table 7.

DISCUSSION

The overall pain relief response of 75% is comparable to

results with strontium-89 and other radiopharmaceuticals that

have been investigated (1-7, 16, 20, 21). Among the five dose




Table 4 NIH myelotoxicity criteria

0 (none) 1 (mild) 2 (moderate) 3 (severe) 4 (unacceptable)

WBC, k/pb �4.0 3.0-3.9 2.0-2.9Platelets, kip.L WNL� 75.0-normal 50.0-74.9

1.0-1.9 <1.025.0-49.9 <25.0

a WNL, within normal limits.

Table 5 Absorbed dose to marrow and myebotoxicity

Myelotoxicity bevel”

Administered activity, pCi/kg” n Calculated average marrow dose, rad 0 1 2 3

78±6(5) 6 63±20 4

150± 12(10) 9 126±44 7

186 ± 8 (12.5) 5 164 ± 12 4

217 ± 13 (16) 8 194 ± 26 7

287 ± 6 (20) 12 228 ± 50 7

All doses 40 33-277 (range) 29

1 1 0

1 0 1

1 0 0

1 0 0

4 1 0

8 2 1

a Dose group (mCiI7O kg) in parentheses.b All toxicity observed was for WBCs. No below-normal bevel of platelets was seen.

Table 6 Myelotoxicity levels

Radiopharmaceutical Dose group (mCi/70 kg) n

No. of patients, grade �2

WBCs Platelets

Sr-89 Cl2 10.8” 67

2.8” 161

Re-l86-HEDP’ 35-80 12Sm-153-EDTMP” 70 20

105 4

210 4

Sn-l 17m DTPA� 10.0 912.5 5

20 12

10-20 34

25 (37%) 41 (6 1%)

48(31%) 48 (31%)

2(17%) 3(25%)3 (15%) 5 (25%)

3 (75%) 1 (25%)

4(100%) 2(50%)

1 (1 1%) 0(0%)0(0%) 0(0%)

1(8%) 0(0%)

2 (6%) 0(0%)

a Ref. 2.b Ref. 24. Only “hematobogical toxicity” grade �2 mentioned.cRef 23.

dRef 3.

e This study.

levels studied by us, however, there was no significant correla-

tion of response to administered dose, an observation similar to

the results obtained following the use of Sr-89 (21). Our series,

however, is too small for a definite conclusion regarding this

observation.

Our interest in studying Sn-l i7m is primarily based upon

the limited range (0.2-0.3 mm) of its conversion electrons,

which should result in reduced marrow toxicity compared to �3

emitters, particularly strontium-89 (16, 20, 21). Although a

larger study needs to be performed to obtain better statistical

significance, the results of the present, limited study are in

agreement with this belief.

Because of the palliative nature of this form of therapy and

the apparent lack of a measurable difference in the magnitude or

character of the response in relation to level of administered

radioactivity in this study, we did not consider it necessary to

pursue higher doses to determine the maximum tolerated dose.

However, it was noted that the time to onset of pain relief (Fig.

1) was shorter (5 ± 3 days) with doses �l2.5 mCi/70 kg (n =

20) than that (19 ± 15 days) at doses � 10 mCi/70 kg (n = 10);

P < 0.05. There remains the possibility that by further increas-

ing the administered radioactivity, a prevention of or delay in

the onset of new metastases and an increase in the duration of

palliation may be achieved (2, 3). These questions were beyond

the scope of the present study and would have to be pursued in

a separate, much larger study.

Statistical analysis (ANOVA) of data in Table 3 (carried

out with assistance from a biostatistician) showed that for

WBCs, compared with an average of the other three agents,

the percentage of drop for Sn-l l7m is significantly bower

(P < 0.01, using the conservative Scheffe method). For

platelets, the percentage of drop from Sn-I l7m is signifi-

cantly lower (P < 0.05) than that from Sr-89, which is the

lowest among the other three agents. The percentage of drop

from Sn- 1 17m has greater significance than the average

percentage of drop for the other three agents (P < 0.01).

Although useful as a guide, these comparisons should be

interpreted with caution. Due to differences in patient popu-



9

66 Treatment of Bone Pain with Sn-I l7m DTPA

Table 7 Dosime try estimates f or various pain palliati on agents (average dose, radlmCi)

Ratio of bone surfacesAgent

Sn-I l7rn DTPA”

Sex a Bone surfaces Red marrow to red marrow

M

F3

465.1

63.29.8

12.66.6

5.0Sr-89 chloride” M/F 63.0 40.7 1.6Srn-l53 EDTMP’ M 7 25.0

15.4”

5.7

2.8”

4.4

5.5”

Re-186 HEDP’ M/F 27 7.0 3.0 2.3

“ This study: MIRDOSE3 used.

‘, Ref. 25. Calculated (International Commission for Radiation Protection 53) for normal adults.(. Ref. 19. MIRDOSE2 used.

