Purpose: In radionuclide therapy, cumulated activity and tumor volume/mass are the principal quantities necessary for the calculation of the absorbed dose to the tumor. When treating a fast-responding macroscopic tumor, there may be a decrease in its mass during therapy, and at any given uptake, this will result in an increase in the absorbed dose. The purpose of the present work is to demonstrate the limitations in current internal dosimetry protocols that assume a fixed tumor mass in lymphoma patients, using a fractionated radioimmunotherapy schedule and using a single infusion.

Experimental Design: Patients with B-cell lymphoma were treated with 90Y-labeled epratuzumab (Immunomedics, Inc., Morris Plains, NJ) using a weekly dose-fractionation schedule for 2–4 weeks. They received either 185 MBq/m2 (5 mCi/m2) in each infusion or, if they had a history of high-dose chemotherapy with stem cell rescue, 92.5 MBq/m2 (2.5 mCi/m2) in each infusion. All patients received 111In-labeled epratuzumab with the first infusion to verify tumor targeting and for dosimetry. The present report is based on three selected patients, in whom repeated assessments of tumor mass were possible. In two patients, 111In-labeled epratuzumab was also coadministered with one of the subsequent treatments, i.e. during the second and third of two and three scheduled infusions. The tumor volume was determined from computer tomography images obtained before the first infusion and on different times after the infusion. An exponential equation was fitted to the decreasing mass of the tumor and implemented in the calculation of the absorbed dose. For comparison, the absorbed dose to the tumor was also calculated using the tumor volume determined from the baseline pretreatment computer tomography examination.

Results: The tumor volume for the patients changed rapidly. For one patient, the pretreatment volume was 19.5 ml, and for another patient, it was 840 ml. For these two patients, the ratio of tumor volume at the beginning of therapy compared with that after 8 days and 14 days of therapy was 0.7 and 0.8, respectively. This rapid decrease in volume and subsequent mass reduction result in an increase of mean absorbed dose to the tumor of as much as a factor of 1.75.

Conclusions: At a given activity uptake, a decrease in tumor mass during therapy will significantly increase the calculated absorbed dose. Taking the change in tumor mass into account when calculating absorbed dose may improve the correlation between the mean absorbed dose to the tumor and the response to the therapy.

In RIT,3 cumulated activity and tumor volume/mass are the principal quantities necessary for the calculation of the absorbed dose to the tumor. To assess the tumor mass, clinical RIT protocols usually include a CT investigation before the start of therapy. This initial tumor mass estimated from the CT scan is used routinely throughout all of the dosimetric calculations. In an ongoing RIT trial at our clinic on lymphoma patients using a fractionation schedule, one of our patients with a large cervical lymphoma received three weekly infusions of radiolabeled monoclonal antibody. After the first week, there was a dramatic decrease in tumor volume, and before the third infusion, there was no longer any palpable disease. This highlighted the problem of accurate tumor dosimetry when tumor mass is not constant. At a given uptake of the radionuclide in the tumor, the calculated absorbed dose, which is inversely proportional to the mass, increases as the tumor volume decreases.

Previously published papers presenting absorbed dose calculations with a time-dependent change in mass/volume include the urinary bladder model (1), a change in volume at the injection site (2, 3), and a model for a tumor that is growing during treatment (4). A generalized description of how to treat a time-varying mass is presented in International Commission on Radiation Units and Measurements Report 67 (5).

Because many malignant lymphomas are highly radiosensitive, a rapid decrease in tumor volume during RIT can be expected, which has implications on tumor dosimetry. The aim of this study is both to highlight the limitations in currently used internal tumor dosimetry, which assumes a fixed mass of the tumor, and to demonstrate its dosimetric relevance in patients participating in our ongoing RIT trial.

Adult patients with histologically confirmed B-cell lymphoma (Revised European-American Lymphoma classification) who relapsed after or were resistant to at least one regimen of standard chemotherapy are eligible. This is a single-center Phase I/II study examining the safety, toxicity, and efficacy of treatment with 90Y-labeled epratuzumab. The primary aim of the RIT study is to find the maximal tolerated dose of 90Y-epratuzumab, using a fractionated schedule. Patients are treated with an increasing number (two to four) of weekly infusions of 90Y-epratuzumab. They receive either 185 MBq/m2 (5 mCi/m2) in each infusion or, if they have a history of high-dose chemotherapy with stem cell rescue, 92.5 MBq/m2 (2.5 mCi/m2) in each infusion. The first infusion for all patients also included 150 MBq (4 mCi) of 111In-labeled epratuzumab for scintigraphic verification of tumor targeting and for dosimetry purposes. In two patients, a second infusion of 111In-labeled epratuzumab was administered just before a subsequent infusion. The study was approved by the local ethics committee, and written informed consent was obtained from all patients.

