Purpose: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients.

Experimental Design:111In-DOTA-2IT-m170 and 111In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated.

Results: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31%; P < 0.01) and lungs (31%; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30% increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.

RIT3 in lymphoma has proven to be clinically useful using several different RICs (1, 2, 3). RIT at myeloablative levels with 131I MAb and bone marrow support has demonstrated higher tumor response, marked increase in complete response, and nonmarrow normal organ toxicities that correlated with the calculated dose to the organs estimated from imaging (1, 4, 5). These studies provided an approach for high-dose RIT with marrow support whereby tolerable administered doses could be selected from imaging-based calculations. Because marrow support can now be provided by APBSCs, high-dose myelotoxic and myeloablative RIT combined with APBSCs could become useful therapy for a broader range of patients and cancers (6). In this general approach, other organs become dose limiting.

MAbs conjugated with RMCs have been increasingly selected to deliver radioisotope therapy because of greater tumor uptake and retention of the radionuclide compared with 131I (7, 8, 9). 90Y provides more homogeneous tumor irradiation because of its energetic β emissions, minimal need for shielding of medical personnel and family members, and predictive dosimetry calculations projected from 111In analogues of the 90Y RICs (1, 10, 11, 12, 13, 14). RIT dosimetry calculations from most RMCs demonstrate the liver to be the next dose-limiting organ after marrow (6, 15, 16). Because a large fraction of RICs are bound to hepatocyte receptors, internalized, and retained, their decay can result in significant absorbed dose to the liver. In contrast, hepatocyte processing removes 131I from 131I MAb in a manner that allows rapid hepatic and body clearance. To take advantage of enhanced tumor uptake and retention of RMCs, we sought to promote hepatocyte cleavage of the RMC from its MAb carrier, in a manner that might result in rapid elimination of the RMC from the liver and body, but not tumor, by placing a peptide having a specific cathepsin B cleavage site between the RMC and MAb (17, 18, 19, 20).

Many investigators over the past 25 years have studied possible hepatocyte biodegradable MAb RMC linkages to reduce liver retention and radiation dose (21, 22, 23, 24, 25). A variety of radiolabeled MAbs with such linkages have been developed and evaluated in vitro and in vivo. A few have demonstrated modestly enhanced TI in animal models (24, 25, 26). Considering a different approach, a peptide originally developed for lysosomotropic prodrug delivery (27), Ala-leu-ala-leu, was evaluated as a MAb-radiochelate linker that might be digested in liver cells, accelerating the clearance of radiolabeled chelate (28). Although in vitro this RIC linkage was rapidly cleaved by the liver protease cathepsin B, in vivo studies in mice demonstrated no decrease in liver retention of the radiometal (22). The possible effect of charge on retention of cleaved RIC, led to the design of a cathepsin degradable linkage in which the cleaved RIC had a net charge of zero (19, 29). This peptide chelate linkage, DOTA-GGGF-ITC, was initially studied in breast cancer patients as the RIC 111In/90Y-DOTA-peptide-ChL6 (30). Decreased liver activity and excellent tumor targeting provided a remarkable tumor:liver TI as high as 35:1 (30). Lack of available ChL6 MAb for additional clinical studies prohibited comparison of the same MAb with different RIC linkers.

Here, we report the comparative study of two RICs of the pancarcinoma MAb m170 (31, 32, 33), differing only in the RIC linkage (Fig. 1). Each patient received 111In-DOTA MAb m170 either with (DOTA-peptide) or without the GGGF tetra-peptide linkage (2IT-BAD). Pharmacokinetics were obtained from quantitative imaging and blood clearance, and the 90Y dosimetry was calculated. Radiation dose (rads/mCi) was evaluated for blood, body, tumor, and normal organs for each patient in the two patient groups, and the groups were compared with the intent to determine whether a clinically relevant decrease in radiation dose to liver was achieved with the GGGF-linked RIC without a significant reduction in the mean tumor dose, or an increased dose to other normal organs.

Patient Characteristics.

Twenty-five patients who had androgen-independent progressive prostate cancer were entered on one of two RIT protocols, each requiring a RIC quantitative imaging pharmacokinetic/dosimetry study 1 week before RIT. Both protocols required a Karnofsky score of 70% and adequate liver function studies (normal bilirubin and aspartate aminotransferase <1.5 × the upper limit of normal), normal renal function, adequate blood counts (neutrophils, >1599 μl; platelets, >100,000/μl; hemoglobin, >10.0), and less than 25% bone marrow involvement. All patients had computed tomography and bone scan evaluations before protocol entry. The initial quantitative imaging pharmacokinetic/dosimetry study from each patient was used in this comparative analysis.

