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Patient-Specific Dosimetry of Pretargeted Radioimmunotherapy Using CC49 Fusion Protein in Patients With Gastrointestinal Malignancies

Posted on: Saturday, 16 April 2005, 03:00 CDT

Pretargeted radioimmunotherapy (RIT) using CC49 fusion protein, comprised of CC49-(scFv)^sub 4^ and streptavidin, in conjunction with ^sup 90^Y/^sup 111^In-DOTA-biotin (DOTA = dodecanetetraacetic acid) provides a new opportunity to improve efficacy by increasing the tumor-to-normal tissue dose ratio. To our knowledge, the patient- specific dosimetry of pretargeted ^sup 90^Y/^sup 111^In-DOTA-biotin after CC49 fusion protein in patients has not been reported previously. Methods: Nine patients received 3-step pretargeted RIT: (a) 160 mg/m^sup 2^ of CC49 fusion protein, (b) synthetic clearing agent (sCA) at 48 or 72 h later, and (c) ^sup 90^Y/^sup 111^In-DOTA- biotin 24 h after the sCA administration. Sequential whole-body ^sup 111^In images were acquired immediately and at 2-144 h after injection of ^sup 90^Y/^sup 111^In-DOTA-biotin. Geometric-mean quantification with background and attenuation correction was used for liver and lung dosimetry. Effective point source quantification was used for spleen, kidneys, and tumors. Organ and tumor ^sup 90^Y doses were calculated based on ^sup 111^In imaging data and the MIRD formalism using patient-specific organ masses determined from CT images. Patient-specific marrow doses were determined based on radioactivity concentration in the blood. Results: The ^sup 90^Y/ ^sup 111^In-DOTA-biotin had a rapid plasma clearance, which was biphasic with <10% residual at 8 h. Organ masses ranged from 1,263 to 3,855 g for liver, 95 to 1,009 g for spleen, and 309 to 578 g for kidneys. The patient-specific mean ^sup 90^Y dose (cGy/37 MBq, or rad/mCi) was 0.53 (0.32-0.78) to whole body, 3.75 (0.63-6.89) to liver, 2.32 (0.58-4.46) to spleen, 7.02 (3.36-11.2) to kidneys, 0.30 (0.09-0.44) to lungs, 0.22 (0.12-0.34) to marrow, and 28.9 (4.18- 121.6) to tumors. Conclusion: Radiation dose to normal organs from circulating radionuclide is substantially reduced using pretargeted RIT. Tumor-to-normal organ dose ratios were increased about 8- to 11- fold compared with reported patient-specific mean dose to liver, spleen, marrow, and tumors from ^sup 90^Y-CC49.

Key Words: gastrointestinal cancer; dosimetry; pretargeted radioimmunotherapy

J Nucl Med 2005; 46:642-651

Metastatic or recurrent gastrointestinal (GI) cancer is a common cause of morbidity and mortality in the United States. If not cured by surgery, chemotherapy regimens produce, at best, modest effects on survival. Once failure occurs with first-line chemotherapy, further attempts at chemotherapy produce minimal benefits and survival is about 3-9 mo. Radiotherapy has a limited local control, palliative role in a small group of patients. Therefore, innovative therapies are needed for metastatic or recurrent GI cancer.

Radioimmunotherapy (RIT) is one innovative approach that systemically delivers localized radiation through an antibody directed to a tumor-associated antigen. Encouraging results have been obtained in RIT for lymphoma (1-4). However, the effect of RIT on metastatic or recurrent GI cancer has been disappointing. Prior phase I and phase II studies with the CC49 antibody have generally shown localization of radiolabeled antibodies to tumor sites but with insufficient radiation delivery to produce objective tumor regression (5-9). The efficacy of radiolabeled antibodies for GI cancer, in general, has been limited by several factors, including (a) slow accumulation at tumor sites, (b) relatively slow clearance from the blood, and (c) radioresistance of the tumors. Consequently, although tumors receive insufficient radiation for an objective response, the radiation dose to radiosensitive normal organs has already exceeded the maximum tolerable limit.