The CT protocols and parameters varied slightly, but the examinations were typically performed after administration of oral (sodium-meglumine diatrizoate; Gastrografin; Schering AG) and i.v. (iodinated, nonionic) contrast agents. Contiguous axial slices of 5–10 mm were produced. The tumor volumes were estimated either by multiplying the relevant area in each slice by the slice thickness or by multiplying the three largest perpendicular diameters of the tumor and dividing the product by 2. It was assumed that the density equaled 1 g/cm3.

Scintillation camera images were obtained at five points in time after each infusion containing 111In. The activity in the tumors was quantified from the scintillation camera images by the geometric mean method (6, 7). Regions of interest were drawn in both the anterior and the posterior images, counts from activity in over- and underlying tissues were subtracted, and corrections were made for attenuation and camera sensitivity. An exponential function was fitted to the time-activity curve for each tumor and 111In infusion. When two 111In infusions were performed close in time, the activity contribution from the first infusion was subtracted from the second so that each infusion could be treated separately. The 111In-activity was converted to 90Y, for which the absorbed dose was calculated.

The mean self-absorbed dose, m(t), for the shrinking tumor was calculated as:

\[{\bar{D}}_{m(t)}\ {=}\ {\tilde{A}}\ {\cdot}\ {{\int}}S(t)dt\ {=}\ {{\int}}A(t)\ {\cdot}\ \frac{En{\phi}(m(t))}{m(t)}\ dt\]

where is the cumulated activity in the tumor, and S(t) is the time-dependent S value, that is, the absorbed dose per decay in the tumor. A(t) is the time-dependent activity in the tumor, E is the energy emitted per particle for the radionuclide, n is the number of particles emitted per decay, φ(m(t)) is the time-dependent absorbed fraction, and m(t) is the time-dependent mass of the tumor. Depending on the radionuclide and the size of the tumor, the absorbed fraction may be assumed to be constant during the time of integration. If the range of emitted particles can be considered to be very small compared with the size of the tumor, and if the energy deposition from emitted photons can be neglected, then the absorbed fraction can be assumed to be constant. Assuming that the absorbed fraction is constant, the variation in the S value will be inversely proportional to the time-varying tumor mass, and the equation for S(t) will be:

\[S(t)\ {=}\ En{\phi}\ {\cdot}\ {{\int}}\frac{1}{m(t)}\ dt\]

For comparison, the absorbed dose was also calculated assuming a constant mass of the tumor, m=initial, that is the pretreatment mass that was estimated from the CT images immediately before starting RIT.

\[{\bar{D}}_{m{=}initial}\ {=}\ {\tilde{A}}\ {\cdot}\ S_{m{=}initial}\]

All S values originate from MIRDOSE3.1, the nodule module (8).

The activity in the tumor as a function of time was calculated for each patient, and one example is given in Fig. 1, where the physical decay of the radionuclide is included in the data. Figure 1 shows when there is a substantial contribution to the cumulated activity and thus the time interval in which the shrinkage of the tumor is important.

Fig. 2 shows the fast response of the tumor size during RIT in three of the patients. The tumor masses are normalized to the time of the first infusion. The absolute values of the tumor masses are given in Table 1. Patient 2, who shows the fastest tumor response, had an initial tumor volume of 19.5 ml and a tumor volume of 13.5 ml after only 1 week of RIT. One of the tumors in patient 3 had disappeared completely at the CT investigation performed 44 days after the first infusion.

Fig. 3 illustrates how the S value for 90Y changes with time for one of the patients (patient 3).

Table 2 gives the differences in the absorbed dose calculated when considering the decrease in the tumor mass compared with the traditional model (that is, using a constant tumor mass). If the shrinkage of the tumor is considered, the calculated absorbed dose increases compared with the standard method. For these patients, the maximum increase in the calculated absorbed dose was 75%.

Malignant lymphomas are generally radiation sensitive, and some are extremely sensitive to radiation (9). This may cause the tumor to shrink during RIT, i.e., during the actual energy deposition, which is well illustrated in the present study. This is in keeping with reports by DeNardo et al.(10, 11) of tumor regression and disappearance shortly after the first therapeutic administration of Lym-1-labeled 131I. Because at any given uptake, the calculated mean absorbed dose is inversely proportional to the mass, a rapid change in mass calls into question the validity of reported calculated absorbed doses in internal dosimetry for lymphomas. The calculated mean absorbed dose of the present three patients increased up to 75% when the reduction in mass was taken into account.