Radiopharmaceuticals.

MAb m170 is a murine IgG developed using a synthetic asialo GM1 terminal disaccharide immunogen related to the Thompson-Friedenreich disaccharide (31, 32, 33). m170 binds to a variety of human adenocarcinomas with high affinity (4 × 108m−1; Ref. 34), and scintigraphic studies previously demonstrated targeting of breast, prostate, lung, and ovarian cancers with no normal tissue targeting (6, 31). m170 (cyclic GMP grade) was obtained in human use form, manufactured under appropriate good manufacturing practice regulations by Biomira, Inc. (Edmonton, Canada), was greater than 95% monomeric IgG by PAGE, and met United States Food and Drug Administration guidelines.

Preparation of ICs.

DOTA was conjugated to m170 as 2IT-BAD-m170 (IC), as described previously (35, 36). Briefly, 2IT-BAD-m170 was prepared as follows. BAD, 2IT, and m170 were combined in 0.1 m tetramethylammonium phosphate (pH 7.8) at final concentrations of 2 mm, 1 mm, and 0.1 mm, respectively. The solution was incubated at 37°C for 30 min. The IC was purified and transferred for radiolabeling to 0.1 m ammonium acetate buffer by molecular sieving filtration (Sephadex G50–80; Pharmacia, Upsala, Sweden; Refs. 37 and 38).

DOTA-peptide-m170 was prepared as follows. DOTA-peptide-ITC was prepared by the methods described previously (39). DOTA-peptide-ITC and m170 were combined in 0.1 m tetramethylammonium phosphate (pH 9) at final concentrations of 1.75 mm and 0.46 mm, respectively. The solution was incubated for 60 min at 37°C. The IC was purified and transferred for radiolabeling to 0.1 m ammonium acetate by molecular sieving filtration. Both ICs were evaluated to assure sterile, pyrogen-free status and one to three metal-binding sites per MAb by published methods (40).

Radiolabeling and Quality Control.

To prepare 111In-2IT-BAD-m170 and 111In-DOTA-peptide-m170, the IC and 111In (Amersham, Arlington Heights, IL; or Nordion, Kanata, Ontario, Canada) were combined in 0.1 m ammonium acetate (pH 5.0) and incubated 30 min at 37°C. To scavenge nonspecifically bound 111In, EDTA was added to a final concentration of 10 mm for 15 min at room temperature. The RICs were purified by molecular sieving chromatography.

RICs were examined by molecular sieving high-performance liquid chromotography (Beckman Coulter System Gold 127; Beckman, San Ramon, CA; SEC-3000 molecular sieving column), cellulose acetate electrophoresis (Gelman Sciences, Inc., Ann Arbor, MI), and RIA (40, 41). Immunoreactivity was assayed retrospectively by allowing the RICs to decay to background, then performing a competitive assay against lightly iodinated 125I-m170. In this competitive assay, the decayed RIC competed with 125I-labeled m170 for binding with rabbit anti-m170 idiotype in the solid state. Unmodified m170 was assayed as a control. High-performance liquid chromotography indicated that 95% or more of radiometal was associated with RICs. Cellulose acetate electrophoresis indicated that 98% or more of all RICs were in monomeric form. Immunoreactivity for all pharmaceutical preparations far exceeded the defined Food and Drug Administration Investigative New Drug guidelines requiring the competitive binding of the decayed pharmaceutical against 125I-m170 to be greater than 50% of unmodified m170.

Pharmacokinetics and Radiation Dosimetry.

111In RIC (5 mCi of 111In with 6–8 mg of m170) was injected i.v., followed by quantitative imaging over the next 7 days, serial blood samples, and quantitated urine samples from each 24-h collection. Blood and urine radioactivity was counted in a gamma well counter and compared with a standard prepared from the radiopharmaceutical that was injected into the patient. The %ID in the blood was calculated using the body weight to estimate blood volume, and daily %ID in urine output was calculated using the collected daily total urine volume; a biexponential function was used to determine cumulated activity in blood.

Pharmacokinetic data from imaging was obtained as described previously (10, 42). Briefly, planar whole body and regional images of conjugate views were acquired immediately, at 4 h, and at least three times during the remaining 7-day period after administration of 111In-2IT-BAD-m170 or 111In-DOTA-peptide-m170 (Ref. 10; Fig. 2). The geometric-mean method was used to quantify activity in the organs and tumors clearly delineated on conjugate views (e.g., liver and spleen), and photon attenuation was corrected using the transmission scan (43). The effective-point source method was used to quantify activity in most tumors and kidneys. For these small organs and tumors, photon attenuation was corrected using measured values that matched the small-source geometry. Lung activity was derived as described previously, using a posterior view area of interest over a central nontumored area of each lung field, normalized to total pixels for the given lung (42).

