Page 1

Potential Increased Tumor-Dose Delivery with

Combined131I-MIBG and90Y-DOTATOC

Treatment in Neuroendocrine Tumors:

A Theoretic Model

Mark T. Madsen, PhD1; David L. Bushnell, MD1; Malik E. Juweid, MD1; Yusuf Menda, MD1;

M. Sue O’Dorisio, MD2; Thomas O’Dorisio, MD3; and Ian M. Besse, BA4

1Department of Radiology, University of Iowa, Iowa City, Iowa;2Department of Pediatrics, University of Iowa, Iowa City,

Iowa;3Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and4Department of Mathematics,

University of Iowa, Iowa City, Iowa

131I-Metaiodobenzylguanidine (MIBG) and90Y-DOTA-D-Phe1-

Tyr3-octreotide (DOTATOC) have been usedasradiotherapeutic

agents for treating neuroendocrine tumors. The tumor dose

delivered by these agents is often insufficient to control or cure

the disease. However, these 2 agents used together could po-

tentiallyincreasetumordosewithoutexceedingthecriticalorgan

dosebecausethedose-limitingtissuesaredifferent.Inthispaper,

we investigate the conditions in which combined-agent therapy

is advantageous and we quantify the expected tumor-dose

gain. Methods: A series of equations was derived that predicted

the optimal combination of agents and the fractional increase in

tumor dose available from combined-agent therapy with respect

to either131I-MIBG or90Y-DOTATOC. The results obtained from

these derivations were compared with direct dose calculations

using published dosimetric organ values for

90Y-DOTATOC along with critical organ-dose limits. Tumor

dose was calculated as a function of the tumor-dose ratio,

defined as the90Y-DOTATOC tumor dose per megabecquerel

divided by the

131I-MIBG tumor dose per megabecquerel.

Comparisons were made between the dose delivered to tumor

with single-agent therapy and the dose delivered to tumor with

combined-agent therapy as a function of the tumor-dose ratio

and the fraction of activity contributed by each agent. Results:

The dose model accurately predicted the optimal combination

of agents, the range at which combined-agent therapy was

advantageous, and the magnitude of the increase. For the

published organ dosimetry and critical organ-dose limits,

combined-agent therapy increased tumor dose when the

tumor-dose ratio was greater than 0.67 and less than 5.93. The

maximum combined-agent tumor-dose increase of 68% oc-

curredfora tumor-doseratioof 2.57,using92%ofthemaximum

tolerated

90Y-DOTATOC activity supplemented with 76% of

the maximum tolerated activity of131I-MIBG. Variations in organ

dose per megabecquerel and dose-limiting values altered

both the magnitude of the increase and the range at which

131I-MIBG and

combined-agent

Combining131I-MIBG and90Y-DOTATOC for radiotherapy of

neuroendocrine tumors can significantly increase the delivered

tumordoseoverthedoseobtainedfromusingeitheragentalone.

Prior knowledge of the normal-organ and tumor dosimetry

of both agents is required to determine the magnitude of the

increase.

therapywasadvantageous.

Conclusion:

Key Words: radionuclide therapy; neuroendocrine cancer;

combined-agent therapy;131I-MIBG;90Y-DOTATOC

J Nucl Med 2006; 47:660–667

Tumors originating from the neuroendocrine system

include neuroblastoma, carcinoids, and pancreatic endo-

crine tumors. Although relatively rare, these tumors may be

life threatening. When the disease has metastasized, 5-y

survival is less than 20% (1,2).131I-Metaiodobenzylguani-

dine (MIBG)and

90Y-DOTA-D-Phe1-Tyr3-octreotide

(DOTATOC) have shown potential as therapeutic agents

in patients with neuroendocrine tumors (3–6). However,

delivering to the tumor a radiation dose sufficient to result

in a high percentage of objective antitumor responses or

cure is challenging because of the radiation-dose limits

imposed by damage to normal tissues. In this paper, we

investigate a possible way to increase the radiation dose

delivered to tumors without exceeding radiation-dose limits

to critical organs by combining both90Y-DOTATOC and

131I-MIBG. As shown in Table 1 (7,8), these 2 agents have

different normal whole-body biodistributions, leading to

different critical organs: the kidney for90Y-DOTATAC and

the red marrow for131I-MIBG (9,10). Our novel approach

is based on the premise that this difference will enable the

combining of large fractions of the maximum tolerated

activity of each agent into a single treatment regimen to

deliver a higher tumor dose without exceeding the dose

limits to normal organs.

Received Oct. 20, 2005; revision accepted Jan. 3, 2006.

Forcorrespondenceorreprints

Department of Radiology, University of Iowa, 200 Hawkins Dr., Iowa City,

IA 52242.

E-mail: mark-madsen@uiowa.edu

contact:MarkT.Madsen,PhD,

660THE JOURNAL OF NUCLEAR MEDICINE • Vol. 47 • No. 4 • April 2006

Page 2

In this paper, a theoretic model of the combined-agent

approach is derived and the results of the model are

compared with direct dose calculations that were based

on published dosimetric data for normal organs and for

tumors. The conditions that are best suited for combined-

agent therapy with

90Y-DOTATOC and

explored, and estimates of potential improvements in the

therapeutic ratios of combined-agent therapy with respect

to either agent used alone under various conditions are

presented.