The present study indicates that the predicted absorbed dose could be underestimated in responding B-cell lymphomas. In the present study, tumor shrinkage might be brought about in part by mechanisms other than absorbed dose. The antibodies per se are important determinants in RIT (12), and several unlabeled antibodies such as rituximab (13), epratuzumab (14), and tositumomab (15) have all been reported to induce remission in their own right. The observation that the antibody used in clinical RIT can induce response by itself is shown by a randomized study of unlabeled tositumomab (15) using the same amount of antibody in both arms. It is thus possible that the observed shrinkage in the present study may be caused in part by epratuzumab alone.

Regardless of the causes of tumor shrinkage, the use of a fixed tumor mass not only leads to absorbed dose calculations being less reliable but also may be partly responsible for the poor correlation between absorbed dose and biological response of tumors observed in RIT of lymphomas.

The shortcomings in dosimetry might impair the revelation of absorbed dose-response relationships and hence hamper the development of RIT. In conclusion, repeated assessments of tumor mass are not only recommended in a dose-fractionation schedule but also may be advisable in treatments using single infusions to assure an accurate estimation of the mean absorbed dose to the tumor.

1

Presented at the “Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates,” October 24–26, 2002, Princeton, NJ. This work was supported by grants from the Swedish Cancer Society; the Mrs. Berta Kamprad Foundation; the Gunnar, Arvid and Elisabeth Nilsson Foundation; Per-Erik and Siv-Inger Andersson’s Foundation; The Lundberg Foundation, Gothenburg; and foundations of the Lund Health District Organization.

3

The abbreviations used are: RIT, radioimmunotherapy; CT, computed tomography.

Fig. 1.

An example of the activity in the tumor during the two first infusions as a function of time (patient 2). The data points show the activity quantified from the scintillation camera images, the bold line indicates the calculated activity in the tumor for the first infusion, and the thin line shows the calculated activity in the tumor for the second infusion.

Fig. 1.

An example of the activity in the tumor during the two first infusions as a function of time (patient 2). The data points show the activity quantified from the scintillation camera images, the bold line indicates the calculated activity in the tumor for the first infusion, and the thin line shows the calculated activity in the tumor for the second infusion.

Close modal
Fig. 2.

The relative change in tumor mass as a function of time for the three patients. The symbols show the tumor volume assessed from the CT scans (•, patient 1; ▪, patient 2; ○, patient 3), and the lines show the results of fitting the equation used in the calculation of the absorbed dose (bold line, patient 1; dotted line, patient 2; thin line, patient 3).

Fig. 2.

The relative change in tumor mass as a function of time for the three patients. The symbols show the tumor volume assessed from the CT scans (•, patient 1; ▪, patient 2; ○, patient 3), and the lines show the results of fitting the equation used in the calculation of the absorbed dose (bold line, patient 1; dotted line, patient 2; thin line, patient 3).

Close modal
Fig. 3.

The change of the S value for 90Y with time in patient 3, for whom the tumor mass changed from 360 to 70 g during 44 days. The figure illustrates the necessity of monitoring the mass change during therapy for proper dosimetry.

Fig. 3.

The change of the S value for 90Y with time in patient 3, for whom the tumor mass changed from 360 to 70 g during 44 days. The figure illustrates the necessity of monitoring the mass change during therapy for proper dosimetry.

Close modal
Table 1

The tumor masses as estimated from CT images at different points in time for three patients

Patient no.Time after first infusion (days)Tumor mass (g)
840 
 14 650 
 55 630 
   
19.5 
 13.5 
   
3 (tumor 1) 360 
 44 70 
   
3 (tumor 2) 85 
 44 
Patient no.Time after first infusion (days)Tumor mass (g)
840 
 14 650 
 55 630 
   
19.5 
 13.5 
   
3 (tumor 1) 360 
 44 70 
   
3 (tumor 2) 85 
 44 
Table 2

The mean absorbed doses to the tumors calculated using the time-varying tumor mass, m(t), and the pretreatment tumor mass, m=initial.