Cumulated activity in tissues other than liver was obtained by fitting pharmacokinetic data to a monoexponential function. In the liver, pharmacokinetic data, as decay-corrected activity, was fit with a cubic spline, assuming constant decay-corrected activity beyond the final time point measured. Cumulative activity of tumors was also determined by area under cublic spline if a monexponential fit was not possible. Cumulated activity was converted to radiation dose for 90Y using the Medical Internal Radiation Dose formula, Medical Internal Radiation Dose S values, and reference-man masses (44). The radiation dose from blood to marrow was calculated as described previously: Dtotal = 0.25 Ãblood Δnp, where Ãblood is the cumulated activity in 1 ml of blood and Δnp is the mean energy emitted per nuclear transition for nonpenetrating 90Y emissions. The constant 0.25 was used to account for the difference between the specific activities of marrow and that of circulating blood (45). Radiation dose determined for marrow to marrow dose was extrapolated as described previously from uptake in three lumbar vertebra in patients without evidence of tumor involvement in this area (36, 43).

For accurate tumor dosimetry, only tumors with a measured volume of 10 ml or greater were used for dosimetric calculations. Tumor dimensions were determined using radiographic measurements; volume was determined as described previously (36). Thirty-two sites of metastatic prostate cancer with 111In-2IT-BAD-m170 and 23 with 111In-DOTA-peptide-m170 met the criteria for dosimetric analysis.

For the initial calculations (Table 1), no dose losses attributable to β particles exiting the tumor volumes were assumed. Absorbed dose values were then calculated based on individual tumor volumes (Ref. 46; Table 2).

Statistical Methods.

The cumulative activity for organs, tumor, and blood and body per patient was determined as described previously. To test for differences between the linkers, a Wilcoxon rank sum test was used. All reported Ps were two tailed.

Pharmacokinetic and imaging studies were performed in the 25 prostate cancer patients, 17 with 111In-2IT-BAD-m170 and 8 with 111In-DOTA-peptide-m170. Quality of the radiopharmaceuticals was equivalent with >98% of the RIC pharmaceuticals in monomeric form at the time of injection, and retrospective analysis demonstrated excellent immunoreactivity. The blood clearances (mean ± 1 SD) for both RICs are shown in Fig. 3 A and were not statistically different.

Data for quantitative analysis of tumor and normal organs in both patient groups are provided in Table 1. The mean cumulative activity and, therefore, the mean liver radiation dose (rads/mCi) for DOTA-peptide-m170 was 30% less than the mean 2IT-BAD-m170 liver dose (Table 2). Mean liver uptake (%ID) of each group over the 7-day study is shown in Fig. 3 B.

The mean urinary excretion of radioactivity from both RICs comprised 16–17% of the injected radioactivity by 6 days after injection and 1–4% by 24 h. Although not statistically different, there was an apparent difference in the mean urinary excretion between the two RIC groups, with the DOTA-peptide-m170 patients excreting >2% more of the injected dose during the first 24 h. This difference was maintained over several days. If 2% of ID radioactivity is converted to μCi/h and calculated as additional uCi/h in the liver of the DOTA-peptide-m170 patients, the 31% difference of mean radiation dose to liver between the two RIC groups (rads/mCi) becomes less than a 15% difference.

The rads/mCi to other normal organs with DOTA-peptide-m170 was either lower (lung) or not statistically different. Imaging studies demonstrated excellent tumor uptake for both RICs (Fig. 2), and calculated tumor dose (rads/mCi) for the two RICs was not statistically different (Table 2). Radiation dose (rads/mCi; marrow to marrow) from lumbar vertebra imaging was indistinguishable between groups (2IT-BAD, 4.1–9.0; DOTA-peptide, 3.6–9.7).

Patients with androgen-independent metastatic prostate cancer have limited therapeutic options. Once metastases have occurred, androgen ablation is the only treatment that prolongs life, resulting in 50% survival at 2.5 years (47, 48, 49). Standard therapies merely provide temporary or incomplete palliation of symptoms. Because this disease has shown little substantial response to cytotoxic chemotherapy, but is relatively responsive to radiation, a therapy that delivers tumoricidal radiation to widespread metastatic deposits has the potential to provide useful impact. Conceptually, tumor-targeted high-dose RIT with marrow support or RIT as part of combined multimodality therapy can offer effective therapy for this lethal disease.