The pretargeted RIT (Pretarget RIT; NeoRx Corp.) system has been developed to address 2 of these factors (10-16). Because a targeting molecule administered first is not radiolabeled, the pretargeted RIT system does not suffer from prolonged radiation to normal organs due to slow accumulation at tumor sites. Since the radionuclide is delivered later on a small molecule (<1 kDa) that is rapidly excreted through the kidneys, radiation dose to normal organs from circulating radionuclide is substantially reduced. Thus, tumor-to- normal organ dose ratios are expected to improve by this approach.

We have conducted a phase I trial using pretargeted CC49 fusion protein. The CC49 fusion protein is a genetic fusion of the single- chain variable region (scFv) of the murine antibody that targets TAG- 72 and streptavidin (SA). Expression results in spontaneous folding into a tetramer containing 4 scFv of CC49 and the 4 subunits of SA. After pretargeting with CC49 fusion protein and use of synthetic clearing agent (sCA) to clear unbound fusion protein, ^sup 111^In/ ^sup 90^Y-DOTA-biotin (DOTA = dodecanetetraacetic acid) was injected to deliver ^sup 90^Y radiation to tumor sites. To our knowledge, this is the first study to determine the tissue distribution of ^sup 90^Y/^sup 111^In-DOTA-biotin after CC49 fusion protein by quantitative imaging and to report its radiation dosimetry for tumors and normal organs.

MATERIALS AND METHODS

Patients

Nine patients with previously treated metastatic colorectal cancer were enrolled in this study. These patients had failed at least 1 and no more than 3 prior therapy regimens. All patients had measurable tumors that were TAG-72 positive (>30% of cells) on immunoperoxidase staining, and patients had a negative antibody response to CC49 fusion protein. The median age was 58 y (range, 53- 78 y).

Pretargeting Components

The 3 steps of administering the pretargeting components have been previously described (11,12). The first of 3 steps involves the injection of the CC49 fusion protein that targets TAG-72. After allowing peak CC49-(scFv)^sub 4^SA levels to accrete at the tumor, a synthetic biotin galactosamine clearing agent (sCA), is injected to remove unbound CC49-(scFv)^sub 4^SA from the circulation. Finally, DOTA-biotin radiolabeled with ^sup 90^Y/^sup 111^In is injected and distributes rapidly throughout the vascular and extravascular space. All components were manufactured, tested, and released by NeoRx Corp. to the University of Alabama at Birmingham. Doses of the components and intervals between them were guided by preclinical studies and prior clinical trials of pretargeted RlT (10-16). All patients received 160 mg/m^sup 2^ of CC49-(scFv)^sub 4^SA. The sCA was administered either 48 or 72 h after CC49-(scFv)^sub 4^SA at a dose of 45 mg/m^sup 2^. The third component, ^sup 90^Y/^sup 111^In- DOTA-biotin, was then administered 24 h after the sCA at a dose of 0.65 or 1.3 mg/m^sup 2^ (Table 1). All patients received 185 MBq(S mCi) ^sup 111^In-labeled DOTA-biotin for imaging and dosimetry purposes, and patients 4-9 also received 370 MBq/m^sup 2^ (10 mCi/ m^sup 2^) of ^sup 90^Y at the same time.

TABLE 1

Patient Cohorts in the Trial

Quantitative Imaging

Planar conjugate whole-body images were acquired with a Philips dual-detector γ-camera interfaced to a nuclear medicine computer system (Philips Medical System). The detectors had a - thick (19 mm) NaI(Tl) crystal. Medium-energy collimators were used to image ^sup 111^In with energy windows centered at 171 and 245 keV (15% width). Transmission scan images were obtained using a ^sup 57^Co sheet source containing about 370 MBq (10 mCi). The same medium-energy collimators were used to image ^sup 57^Co with an energy window centered at 122 keV (15% width).