131I-MIBG are

MATERIALS AND METHODS

Theory

This section presents a set of equations that describe the

combined-agent approach and the expected benefits from its

application. Although the equations were developed with131I-

MIBG and90Y-DOTATOC in mind, the method is completely

general and can easily be adapted to any similar pair or to a larger

number of radiotherapeutic agents. The terms used in the equa-

tions are summarized in Table 2. The maximum activity that can

be administered for a therapeutic agent is limited by the critical

organ dose. Thus, the maximum activity of131I-MIBG adminis-

tered as a single agent, AMIBG, is given by

AMIBG5 MLD=mMIBG;

Eq. 1

where MLD is the maximum dose tolerated by the red marrow and

mMIBGis the dose per megabecquerel delivered by131I-MIBG to

the red marrow.

Similarly, the maximum activity of90Y-DOTATOC adminis-

tered as a single agent, ADOTA, is given by

ADOTA5 KLD=kDOTA;

Eq. 2

where KLD is the maximum dose tolerated by the kidneys and

kDOTAis the dose per megabecquerel delivered by90Y-DOTATOC

to the kidneys.

The dose delivered to tumor by each of the agents administered

singly is given by

TMIBG5 AMIBG· tMIBG

where TMIBGand TDOTAare the tumor doses delivered by the

agents and tMIBGand tDOTAare the respective tumor dose per

megabecquerel.

The following equations describe the situation in which both

agents are combined to treat a subject:

andTDOTA5 ADOTA· tDOTA;

CombinedtumordoseðCTDÞ 5 aAMIBGtMIBG

1bADOTAtDOTA

Eq. 3

CombinedmarrowdoseðCMDÞ 5 aAMIBGmMIBG

1bADOTAmDOTA

Eq. 4

CombinedkidneydoseðCKDÞ 5 aAMIBGkMIBG

1bADOTAkDOTA:

Eq. 5

a and b are fractions with a range of 021.

When combined-agent therapy is more advantageous (i.e.,

delivers more tumor dose) than therapy with either single agent,

the optimal combination of tracers occurs when the combined

marrow dose is equal to the marrow limiting dose and the

combined kidney dose is equal to the kidney limiting dose. When

that occurs, Equations 4 and 5 are simultaneous equations and

a and b can be uniquely solved using the method of determinants:

aopt5 ðMLD · ADOTAkDOTA2 KLD

· ADOTAmDOTAÞ=DENOM;

Eq. 6

where DENOM 5 ðAMIBGmMIBG· ADOTAkDOTA

2AMIBGkMIBG· ADOTAmDOTAÞ;

and

bopt5 ðAMIBGmMIBG· KLD 2 AMIBGkMIBG

· MLDÞ=DENOM:

To judge whether combined-agent therapy is advantageous, we

consider the fractional increase in tumor dose, defined as

Eq. 7

ðCTD 2 single-agenttumordoseÞ=single-agenttumor-dose;

Eq. 8

TABLE 1

90Y-DOTATOC (7) and131I-MIBG (8) Dosimetry

90Y-DOTATOC

131I-MIBG

SitemGy/MBqrad/mCimGy/MBqrad/mCi

Intestine

Red marrow

Liver

Urinary bladder

Spleen

Kidneys

Kidneys with

amino acids

0.05

0.05

0.66

1.03

2.32

2.73

2.16

0.18

0.18

2.43

3.81

8.58

10.09

8.0

0.08

0.07

0.78

0.76

0.05

0.09

0.29

0.27

2.90

2.80

0.18

0.33

TABLE 2

Definition of Terms Used in the Combined-Agent Model

TermDefinition

MLD

KLD

CTD

CMD

CKD

AMIBG

ADOTA

mMIBG

mDOTA

Marrow limiting dose (Gy)

Kidney limiting dose (Gy)

Combined-agent tumor dose (Gy)

Combined-agent marrow dose (Gy)

Combined-agent kidney dose (Gy)

Maximum single-agent131I-MIBG activity

Maximum single-agent90Y-DOTATOC activity

131I-MIBG red marrow dose per megabecquerel

90Y-DOTATOC red marrow dose per

megabecquerel

131I-MIBG kidney dose per megabecquerel

90Y-DOTATOC kidney dose per megabecquerel

131I-MIBG tumor dose per megabecquerel

90Y-DOTATOC tumor dose per megabecquerel

tDOTA/tMIBG Tumor-dose ratio

aopt

Optimal fraction of AMIBGfor combined-agent

therapy

bopt

Optimal fraction of ADOTAfor combined-agent

therapy

kMIBG

kDOTA

tMIBG

tDOTA

POTENTIAL INCREASED TUMOR-DOSE DELIVERY • Madsen et al.661

Page 3

where the highest dose resulting from either90Y-DOTATOC or

131I-MIBI is used in the calculation. By combining Equations 3

and 4, we can eliminate a from the equation, yielding

CTD 5 ððCMD 2 b ADOTAmDOTAÞ=mMIBGÞtMIBG

1 bADOTAtDOTA;

which can be rewritten as

CTD 5 CMDtMIBG=mMIBG1 bADOTAðtDOTA

2tMIBGmDOTA=mMIBGÞ:

Eq. 9

Equation 9 is a linear function of b with the slope equal to

ADOTA(tDOTA 2 tMIBG mDOTA/mMIBG). In order for CTD to

increase, we require a positive slope, and this implies that

tDOTA=tMIBG. mDOTA=mMIBG:

Eq. 10

The ratio of the90Y-DOTATOC tumor dose per megabecquerel

to the131I-MIBG tumor dose per megabecquerel, tDOTA/tMIBG,

which we refer to as the tumor-dose ratio, is the independent

variable for the function defined by Equation 8. When the tumor-

dose ratio is less than mDOTA/mMIBG,131I-MIBG is the best single

agent and delivers more dose to the tumor than does the combi-

nation therapy. In a similar fashion, Equations 3 and 5 can be

combined to yield the upper limit of the tumor-dose ratio at which

combined-agent therapy is effective, with the following result:

tDOTA=tMIBG, kDOTA=kMIBG:

Eq. 11

When the tumor-dose ratio is greater than kDOTA/kMIBG,90Y-

DOTATOC is the best single agent and delivers more dose to the

tumor than does the combination therapy. Over the tumor-dose

ratio range from mDOTA/mMIBGto kDOTA/kMIBG,the combination

of131I-MIBG and90Y-DOTATOC will deliver more dose to the

tumor than will the use of either single agent without exceeding

the critical organ doses.

The tumor-dose ratio that results in the maximum fractional dose

increase can be found from the realization that Equation 8 is maxi-

mized when the denominator is as small as possible. This occurs

when the total single-agent tumor dose from each tracer is the same:

AMIBG· tMIBG5 ADOTA· tDOTA:

Eq. 12

Thus, the combined-agent therapy will be most advantageous

when

tDOTA=tMIBG5 AMIBG=ADOTA:

Eq. 13

It is also possible to calculate the magnitude of the fractional

increase of the combined-agent approach, compared with the

better of the 2 single agents, from the equations presented above.

When131I-MIBG is the best single agent,

Fractiontumor-doseincrease

5 ðCTD 2 AMIBGtMIBGÞ=AMIBGtMIBG

5 ðaoptAMIBGtMIBG1 boptADOTAtDOTA

2 AMIBGtMIBGÞ=AMIBGtMIBG

5 aopt1 boptðADOTA=AMIBGÞ · ðtDOTA=tMIBGÞ 2 1:

Eq. 14

When90Y-DOTATOC is the best single agent,

Fractiontumor-doseincrease

5 ðCTD 2 ADOTAtDOTAÞ=ADOTAtDOTA

5 aoptðAMIBG=ADOTAÞ · ðtMIBG=tDOTAÞ 1 bopt2 1:

Eq. 15

Using either of these equations, we can estimate the maxi-

mum possible fractional increase in tumor dose from using the

combined-agent approach. Recalling from Equation 13 that at the

maximum fractional increase AMIBG/ADOTA5 tDOTA/tMIBG, Equa-

tions 14 and 15 both reduce to

ðCTD 2 AMIBGtMIBGÞ=AMIBGtMIBG

5 ðCTD 2 ADOTAtDOTAÞ=ADOTAtDOTA

5 aopt1 bopt2 1:

Eq. 16

The equations can also be used to define the range of tumor-

dose ratios at which the fractional increase will be greater than a

desired amount. For example, to calculate the tumor-dose rate

when the fractional increase is greater than or equal to 0.25, we

proceed as follows. The lower limit of the tumor-dose ratio is

calculated from

ðCTD 2 AMIBGtMIBGÞ=AMIBGtMIBG5 0:25

5 aopt1 boptðADOTA=AMIBGÞ · ðtDOTA=tMIBGÞ 2 1

tDOTA=tMIBG5 ð0:25 1 1 2 aoptÞ=boptðADOTA=AMIBGÞ:

Eq. 17

The upper limit of the tumor-dose ratio is calculated from

ðCTD 2 ADOTAtDOTAÞ=ADOTAtDOTA5 0:25

5 aoptðAMIBG=ADOTAÞ · ðtMIBG=tDOTAÞ 1 bopt21

tDOTA=tMIBG5 aoptðAMIBG=ADOTAÞ=ð0:25 1 1 2 boptÞ:

Eq. 18

Spreadsheet Calculations

To verify the model of combined radionuclide therapy with

131I-MIBG and90Y-DOTATOC, we calculated doses using the

published dosimetric values for the 2 agents shown in Table 3. An

Excel (Microsoft) spreadsheet was configured to perform the

following operations. First, the optimum administered activity

for90Y-DOTATOC was calculated to achieve the assumed kidney

critical organ dose (23 Gy) using Equation 2. Next, the amount of

90Y-DOTATOC activity was reduced in 1% increments and the

associated amount of131I-MIBG activity that could be addition-

ally given without exceeding either the kidney or the red marrow

limiting dose was calculated. The resultant90Y-DOTATOC and

TABLE 3

Dosimetric Values used in the Spreadsheet Calculations

ParameterKidneysRed marrow

Optimum dose (Gy)

131I-MIBG dose (mGy/MBq)

90Y-DOTATOC dose (mGy/MBq)

232

0.07

0.05

0.09

2.16

662THE JOURNAL OF NUCLEAR MEDICINE • Vol. 47 • No. 4 • April 2006

Page 4

131I-MIBG activities from these operations were used to calculate

the dose delivered to a tumor as a function of the tumor-dose ratio.

The tumor-dose ratio was varied from 0.1 to 30. In the dose

calculations, the tumor dose per megabecquerel for131I-MIBG

was assumed to be 2.9 mGy/MBq, which corresponds to the mean

tumor dose reported by Matthay et al. (11) for 27 patients with

neuroblastoma treated with

131I-MIBG. The tumor dose per

megabecquerel for

90Y-DOTATOC was determined from the

tumor-dose ratio. This approach allows the calculation of tumor

dose from each of the agents separately as well as in combination,

and from those results the fractional increase in tumor dose from

the combined-agent approach was determined.

Using the spreadsheet, we investigated different aspects of the

combined-agent therapy and compared them directly with the

model results. Because tumor and normal-tissue uptake and

residence times are expected to vary widely among individuals,

we changed the assumed values for the limiting critical organ dose

and the critical organ dose per megabecquerel and calculated

examples using these values. Specifically, changes were made to

the kidney dose limit, and the red marrow dose per megabecquerel

value.

RESULTS

The values in Table 3 were used to determine the optimal

fractions of each of the agents resulting in an aoptof 0.76

and a boptof 0.92. These results match the fractions found

by inspecting the spreadsheet calculations that yield the

maximum dose delivery for the combined-agent approach.

The optimal values of a and b found from the spreadsheet

calculations are independent of the tumor-dose ratio within

the range at which the combined-agent approach provides

an increased dose. This result is consistent with the model

prediction. Figure 1 shows a plot of the percentage increase

in dose for combined-agent therapy as a function of the

tumor-dose ratio using the dosimetric values in Table 3, and

the results from the model calculations are given in Table 4.

The numeric results from the model calculations exactly

match the plotted results. When the tumor-dose ratio is less

than mDOTA/mMIBG, there is no advantage to combined-

agent therapy and131I-MIBG is the best agent. Above that

limit, the combined-agent method provides an increased

dose, reaching a maximum fractional increase of 0.68 at a

tumor-dose ratio of 2.57. Beyond the maximum, the dose

advantage decreases with increasing tumor-dose ratio,

reaching 0 at a tumor-dose ratio of 24.24. Beyond that

point, treating with only90Y-DOTATOC yields the highest

tumor dose. Within the tumor-dose ratio range from 1.37 to

5.93, the dose advantage for the combined-agent approach

exceeds 25%.

Figure 2 shows how the percentage increase in tumor

dose from the combined-agent approach depends on the

relative amount of each agent. The graph was plotted for

the optimal tumor-dose ratio of 2.57, again using the

normal-tissue dose values and limits from Table 3. The

lower x-axis is expressed in terms of the percentage of

the optimum activity that could be administered for

90Y-DOTATOC alone (ADOTA), whereas the upper x-axis

is expressed in terms of the percentage of the administered

131I-MIBG activity as the only agent (AMIBG). The optimal

combination occurs for 92% of the maximum tolerated90Y-

DOTATOC administered activity and 76% of the maximum

tolerated131I-MIBG administered activity, again matching

the results of the model. As noted on the graph, points

to the left of maximum represent marrow-dose–limited

administered activity whereas points to the right of max-

imum represent kidney-dose–limited administered activity.

The next figures illustrate how changes in the dosimetric

parameters affect the performance of the combined-agent

approach. Figure 3 shows a series of plots from the

spreadsheet results as the90Y-DOTATOC kidney dose per

megabecquerel varies from 0.7 to 2.8 mGy/MBq, keeping

FIGURE 1.

combined-agent therapy with respect to single-agent therapy

as function of90Y-DOTATOC–to–131I-MIBG tumor-dose ratio.

Benefit from combined-agent therapy is optimal when tumor-

dose ratio is 2.57, at which the combined-agent approach

delivers 68% more dose to tumor than does either agent used

alone.131I-MIBG is the better of the 2 agents used alone when

tumor-dose ratio is less than 2.57 (left of dotted line), and90Y-

DOTATOC is the better single agent when tumor-dose ratio is

greater than 2.57 (right of dotted line).