“ Above data recalcuated using MIRDOSE3.

‘- Ref. 26: MIRDOSE3 used.

Fig. 3 Bone scintigraphy of a patient with advanced osseous involvement of the skeleton with carcinoma of the prostate. The Tc-99m MDP images

(two images on frft) were obtained just prior to treatment. Two images on the right were obtained at 8 days following the administration of 10.2 mCi

of Sn-l l7m (4+) DTPA. There is exact correlation of distribution of radioactivity in these two superscans. (Reproduced with permission from the

Journal of Nuclear Medicine: Ref. 1 1

lation, tumor burden, and previous therapy and the varying

dosages used, it is hard to find comparable data from the

literature that allow a reliable and valid comparison.

With regard to the myelotoxicity bevels as defined using

the NIH criteria, statistical analysis showed that a signifi-

cantly lower proportion of patients displayed toxicity of

grade 2 or greater after treatment with Sn-b l7m (Table 5) in

comparison with the various dose bevels of other agents

(Table 6). In terms of WBC count, 3 of 40 patients (8%)

showed grade 2 or 3 toxicity with Sn-b b7m; in comparison,

3 of 20 patients (15%) showed grade 2, 3, or 4 toxicity with

a I mCi/kg dose of Sm-153 (P < 0.05). In a similar com-

parison, a significantly lower proportion of patients (P <

0.05) experienced toxicity of grade 2 or greater after treat-

ment with Sn-l 17m than after treatment with standard doses

of Sr-89 (0.04 mCi/kg) or Re-l86 (- 1 mCi/kg). With respect

to platelets, no patients treated with Sn-l 17m in our present

series showed any level of toxicity. This is an unexpected

result that we cannot explain.

The radiation absorbed dose to bone and red marrow based

on MIRDOSE3 was much bower than that obtained earlier (9)

using MIRDOSE2. However, the ratio of bone:red marrow dose




was still very favorable (-6.6), especially in comparison to

other agents (Table 7). It should be recognized that the doses

calculated for bone pain palliative agents are average doses

based on uniform distribution of the radioactivity in bone.

approximately one-half in cortical bone and one-half in trabec-

ular bone (10, 17). In practice, it is likely that the patient with

extensive bone metastases may experience a reduced radiation

effect to the total bone marrow compared to an individual with

fewer metastatic sites. In extensive metastatic bone involve-

ment, the marrow adjacent to the areas of greatly increased

activity would have a very high absorbed dose, but a major

fraction of the marrow would remain unaffected.

The high ratio of bone surface dose to red marrow dose

from Sn-l b7m, based on the limited range of its moderately

low-energy conversion electrons, is of particular advantage in

patients with breast cancer. These patients have usually been

subjected to considerable chemotherapy, compromising the

bone marrow, and as a consequence, they have limited mar-

row reserves. The low marrow toxicity from Sn- 1 17m DTPA

may also be an important factor in using this compound as an

adjuvant combined with chemotherapy or radiation therapy

(2).

Other favorable characteristics of Sn-l 17m DTPA are (a)

an imageabbe gamma photon (158.6 keV, 86.4%) to monitor

distribution for dosimetry (Fig. 3); (b) an administered radioac-

tivity level that does not require hospitalization; (c) an interme-

diate physical half-life ( 14.0 days) that provides a reasonable

shelf life (up to 30 days postcalibration) for ease of manufacture

and shipping; and (d) the prolonged chemical and radiochemical

stability (>3 months at room temperature) of the preparations

(13), which obviates the need for bow-temperature shipping or

storage.

The high degree of efficacy and the lack of any significant

toxicity, and the resultant high safety profile, warrant a larger-

scale clinical trial to further evaluate Sn- 1 17m DTPA as an

improved agent for pain palliation in patients with bony metas-

tases. Such a multicenter extended Phase Il/Phase III clinical

trial, involving three dose bevels of Sn-ll7m DTPA, and Sr-89

as a fourth arm for comparison, is to begin soon. The goal of this

trial is to eventually establish efficacy and lack of toxicity

relative to other radiopharmaceuticals used for bone pain palli-

ation.

ACKNOWLEDGMENTS

We gratefully acknowledge help provided by S. Mirzadeh and F. F.Knapp, Jr., with tin- 1 17 irradiations at the HFIR at Oak Ridge National

Laboratory (supported by the United States Department of Energy under

Contract DE-ACO5-960R22464 with Lockheed Martin Energy ResearchCorporation). Thanks are due to Susan Cataldo for assistance with the

preparation of the manuscript.

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1998;4:61-68. Clin Cancer Res S C Srivastava, H L Atkins, G T Krishnamurthy, et al. diethylenetriaminepentaacetic acid: a phase I/II clinical study.Treatment of metastatic bone pain with tin-117m Stannic

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