Phantom Study. To determine attenuation correction factors for the dual-detector γ-camera, 3 plastic bottles containing 50, 150. and 1,570 mL of ^sup 111^In solution were used to simulate tumor, kidney/spleen, and liver, respectively. Liver was quantified using geometric-mean quantification (17), and an attenuation correction factor was determined by flood transmission scan. Transmission images were acquired with the liver phantom ^sup 111^In solution placed on solid water blocks of various thickness (2-24 cm). Transmission fractions were determined by comparing counts in the liver phantom region of interest (ROI) with and without solid water blocks. ^sup 57^Co flood transmission images were also acquired with 2- to 24-cm solid water blocks. The liver phantom ROI defined from the ^sup 111^In image was transferred to define the ROI for the ^sup 57^Co images. Transmission fractions of ^sup 57^Co counts were determined by comparing counts in the ROI with and without solid water blocks. Effective linear attenuation coefficients, ^sub ^sup 57^Co^, were determined from these transmission fractions.

Since previous studies suggested that geometric-mean quantification was accurate only for a large source that was visible on both conjugate views, attenuation correction factors for kidney, spleen, and tumor were determined by the effective point source method (18). Attenuation correction factors for relatively small sources were determined using 50- and 150-mL ^sup 111^In sources placed on solid water blocks. Transmission fractions were determined by comparing counts in the source ROI with and without the blocks of various thickness (2-24 cm).

Patient Studies. Planar conjugate views of the whole body were acquired immediately after administration of ^sup 90^Y/^sup 111^In- DOTA-biotin and at 2, 24, 48\, and 120 or 144 h. Whole-body images were acquired in a 256 1,024 word matrix with a scan speed of 8-10 cm/min. Each patient's position on the imaging table and vertical positions of the camera detectors were recorded in the first imaging session and were used throughout the sequential imaging studies for reproducible detector-to-patient positioning. A 20-mL ^sup 111^In reference source containing 1.9-3.7 MBq (50-100 Ci) was placed on the imaging table at least 10 cm away from the patient's feet. The number of counts from this reference source was used to convert the counts in the tissue ROI to radioactivity in the tissue.

Before processing images, the operator reviewed the medical record, CT report, and CT images with the physicians for organ and tumor ROI determination. Major organs that were visible above body background after clearance of the blood pool were quantified. Although tumors were visible for each patient, tumors were quantified only if they met the following criteria for adequate accuracy: (a) ≥1 cm in diameter, (b) tumor-to-background pixel counts ratio of ≥ 1.5 (19), and (c) clear tumor ROI boundary. Some liver tumor masses were diffusely distributed and were excluded from image quantification. If a liver tumor appeared as a single mass (ROI) on γ-camera images but appeared as a group of several adjacent masses within the ROI on CT images, tumor mass was determined by excluding the portion of normal liver within the ROI on CT images.

Counts in ROIs were background corrected to subtract counts contributed from radioactivity in the background volume. Background ROIs were selected in regions of the body that had a thickness equivalent to that of the overlapping background volume for the organ or tumor for background ROI subtraction. Special attention was given to background subtraction for liver tumors because the tumors overlapped normal liver and softtissue background volumes. Two background ROIs were determined: one outside the liver and one adjacent to the tumor inside the liver. The thickness of the body background ROI outside the liver, the thickness of the liver ROI next to the tumor, and the thickness of the body soft tissue that overlapped with the tumor ROI and liver ROI were measured from CT for each liver tumor. These measurements were used to adjust the counts contributed from overlapped liver and soft-tissue background volumes.

Uptake of ^sup 90^Y/^sup 111^In in organs and tumors was expressed as the percentage of injected dose (%ID) at various imaging time points. The cumulated activity and biologic clearance half-life (t^sub b1/2^) were determined by fitting the uptake data with a monoexponential curve. If fit of a monoexponential curve was not possible, as uptake data continuously increased during the period of sequential imaging, cumulated activity was determined using the trapezoid method and a conservative estimation of the tail was used with a clearance rate of the physical half-life. For dosimetry purposes, the cumulated activity of ^sup 90^Y was determined from the biodistribution of ^sup 111^In and adjusted for the small difference in the physical half-life between ^sup 111^In and ^sup 90^Y.

FIGURE 1. Mean serum ([black circle]) pharmacokinetic values (%ID/ mL) after injection of ^sup 90^Y-DOTA-biotin. Error bars represent minimum and maximum values of 9 patients.