Percentage increase in delivered tumor dose from

TABLE 4

Model Results for the Dosimetric Values in Table 3

ParameterValue

aopt

bopt

tDOTA/tMIBGmaximum

Maximum fractional increase

tDOTA/tMIBG*

tDOTA/tMIBGy

tDOTA/tMIBG0.25*

tDOTA/tMIBG0.25y

0.76

0.92

2.58

0.68

0.67

24.24

1.37

5.93

*Lower level for tumor-dose ratio.

yUpper level for tumor-dose ratio.

POTENTIAL INCREASED TUMOR-DOSE DELIVERY • Madsen et al. 663

Page 5

the other parameters in Table 3 constant. The results from

the model calculations are given in Table 5, and they

accurately represent the plotted curves. When the doses per

megabecquerel for the critical organs are similar, such as

when kDOTAis 0.7 mGy/MBq, there is little gain in the

combined-agent approach regardless of the tumor-dose

ratio. As kDOTAincreases with respect to the MIBG red

marrow dose per megabecquerel, the percentage increase in

tumor dose from the combined agents increases substan-

tially, along with the range of tumor-dose ratios, when the

combined-agent approach is advantageous.

Figure 4 shows a series of plots as the red marrow dose

limit is varied from 1.5 to 3.0 Gy, keeping the other param-

eters in Table 3 constant. As this limit is increased, the plot

broadens and a shift to higher values occurs for the90Y-

DOTATOC–to–131I-MIBG tumor-dose ratio at which the

fractional increase of tumor dose with combined therapy

maximizes. However, the percentage increase in the tumor

dose from the combined approach, compared with single-

agent therapy, does not increase significantly. The reason for

this interesting finding is that as the red marrow dose limit

increases, treatment with131I-MIBG becomes more favor-

able and the activity that can be administered increases.

While more tumor dose is delivered by the combined-agent

method, the single-agent treatment dose with131I-MIBG is

also increased. As a result, the magnitude of the fractional

increase in tumor dose from combined-agent therapy

changes little as the marrow limiting dose is increased. The

FIGURE 2.

agent therapy with respect to single-agent therapy plotted as

function of fraction of optimal administered activities of90Y-

DOTATOC and131I-MIBG. Plot uses results obtained at optimal

tumor-dose ratio (2.57). Maximum fraction increase occurs

when a 5 0.76 and b 5 0.92 as predicted by model.

Percentage tumor-dose increase from combined-

FIGURE 3.

apy with respect to single-agent therapy as function of90Y-

DOTATOC kidney dose in mGy/MBq. Kidney dose was varied

from 0.7 to 2.8 mGy/MBq while keeping all other parameters in

Table 3 constant. Curves represent kDOTAvalues of 0.7 (A), 1.4

(B), 2.1, (C), and 2.8 (D) mGy/MBq.

Tumor-dose increase from combined-agent ther-

TABLE 5

Model Results for Various90Y-DOTATOC Kidney Doses

per Megabecquerel

kDOTA(mGy/MBq)

Parameter0.7 1.42.12.8

aopt

bopt

tDOTA/tMIBGmaximum

Maximum fractional increase

tDOTA/tMIBG*

tDOTA/tMIBGy

tDOTA/tMIBG0.25*

tDOTA/tMIBG0.25y

0.22

0.98

0.83

0.20

0.67

7.85

0.67

0.88

0.63

0.93

1.67

0.56

0.67

15.70

1.11

3.30

0.76

0.92

2.58

0.68

0.67

24.24

1.37

5.93

0.82

0.91

3.34

0.73

0.67

31.39

1.58

8.10

*Lower level for tumor-dose ratio.

yUpper level for tumor-dose ratio.

FIGURE 4.

apy with respect to single-agent therapy as function of red

marrow dose limit, which was varied from 1.5 to 3.0 Gy while

keeping all other parameters in Table 3 constant. Curves

represent MLD values of 1.5 (A), 2.0 (B), 2.5 (C), and 3.0 (D) Gy.

Tumor-dose increase from combined-agent ther-

664THE JOURNAL OF NUCLEAR MEDICINE • Vol. 47 • No. 4 • April 2006

Page 6

model results corresponding to Figure 4 are presented in

Table 6 and show excellent agreement with the plotted

curves.

Figure 5 shows a series of plots as the131I-MIBG red

marrow dose is varied from 0.024 to 0.120 mGy/MBq,

keeping the other parameters in Table 3 constant. As the red

marrow dose per megabecquerel increases, the plots shift to

the left, changing the threshold of the optimal tumor-dose

ratio from 7.0 at a red marrow dose of 0.024 mGy/MBq to

0.6 at a red marrow dose of 0.12 mGy/MBq. This change

occurs because as the131I-MIBG red marrow dose per

megabecquerel increases, the amount of131I-MIBG that

can be administered in single-agent therapy decreases,

thereby improving the dose that can be delivered with the

combined-agent approach. At a lower131I-MIBG red mar-

row dose per megabecquerel, more

administered as a single agent. Thus, the advantage from

combined-agent therapy is realized only at higher90Y-

DOTATOC–to–131I-MIBG tumor-dose ratios. The model

results corresponding to Figure 5 are presented in Table 7

and show excellent agreement with the plotted curve.