Patient no.Infusionm(t) (Gy)m=initial (Gy)
5.2 4.5 
2.0 1.5 
2.3 1.7 
2.1 1.2 
3 (tumor 1) 2.6 2.2 
Patient no.Infusionm(t) (Gy)m=initial (Gy)
5.2 4.5 
2.0 1.5 
2.3 1.7 
2.1 1.2 
3 (tumor 1) 2.6 2.2 

The antibody epratuzumab was kindly provided by Prof. David Goldenberg (Immunomedics, Inc., Morris Plains, NJ).

1
Thomas S. R., Stabin M. G., Chen C-T., Samaratunga R. C. MIRD Pamphlet No. 14 revised: a dynamic urinary bladder model for radiation dose calculations.
J. Nucl. Med.
,
40
:
102s
-123s,  
1999
.
2
Bergqvist L., Strand S-E., Persson B., Hafström L., Jönsson P-E. Dosimetry in lymphoscintigraphy of Tc-99m antimony sulfide colloid.
J. Nucl. Med.
,
23
:
698
-705,  
1982
.
3
Grafström G., Strand S-E., Kontestabile E., Almén A., Bergqvist L., Larsson I. Extravasation of radiopharmaceuticals. A study of its frequency and estimation of absorbed doses in diagnosis and therapy.
Proceedings of the Sixth International Radiopharmaceutical Dosimetry Symposium
,
522
-531, Oak Ridge Associated Universities  
1999
.
4
Howell R. W., Narra V. R., Rao D. V. Absorbed dose calculations for rapidly growing tumors.
J. Nucl. Med.
,
33
:
277
-281,  
1992
.
5
ICRU Report 67. Absorbed dose specification in nuclear medicine. J. ICRU, 2: 2002.
6
Thomas S. R., Maxon H. R., Kereiakes J. G. In vivo quantitation of lesion radioactivity using external counting methods.
Med. Phys.
,
3
:
253
-255,  
1976
.
7
Siegel J. A., Thomas S. R., Stubbs J. B., Stabin M. G., Hays M. T., Koral K. F., Robertson J. S., Howell R. W., Wessels B. W., Fisher D. R., Weber D. A., Brill A. B. MIRD Pamphlet No. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.
J. Nucl. Med.
,
40
:
37s
-61s,  
1999
.
8
Stabin M. G. MIRDOSE: Personal computer software for internal dose assessment in nuclear medicine..
J. Nucl. Med.
,
37
:
538
-546,  
1996
.
9
Richaud P. M., Soubeyran P., Eghbali H., Chacon B., Marit G., Broustet A., Hoerni B. Place of low-dose total body irradiation in the treatment of localized follicular non-Hodgkin’s lymphoma: results of a pilot study..
Int. J. Radiat. Oncol. Biol. Phys.
,
40
:
387
-390,  
1998
.
10
DeNardo S. J., DeNardo G. L., O’Grady L. F., Macey D. J., Mills S. L., Epstein A. L., Peng J-S., McGahan J. P. Treatment of a patient with B cell lymphoma by I-131 LYM-1 monoclonal antibodies.
Int. J. Biol. Markers
,
2
:
49
-53,  
1987
.
11
DeNardo G. L., DeNardo S. J., Lamborn K., Goldstein D. S., Levy N. B., Lewis J. P., O’Grady L. F., Raventos A., Kroger L. A., Macey D. J., McGahan J. P., Mills S. L., Shen S. Low-dose, fractionated radioimmunotherapy for B-cell malignancies using 131I-LYM-1 antibody.
Cancer Biother. Radiopharm.
,
13
:
239
-254,  
1998
.
12
Illidge T. M., Cragg M. S., McBride H. M., French R. R., Glennie M. J. The importance of antibody-specificity in determining successful radioimmunotherapy of B-cell lymphoma.
Blood
,
94
:
233
-243,  
1999
.
13
McLaughlin P., Grillo-López A. J., Link B. K., Levy R., Czuczman M. S., Williams M. E., Heyman M. R., Bence-Bruckler I., White C. A., Cabanillas F., Jain V., Ho A. D., Lister J., Wey K., Shen D., Dallaire B. K. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program..
J. Clin. Oncol.
,
16
:
2825
-2833,  
1998
.
14
Press O. W., Leonard J. P., Coiffier B., Levy R., Timmerman J. Immunotherapy of non-Hodgkin’s lymphoma.
Hematology
,
:
221
-240,  
2001
.
15
Davis T. A., Kaminski M. S. Results of a randomized study of Bexxar (tositumomab and iodine 131 tositumomab) vs. unlabeled tositumomab in patients with relapsed or refractory low-grade or transformed non-Hodgkin’s lymphoma (NHL).
Blood
,
98
:
843
2001
.