For comparison, standard radiation dose estimates were also calculated using MlRD Pamphlet No. 11 (26) based on Reference Man's phantom data, which generate results similar to those using the MIRDOSE III program (27).

RESULTS

Quantification of ^sup 90^Y/^sup 111^In in Serum

With most elimination through the urine, <10% of the injected ^sup 90^Y/^sup 111^In-DOTA-biotin remained in the circulation after 8 h. The biphasic serum clearance curve of ^sup 90^Y/^sup 111^In- DOTA-biotin is illustrated in Figure I. The concentration of ^sup 90^Y- DOTA-biotin in serum quickly dropped below 0.002 %ID/mL about 2 h after injection of ^sup 90^Y-DOTA-biotin. The range (minimum to maximum) of variation among 9 patients was modest (Table 2). The α-clearance phase, accounting for 90% of the dose, had a mean biologic half-life of 0.5 h, with a mean intercept of 0.0075 %ID/ mL. The β-clearance phase had a mean biologic half-life of 18.3 h and a mean intercept of 0.0012 %lD/mL.

TABLE 2

Biphasic Clearance Parameters for Pharmacokinetics of ^sup 90^Y- DOTA-Biotin in Serum

In patients 4-9, serum clearance between ^sup 111^In and ^sup 90^Y measurements was fairly close for each of these 6 patients (Fig. 2). The difference in mean weighted %ID/mL between ^sup 111^In and ^sup 90^Y was -2.8% for patient 4, 18.9% for patient 5, 21.4% for patient 6, -25.4% for patient 7, -3.0% for patient 8, and 13.2% for patient 9. The mean difference of absolute values in mean weighted %ID/mL was 14.1% (mean difference, 3.7%) between ^sup 111^In and ^sup 90^Y.

Quantitative Imaging

Phantom Studies. Transmission counts versus depth almost fit a straight line on a semilogarithmic plot for 50-and 150-mL ^sup 111^In sources (Fig. 3), with the linear regression correlation coefficient R^sup 2^ > 0.99. The linear attenuation coefficients (^sub ^sup 111^In^) were determined to be 0.126 cm^sup -1^ for the 50-mL ^sup 111^In source and 0.122 cm^sup -1^ for the 150-mL ^sup 111^In source. Subsequently, the value of 0.126 cm^sup -1^ was used for attenuation correction of tumors ≤50 g. A value of 0.122 cm^sup -1^ was used for attenuation correction of kidney, spleen, and large tumors of ≥150 g.

Transmission fractions were determined for a liver phantom at various depths (Fig. 4). There was a small difference between the linear attenuation coefficient obtained from transmission of the ^sup 111^In in the liver phantom (0.113 cm^sup -1^) and that obtained from the transmission scan using a ^sup 57^Co sheet source (0.119 cm^sup -1^) (Fig. 3). Subsequently, the ACF for the following patient studies was determined by (N^sub no pt^/N^sub pt^)^sup 0.475^ for liver quantification according to Equation 2.

Patient Studies. In addition to whole-body ROI counts, ROI counts were obtained for liver, spleen, kidneys, bladder, and tumors, as they were visualized above body background (Fig. 5). Except for the whole body, tissue uptake in %ID/g was determined using patient- specific tissue masses measured from CT images. The mean patient body weight was 86.5 kg, with a range of 63.6-113.0 kg. The mean organ masses were 2,616 g (range, 1,263-3,855 g) for liver, 380 g (range, 95-1,009 g) for spleen, 437 g (range, 307-598 g) g for kidneys, and 2,044 g (range, 1,560-2,884 g; n = 3, assuming lung density of 0.3 g/mL (28)) for lungs (Table 3). Although tumors were visualized in each patient, 13 tumors in 7 of 9 patients met the criteria for image quantification as described and were quantified. The mean tumor mass was 38.3 g (range, 1.1-200.0 g). The mean depth (from the center of the organ to the body surface) was 10.6 cm for kidneys and 8.3 cm for the spleen. Correspondingly, the mean attenuation correction factor was 3.64 for kidneys and 2.75 for spleen using the above measured ^sub ^sup 111^In^.