131I-MIBG can be

DISCUSSION

The results of this investigation show that combined

radionuclide therapy with90Y-DOTATOC and131I-MIBG

has the potential to substantially increase the dose delivered

to the tumor while staying within the dose limits of the

critical organs. As the model shows and the calculations

support, increases in both the range and the magnitude of

the dose depend on the respective kidney, red marrow, and

tumor dose per megabecquerel for each agent. Thus,

patient-specific dosimetry for the tumor and critical organs

must be evaluated to allow prediction of the expected dose

improvement from combined-agent therapy.

Using the 2.9 mGy/MBq average tumor dose reported for

131I-MIBG in patients with neuroblastoma, we showed that

a tumor-dose ratio of 2.57 resulted in the maximum

fractional increase in tumor dose from combined therapy

using the parameters in Table 3. Interestingly, this ratio is

quite realistic and, on the basis of reported dosimetric

estimates with90Y-DOTATOC, may be expected for the

‘‘average’’ patient population. For example, Pauwels et al.

(12) showed that the mean tumor dose for patients with

neuroendocrine tumors treated with90Y-DOTATOC was

about 4.4 mGy/MBq, yielding a90Y-DOTATOC–to–131I-

MIBG ratio of about 1.53. This result is not much lower

than the predicted optimal ratio of 2.57 and would, on the

basis of our model, result in a 32% increase in tumor dose

from combined, compared with single-agent, therapy. We

cannot overemphasize, however, that these are only ‘‘aver-

aged’’ estimates and that the tumor radiation doses from

90Y-DOTATOC and131I-MIBG may vary substantially even

in the same patient and for the same tumor. In fact, the

study of Matthay et al. (11) showed that the tumor dose

from131I-MIBG ranged from 0.95 to 9.53 mGy/MBq for

the various tumors studied. Similar variability was reported

TABLE 6

Model Results for Various Marrow Limiting Doses

Marrow limiting dose (Gy)

Parameter 1.52.0 2.5 3.0

aopt

bopt

tDOTA/tMIBGmaximum

Maximum fractional increase

tDOTA/tMIBG*

tDOTA/tMIBGy

tDOTA/tMIBG0.25*

tDOTA/tMIBG0.25y

0.67

0.95

1.93

0.62

0.67

24.24

1.18

4.29

0.76

0.92

2.58

0.68

0.67

24.24

1.37

5.93

0.82

0.89

3.22

0.71

0.67

24.24

1.57

7.33

0.85

0.86

3.86

0.72

0.67

24.24

1.78

8.53

*Lower level for tumor-dose ratio.

yUpper level for tumor-dose ratio.

FIGURE 5.

apy with respect to single-agent therapy as function of131I-

MIBG red marrow dose in mGy/MBq. Red marrow dose was

varied from 0.024 to 0.12 mGy/MBq while keeping all other

parameters in Table 3 constant. Curves represent mMIBGvalues

of 0.024 (A) 0.048 (B), 0.072 (C), 0.096 (D), and 0.12 (E)

mGy/MBq.

Tumor-dose increase from combined-agent ther-

TABLE 7

Model Results for Various131I-MIBG Marrow Doses

per Megabecquerel

mMIBG(mGy/MBq)

Parameter 0.0240.048 0.0720.0960.12

aopt

bopt

tDOTA/tMIBGmaximum

Maximum fractional

increase

tDOTA/tMIBG*

tDOTA/tMIBGy

tDOTA/tMIBG0.25*

tDOTA/tMIBG0.25y

0.81

0.74

7.91

0.55

0.77

0.88

3.92

0.65

0.76

0.92

2.61

0.68

0.76

0.94

1.96

0.70

0.75

0.95

1.57

0.71

2.05

24.24

4.73

12.45

1.01

24.24

2.13

8.08

0.68

24.24

1.39

5.99

0.51

24.24

1.03

4.77

0.41

24.24

0.82

3.95

*Lower level for tumor-dose ratio.

yUpper level for tumor-dose ratio.

POTENTIAL INCREASED TUMOR-DOSE DELIVERY • Madsen et al. 665

Page 7

by Pauwels et al. (12), who showed that the tumor dose

from90Y-DOTATOC ranged from 0.88 to 48.8 mGy/MBq

in their patients. It is likely that many of these patients

would have much better tumor targeting with the one agent

than with the other and that, therefore, the90Y-DOTATAC–

to–131I-MIBG tumor-dose ratio might vary considerably

among patients and even for multiple tumors in the same

patient. This possibility has been indirectly shown by

several investigators (13,14), who observed considerable

variability in tumor imaging with123I- or131I-MIBG and

111In-pentetreotide in the same patients and even for the

same tumors in some patients. The implication is that there

exists a combination of tumor sites with good somatostatin

analog uptake together with poor MIBG uptake, and vice

versa. In a recent study, each of 92 patients with an existing

diagnosis of carcinoid tumor underwent both123I-MIBG

imaging and111In-pentetreotide imaging. Although 30%

of the combination studies showed effectively the same

tumor-targeting pattern for each agent, 15% of subjects

had completely negative

123I-MIBG findings for

pentetreotide–positive lesions, and 6% had completely

negative111In-pentetreotide findings for123I-MIBG–positive

metastases (15). Most important, fully 48% of the 92

subjects showed positive111In-pentetreotide findings and

negative123I-MIBG findings in combination with positive

123I-MIBG findings and negative111In-pentetreotide find-

ings in the same patient. These data clearly emphasize the

importance of performing patient-specific dosimetry for

both the tumor and the critical organs before administering

combined-agent therapy.