Using CC49, 131I RIT studies in prostate cancer patients have demonstrated only modest tumor targeting, with no patients having objective criteria for response (50, 51). In a recently reported Phase I maximum tolerated dose study of 111In/90Y-2IT-BAD-m170 in patients with metastatic prostate cancer, excellent targeting of both bony and soft tissue metastasis, as well as temporary palliation of pain and effect on prostate-specific antigen levels were demonstrated (52). Other RMC/RIT pharmaceuticals under development have been reported to have therapeutic response in animal models (53) and excellent tumor targeting in clinical studies (54). Such RMCs for RIT have generally resulted in greater tumor radiation dose per administered radionuclide dose than was demonstrated in 131I RIT studies, but this has been accompanied by a substantial increase in the radiation dose to liver (7, 8, 54). Published studies provide 90Y dosimetry (rads/mCi) calculated from 111In kinetics with liver dose ranging from 17 rads/mCi of 90Y anti-CD20 (Zevalin) in 27 patients specifically evaluated for dosimetry (15) to 29 rads/mCi of 90Y-DTPA-C84.66 in patients with metastatic carcinoembryonic antigen-producing malignancies (16). Similar results have been reported by others (55, 56, 57). Because the hepatic toxicity dose limit approximates 3000 rads from external beam irradiation (58), such a limitation, if applicable, would allow 100–150 mCi of 90Y MAb for APBSC-supported RIT therapy with these respective RICs.

To provide tumor-targeted therapy to metastatic prostate cancer at a level that can be tumoricidal, enhancing the TI between the radiation dose to tumor and that delivered to the most sensitive and, therefore, dose-limiting tissue becomes the key to success. Because bone marrow support by APBSC is now available to ameliorate hematological toxicity, the radiation dose to liver becomes the limiting factor. As described previously, a peptide having a specific cathepsin B cleavage site was placed between the RMC DOTA and the MAb m-170 to increase elimination of radioactivity from the liver and, thus, minimize the hepatic dose. Here, we have reported the comparison of yttrium dosimetry from indium pharmacokinetics for this RIC, In-DOTA-peptide-m170, and In-2IT-BAD-m170 in two similar groups of prostate cancer patients. The m170 MAb has been studied previously as an imaging agent as both 111In DTPA MAb and 99mTc-MAb (32), and RIT studies with 111In/90Y-2IT-BAD-m170 have been reported in breast cancer patients (6, 59). The therapeutic potential of 90Y-2IT-BAD-m170 in metastatic breast cancer was minimized by a mean liver dose of 18 rads/mCi, although excellent tumor targeting was achieved.

In this study, the prostate cancer patients receiving 111In/90Y-2IT-BAD-m170 had excellent targeting of tumor in both bone and soft tissue, with a mean tumor radiation dose of 36.4 rads/mCi but a mean liver dose of 14.7. The patients receiving 111In-DOTA-peptide-m170 had 31% less cumulative radioactivity in the liver (10.2 rads/mCi), whereas the tumor dose between the two groups was not statistically different (Table 2). Because both RIC pharmaceuticals were documented to meet the same rigorous standards at the time of administration, including the molecular size profile, and the resulting blood clearances (Fig. 3,A) were remarkably equivalent, the difference in liver cumulative activity and radiation dose likely results from differences in RIC kinetics in liver cells. The liver uptake (%ID) demonstrated a difference in the mean uptake of each group, and the difference during the first 48 h is approximately 4%ID (Fig. 3,B). The mean %ID excreted in the urine by the two groups is not statistically different, but because only a difference in 4–5%ID dose in the liver results in 31% difference in liver radiation dose between the RICs, it should be noted that the mean of the measured excreted radioactivity of DOTA-peptide-RIC was >2% greater than that from 2IT-BAD-RIC. It is possible that small differences in excretion of the ID radioactivity in the urine, which are difficult to document, may account for the RIC difference in net liver %ID and, thus, in calculated radiation dose. Thus, the 31% reduction of the mean liver dose/mCi between the two RICs could be because of small differences in net hepatic uptake, processing, and excretion of the radioactive portion of DOTA-peptide-m170. The divergence of the mean %ID in liver between the two RIC groups over time (Fig. 3 B), as the blood radioactivity is decreasing toward 10%ID, may suggest an ongoing hepatic output function for the DOTA-peptide-RIC not occurring with 2IT-BAD. Of note, only minimal bowel radioactivity (<2%) was detected in stool collections of patients in either group (data not shown).