FIGURE 2. Serum concentration (%ID/ mL) of ^sup 90^Y-DOTA-biotin and ^sup 111^In-DOTA-biotin measured in patients 4-9. Serum clearance between ^sup 90^Y and ^sup 111^In measurements was fairly close.

The peak uptake in normal organs usually occurred at the initial imaging time point. The peak occurred at a later imaging time in 5 of 13 tumors (Fig. 6) and in liver for 2 of the 9 patients. In general, the t^sub b1/2^ of kidneys was shorter than that of liver and spleen. The mean t^sub b1/2^ was 48 h for the whole body, 207 h for normal liver, 97 h for spleen, 77 h for kidney, 65 h for lung, and 133 h for tumors. Tumors had the highest peak uptake per gram of tissue mass (%ID/g) among all tissues (Table 4). The mean peak %ID/ g was 0.032 for tumor, 0.0028 for normal liver, 0.0032 for spleen, 0.012 for kidney, and 0.0005 for lung.

FIGURE 3. Transmission counts vs. source depth. ^sup 111^In sources of 50 and 150 mL were used to simulate tumor and kidney/ spleen, respectively. Source depth was defined as solid water thickness added to distance of source center from source surface. Caret (^) is exponentiation operator.

FIGURE 4. Transmission counts vs. source depth. ^sup 111^In source of 1,570 mL was used to simulate liver ([white triangle up]). Liver phantom transmission counts were also determined using ^sup 57^Co sheet source ([black circle]). Source depth was defined as solid water thickness (2-24 cm) added to distance of source center from source surface. Caret (^) is exponentiation operator.

Patient-Specific Dosimetry

Organ doses based on MIRD Reference Man's phantom mass versus patient-specific masses are compared in Table 5. The mean patient- specific body dose was 0.53 cGy/37 MBq. The mean patient-specific organ doses include 3.75 cGy/37 MBq for normal liver, 2.32 cGy/37 MBq for spleen, 7.02 cGy/37 MBq for kidneys, 0.30 cGy/37 MBq for lungs, 0.22 cGy/37 MBq for marrow, and 28.9 cGy/37 MBq for tumors. The tumor-to-normal tissue dose ratio was 54.5 for the whole body, 7.7 for normal liver, 12.5 for spleen, 4.1 for kidney, 96.3 for lung, and 131.4 for marrow.

FIGURE 5. Whole-body images of ^sup 111^In- DOTA-biotin immediately, 3 h, 1 d, 2 d, and 4 d after injection. Liver, spleen, kidneys, bladder, and tumors in liver were visualized above body background. Ant = anterior; Post = posterior.

There was substantial variation in organ dose from patient to patient. The ratios of the highest dose to the lowest dose among 9 patients were 10.9 for normal liver, 7.7 for spleen, 3.3 for kidneys, 4.9 for lungs, and 2.8 for marrow. Considerable differences in organ doses were noted dependent on use of MIRD Reference Man's phantom data versus patient-specific masses. The deviation of actual dose from MIRD Reference Man's model was as muchas 11% underestimation or 59% overestimation for the whole body, 30% underestimation or 1 13% overestimation for normal liver, 47% underestimation or 454% overestimation for spleen, 92% overestimation for kidney, and 190% overestimation for lung.

DISCUSSION

CC49 is a second-generation murine antibody with anti-TAG-72 (tumor-associated antigen) reactivity to gastric, pancreatic, and colon adenocarcinomas (29). A single intravenous administration of ^sup 131^I-CC49 has been used in phase I and phase II clinical trials at multiple institutions for metastatic GI cancers (5-7,30). With 1.11-3.33 GBq/m^sup 2^ (30-90 mCi/m^sup 2^), no objective tumor responses were observed and limited normal organ and tumor dosimetry was reported. In a high-dose study (7), patients received a single dose of 1.85-11.1 GBq/m^sup 2^ (50-300 mCi/m^sup 2^) ^sup 131^I- CC49 after collection and cryopreservation of hematopoietic stem cells adequate for 2 autologous transplants. No objective responses were observed with a mean tumor-to-marrow ratio of 4.0 (range, 2.5- 6.1) in the 5 patients analyzed. Although extrahematopoietic dose- limiting toxicity was neither observed nor predicted, suboptimal tumor uptake (%ID/g, 0.0002-0.0021) suggested that further escalation of ^sup 131^I-CC49 would not be useful (7).