To demonstrate how combined-agent therapy would be

used in the situation of multiple tumors with different

affinities for131I-MIBG and90Y-DOTATOC, we offer the

following example. We assume that there is a patient with 5

known neuroendocrine tumors. First, imaging studies

would have to be performed to determine the absorbed

dose per megabecquerel for the critical organs (red marrow

and kidneys) and the absorbed dose per megabecquerel for

each of the tumors. The dosimetry for131I-MIBG can be

measured directly using a diagnostic administration,

whereas the dosimetry for90Y-DOTATOC will have to be

inferred from using either111In-pentetreotide as a surrogate

or, if available,86Y-DOTATOC. The optimal fractions of

131I-MIBG and90Y-DOTATOC used in combination de-

111In-

pend only on the critical organ dose per megabecquerel and

are independent of the tumor dose per megabecquerel.

Thus, the values of aoptand boptdetermined by Equations

6 and 7 are also appropriate for delivering the highest

combined-agent dose when applied to multiple tumors. In

this example, it will be assumed that the measured doses

per megabecquerel for the red marrow and kidney, as well

as the limiting doses, are the same as those given in Table 3.

Table 8 gives hypothetical but realistic values for the tumor

dose per megabecquerel that span the range of tumor-dose

ratios to include 1 lesion to which131I-MIBG delivers the

largest dose and 1 lesion to which90Y-DOTATOC delivers

the largest dose, with the remaining lesions obtaining the

largest dose from combined-agent therapy. This informa-

tion is used to calculate the tumor dose for each lesion for 3

different treatments:131I-MIBG given as a single agent,

90Y-DOTATOC given as a single agent, and131I-MIBG and

90Y-DOTATOC used in combination with the optimal

fractions obtained from Equations 6 and 7.

The calculated doses resulting from the model given in

Table 8 show that the mean dose delivered to all the tumors

is 50% greater with combined-agent therapy than with only

131I-MIBG and 90% greater with combined-agent therapy

than with only90Y-DOTATOC. More important, the dose

delivered to each of the 5 tumors with combined therapy is

either greater than (lesions 2, 3, and 4), similar to (lesion 5),

or only slightly lower than (lesion 1) the dose that would be

delivered using either of the 2 agents as a single therapy.

However, if single-agent therapy is used, at least 1 of the 5

tumors would receive an extremely low tumor dose (lesion

1 with

90Y-DOTATOC and lesion 5 with

essentially precluding any significant antitumor effect for

that particular lesion. From this example, it is clear that the

single-agent approach is the best choice only when the

tumor-dose ratios for all the lesions are very low, when131I-

MIBG will work best, or very high, when90Y-DOTATOC

will work best. For multiple tumors with variation across

the tumor-dose range, as the example illustrates, the

combined-agent approach is clearly superior because every

tumor at worst will receive a substantial fraction of the best

single-agent dose.

Even when combined therapy does not offer any signif-

icant dose advantage, there might still be a therapeutic

advantage. Evidence suggests that the distribution within

131I-MIBG),

TABLE 8

Example Results for Multiple Tumors with Variable Tumor-Dose Ratios

Tumor dose (mGy) per megabecquerelTumor dose (Gy)

Lesion no.tMIBG

tDOTA

tDOTA/tMIBG

131I-MIBG

90Y-DOTATOC Combined

1

2

3

4

5

Mean

2.9

2.9

1.5

0.5

0.1

0.3

2.9

4.4

4.4

4.4

0.10

1.00

2.93

8.80

44.00

82.9

82.9

42.9

14.3

2.9

45.1

3.2

30.9

46.9

46.9

46.9

34.9

64.9

91.3

76.7

55.3

46.8

67.0

666THE JOURNAL OF NUCLEAR MEDICINE • Vol. 47 • No. 4 • April 2006

Page 8

neuroendocrine tumor sites for DOTATOC and MIBG is

not the same and that combining them could therefore

ensure that all parts of the tumor receive a radiation dose

(16). Another consideration is the energy of the b-particles

emitted by90Y and131I.90Y emits a b-particle with a

maximum energy of 2.27 MeV, which is better suited for

tumors larger than 2 cm in diameter, whereas the b-particle

of131I, with a maximum energy of 0.6 MeV, is better suited

for tumors smaller than 1 cm. Because it is possible and

even likely that a patient will have multiple lesions of

varying size, using combined-agent therapy will potentially

be more efficacious than using either radiotracer alone.