TABLE 3

Patient Body Weight and Organ/Tumor Masses Determined by CT Images

In a subsequent high-dose study using long-range β- radiation, patients received a single dose of 11.1-18.5 MBq/kg (0.3- 0.5 mCi/kg) ^sup 90^Y-CC49 after collection and cryopreservation of hematopoietic stem cells (9). Although 2 of 12 patients had stable disease durable for 2 and 4 mo, no objective responses were observed. The patient-specific dose for liver, spleen, and tumor based on SPECT plus the marrow dose based on activity in the blood were reported (Table 6) (9,30). Because our current study and the studies of Tempero et al. (9) and Leichner et al. (30) used the same radionuclides, ^sup 90^Y/^sup 111^In, the difference in tissue dosimetry should be mainly due to the difference in tissue distribution of intact antibody CC49 and pretargeted CC49- (scFv)^sub 4^SA. The radiation dose per injected activity to each reported normal organ (liver, spleen, and marrow) was smaller using pretargeted CC49-(scFv)4SA compared with that of intact CC49 (Table 6), whereas the tumor-to-normal organ dose ratios were >8-fold greater for liver and marrow.

FIGURE 6. Tumor %ID/g vs. time for 13 tumors in 7 patients.

A few previous clinical trials using the pretargeted system have been performed. 90Y-DOTA-biotin after NR-LU-10-SA has been conducted for patients with metastatic colon cancer (11). Unfortunately, the results of this phase II trial were not encouraging due to a high incidence of GI toxicity resulting from cross-reactivity of the NR- LU-IO with the bowel epithelium. The estimated mean radiation dose to the small intestine could be as high as 66.5 cGy/37 MBq (or rad/ mCi) (77). Consequently, the advantage of pretargeting was not realized using NR-LU-IO antibody. Imaging (Fig. 5) and dosimetry (Table 5) results of the current study are consistent with prior clinical trials of murine CC49 antibody, demonstrating no observable cross-reactivity with normal tissues. The proof of principle of the potential advantages of pretargeting has been demonstrated in lymphoma patients, where tumor-to-normal tissue ratios for liver, spleen, and marrow have been >50 (14,16).

Because of the relatively small molecular size of the DOTA- biotin and rapid urinary excretion of unbound ^sup 90^Y- DOTA- biotin, the kidney could be the potential dose-limiting organ for pretargeting with CC49-(scFv)4. Though there was no direct report on kidney dosimetry for colon cancer trials using CC49, a similar trial using ^sup 131^I-CC49 and α-interferon for prostate cancer reported a kidney dose of 4.9 cGy/37 MBq (4.9 rad/mCi) (31). The mean tumor-to-kidney dose ratio was 3.9 for ^sup 131^I-CC49 compared with a mean dose ratio of 4.1 for pretargeted CC49-(scFv)^sub 4^ of the current study. Projecting for a kidney dose at tolerance level (TD^sub 5/5^ [the probability of 5% complication within 5 yj) of 2,300 cGy, as used for fractionated external-beam radiation (32), the mean radiation dose to tumor from the pretargeting scheme of CC49-(scFv)^sub 4^SA followed by ^sup 90^Y- DOTA-biotin would be 9,460 cGy. This mean dose is much higher than reported-180-3,000 cGy from ^sup 90^Y-CC49 (9) or 630-3,300 cGy from ^sup 131^I-CC49 (7)- and is expected to be cytotoxic to GI adenocarcinomas.

TABLE 4

t^sub b1/2^ and Peak Tissue Uptake as Percentage Injected Dose per Gram (%ID/g)

MIRD dosimetry based on a patient population-averaged Reference Man's phantom provides a convenient method for organ dose estimates when exact organ masses are not available or are difficult to obtain. However, organ dose can be substantially under- or overestimated because of the large variation in organ size. In the current study, we noted that organ doses were more likely to be overestimated using Reference Man's mass. This is likely due to the tendency that body weight and organ masses in the current population are larger than that of Reference Man measured decades ago (33).