One potential concern with the proposed combined

therapy with90Y-DOTATOC and131I-MIBG is that com-

bining these 2 agents may cause some other organ or tissue,

such as the lungs or liver, to reach the critical dose.

Fortunately, this situation does not seem to occur with

these 2 agents. The liver dose will not exceed its limit of 30

Gy even if the optimum amounts of90Y-DOTATOC and

131I-MIBG are administered to the same patient. The lung

uptake for both these agents is low, and the dose to the

lungs from optimal administrations will be nearly a factor

of 10 less than the 20-Gy limiting dose for this organ.

CONCLUSION

Use of90Y-DOTATOC and131I-MIBG together as ther-

apy for neuroendocrine tumors has the potential to increase

tumor-dose delivery without exceeding critical organ limits.

Calculations predict tumor-dose increases exceeding 65%

of the maximum tumor dose that could be delivered by use

of either agent alone. Combined-agent therapy may also

have additional targeting and dose delivery benefits. The

magnitude of the fractional dose increase associated with

combined-agent therapy depends on the tumor and critical

organ dose per megabecquerel values and on the maximum

dose that can be delivered to each critical organ. Individual

dosimetry studies are required to determine which patients

will benefit from combined-agent therapy.

REFERENCES

1. Schramm A, Schulte JH, Klein-Hitpass L, et al. Prediction of clinical outcome

and biological characterization of neuroblastoma by expression profiling.

Oncogene. 2005;24:7902–7912.

2. Jensen R, Doherty G. Carcinoid tumors and carcinoid syndrome. In: Devita VT,

ed. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA:

Lippincott, Williams and Wilkins; 2001.

3. Otte A, Mueller-Brand J, Dellas S, Nitzsche EU, Herrmann R, Maecke HR.

Yttrium-90-labelled somatostatin-analogue for cancer treatment. Lancet. 1998;

351:417–418.

4. Howard JP, Maris JM, Kersun LS, et al. Tumor response and toxicity with

multiple infusions of high dose131I-MIBG. Pediatr Blood Cancer. 2005;44:

232–239.

5. Safford SD, Coleman RE, Gockerman JP, et al. Iodine-131 metaiodobenzyl-

guanidine treatment for metastatic carcinoid. Cancer. 2004;101:1987–1993.

6. Bushnell D, O’Dorisio T, Menda Y, et al. Evaluating the clinical effectiveness of

90Y-SMT 487 in patients with neuroendocrine tumors. J Nucl Med. 2003;44:

1556–1560.

7. Forster GJ, Engelbach MJ, Brockmann JJ, et al. Preliminary data on

biodistribution and dosimetry for therapy planning of somatostatin receptor

positive tumours: comparison of86Y-DOTATOC and111In-DTPA-octreotide.

Eur J Nucl Med. 2001;28:1743–1750.

8. Stabin M, Stubbs J, Toohey R. Radiation Dose Estimates for Radiopharmaceu-

ticals. Oak Ridge, TN: Oak Ridge Institute for Science and Education; 1996.

9. Lashford LS, Lewis IJ, Fielding SL, et al. Phase I/II study of iodine 131

metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom

Children’s Cancer Study Group investigation. J Clin Oncol. 1992;10:1889–1896.

10. Boerman OC, Oyen WJ, Corstens FH. Between the Scylla and Charybdis of

peptide radionuclide therapy: hitting the tumor and saving the kidney. Eur J Nucl

Med. 2001;28:1447–1449.

11. Matthay KK, Panina C, Huberty J, et al. Correlation of tumor and whole-body

dosimetry with tumor response and toxicity in refractory neuroblastoma treated

with131I-MIBG. J Nucl Med. 2001;42:1713–1721.

12. Pauwels S, Barone R, Walrand S, et al. Practical dosimetry of peptide receptor

radionuclide therapy with90Y-labeled somatostatin analogs. J Nucl Med. 2005;

46:92S–98S.

13. Taal BG, Hoefnagel CA, Valdes Olmos RA, Boot H. Combined diagnostic

imaging with131I-metaiodobenzylguanidine and111In-pentetreotide in carcinoid

tumours. Eur J Cancer. 1996;32A:1924–1932.

14. Kaltsas G, Korbonits M, Heintz E, et al. Comparison of somatostatin analog

and meta-iodobenzylguanidine radionuclides in the diagnosis and localization

of advanced neuroendocrine tumors. J Clin Endocrinol Metab. 2001;86:

895–902.

15. Quigley A, Buscombe J, Gopinath G, Caplin M, Hilson A. In-vivo characteristics

of the functional aspects of carcinoid tumors by imaging somatostatin receptors

and amine uptake [abstract]. J Nucl Med. 2003;44(suppl):74P.

16. Nocaudie-Calzada M, Huglo D, Carnaille B, Proye C, Marchandise X. Com-

parison of somatostatin analogue and metaiodobenzylguanidine scintigraphy for

the detection of carcinoid tumours. Eur J Nucl Med. 1996;23:1448–1454.

POTENTIAL INCREASED TUMOR-DOSE DELIVERY • Madsen et al.667