TABLE 5

Radiation Dose per Injected Activity (cGy/37 MBq) Based on MIRD Reference Man's Mass and Patient-Specific Organ Mass

The experimental methods described here to determine ^sub ^sup 111^In^ and ACF^sub ^sup 111^In^ using the ^sup 111^In phantom and ^sup 57^Co flood source can be applied to determine μ and ACF for other radionuclides. However, the numeric values of ^sub ^sup 111^In^ and ACF^sub ^sup 111^In^ reported here cannot be simply applied to γ-cameras of different specifications without confirmation. Our camera had -in. NaI(Tl) crystals compared with 3/ 8-in. crystals commonly used in most clinical settings.

There are uncertainties in marrow dose estimation using the standard blood method for ^sup 111^In/^sup 90^Y-labeled pharmaceuticals (34) since the small portion of free ^sup 90^Y- chelator or ^sup 90^Y could have a different distribution compared with that of the small portion of free ^sup 111^In-chelator or ^sup 111^In (35). The blood method assumes no specific uptake of ^sup 111^In/^sup 90^Y in marrow. This assumption becomes invalid if marrow has active uptake or free ^sup 111^In/^sup 90^Y or ^sup 111^In/^sup 90^Y-cheletor is recycled into the marrow spaceTtrabecular bone surface after radiopharmaceuticals are metabolized. In the current study, CC49 fusion protein does not bind to marrow. The amount of free ^sup 111^In/ ^sup 90^Y or ^sup 111^In/ ^sup 90^Y-chelator recycled into the marrow space/ trabecular bone surface may not be significant because marrow was not visualized above body background in our patient images. In other ^sup 111^In/ ^sup 90^Y-antibody studies, ^sup 111^In was visualized in the marrow even when the antibodies were nonmarrow binding (34). In pretargeted NR-Lu-10/ SA, where ^sup 111^In was not visible in marrow, the blood method worked well for predicting ^sup 90^Y-induced toxicity (r = 0.77) (TO). Extrapolation of ^sup 90^Y concentration in serum from ^sup 111^In introduces another uncertainty. However, in the current study, serum clearance between ^sup 111^In and ^sup 90^Y measurements was fairly close for each of these 6 patients (Fig. 2). The mean difference of absolute values in mean weighted %ID was 14.1% between ^sup 111^In and ^sup 90^Y in 6 patients.

TABLE 6

Comparison of Mean (and Range) of Patient-Specific Organ and Tumor Doses for Directly Labeled Intact ^sup 90^Y/^sup 111^In-CC49 Antibody and Pretargeted CC49 Fusion Protein Followed by ^sup 90^Y- DOTA-Biotin

CONCLUSION

The dosimetry results of the current study demonstrate substantially improved tumor-to-normal tissue dose ratios compared with that of previously reported RIT trials for metastatic Gl cancer.

ACKNOWLEDGMENTS

This work was partly supported by NeoRx Corp. and grants P50 CA89019-03 and MOl RR 00032 from the National Cancer Institute.

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Sui Shen, PhD1; Andres Forero, MD2; Albert F. LoBuglio, MD2; Hazel Breitz, MD3; M.B. Khazaeli, PhD1; Darrell R. Fisher, PhD4; Wenquan Wang, PHD5; and Ruby F. Meredith, MD, PhD1

1 Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; 2 Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; 3 NeoRx Corp., Seattle, Washington; and 4 Pacific Northwest National Laboratory, Richland, Washington; and 5 Biostatistics Division, Comprehensive Cancer Center, Universitv of Alabama at Birmingham, Birmingham, Alabama

Received Mar. 25, 2004; revision accepted Nov. 17, 2004.

For correspondence or reprints contact: Sui Shen, PhD, Department of Radiation Oncology, University of Alabama at Birmingham, 1824 6th Ave. S., Wallace Tumor Institute Room 124, Birmingham, AL 35294.

E-mail: sshen@uabmc.edu

Copyright Society of Nuclear Medicine Apr 2005

Source: Journal of Nuclear Medicine, The

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