Here, we describe the pharmacokinetics and 90Y dosimetry for two RICs for prostate cancer RIT. The new radiopharmaceutical differs only in the RIC peptide linkage, a cathepsin B cleavable linkage, resulting in a small noncharged RMC peptide product in the published in vitro studies (20). The RICs pharmacokinetics and calculated tumor- and normal organ-absorbed radiation doses were similar, except for a significant decrease in the dose to the liver and lungs with the DOTA-peptide IC. No reasons could be found for the decrease in lung dose. Because mean tumor dose was not statistically different, the increase in calculated TI provides radiation dose estimates that suggest a substantial impact could be achieved using APBSC to ameliorate hematological toxicity. This should allow dosimetry-driven escalation of the administered dose of this RIC in metastatic prostate cancer patients to achieve clinically relevant therapeutic levels.

1

Presented at the “Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates,” October 24–26, 2002, Princeton, NJ. This study was supported by grants from the National Cancer Institute (PO1-CA47829), the Department of Energy (DE-FG01-00NE22944), and the Department of Defense (DAMD 17-01-1-0177).

3

The abbreviations used are: RIT, radioimmunotherapy; 131I, iodine-131; ChL6, chimeric mouse-human IgG1 L6 monoclonal antibody; 111In, indium-111; 90Y, yttrium-90; DOTA, 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid; 2IT, 2-iminothiolane; BAD, 2-[p(bromoacetamido)benzyl]-1,4,7,10-tetraazocyclododecane-N,N′,N″,N‴-tetraacetic acid; RIC, radioimmunoconjugate; IC, immunoconjugate; DTPA, diethylenetriaminepentaacetic acid; %ID, percentage of injected dose; MAb, monoclonal antibody; TI, therapeutic index; DOTA-GGGF-ITC, DOTA-glycylglycylglycyl-l-p-isothiocyanatophenylalanine amide; DOTA-peptide-m170, 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-glycylglycylglycyl-l-(p-isothiocyanate)-phenylalanine amide; m170, MAb 170H.82; APBSC, autologous peripheral blood stem cell; RMC, radiometal chelate.

Fig. 1.

Schematic illustrating the two linkages of DOTA Mab: 2IT-BAD-m170 (top) and DOTA-GGGF-m170 (DOTA-peptide; bottom) linkage designed for cleavage by cathepsin B (→). MAb m170 was used in both ICs.

Fig. 1.

Schematic illustrating the two linkages of DOTA Mab: 2IT-BAD-m170 (top) and DOTA-GGGF-m170 (DOTA-peptide; bottom) linkage designed for cleavage by cathepsin B (→). MAb m170 was used in both ICs.

Close modal
Fig. 2.

Planar scintigraphic images of the posterior pelvis of two prostate cancer patients 3 days after receiving 111In-DOTA-peptide-m170 (A) and 111In-2IT-BAD-m170 (B). Tumor uptake is easily visualized.

Fig. 2.

Planar scintigraphic images of the posterior pelvis of two prostate cancer patients 3 days after receiving 111In-DOTA-peptide-m170 (A) and 111In-2IT-BAD-m170 (B). Tumor uptake is easily visualized.

Close modal
Fig. 3.

A, blood clearance (mean ± SD) 111In-2IT-BAD-m170 (▪) and 111In-DOTA-peptide-m170 (•) from the two groups of prostate cancer patients. B, liver uptake (%ID; mean ± SD) at 1, 4, 24, 72, and 144 h after injection of 111In-2IT-BAD-m170 (▪) and 111In-DOTA-peptide-m170 (•). The difference in uptake of the two RICs in liver not only occurred early but increased over time.

Fig. 3.

A, blood clearance (mean ± SD) 111In-2IT-BAD-m170 (▪) and 111In-DOTA-peptide-m170 (•) from the two groups of prostate cancer patients. B, liver uptake (%ID; mean ± SD) at 1, 4, 24, 72, and 144 h after injection of 111In-2IT-BAD-m170 (▪) and 111In-DOTA-peptide-m170 (•). The difference in uptake of the two RICs in liver not only occurred early but increased over time.

Close modal
Table 1

Radiation dose (rads/mCi) to organs in each patient

PatientLinkerBodyLiverKidneySpleenLungTumor (n)aBld/Marb
2IT 2.4 17.3 6.1 14.7 6.0 26.8 (1) 2.4 
2IT 2.3 11.7 7.3 7.8 4.6 29.9 (3) 2.2 
2IT 2.3 12.0 5.6 17.8 4.3 41.1 (1) 2.9 
2IT 2.3 10.9 10.0 10.3 8.5 37.7 (4) 3.6 
2IT 2.2 15.9 6.0 4.8 6.4 35.8 (1) 2.1 
2IT 2.1 17.2 10.9 8.7 5.3 39.1 (3) 1.8 
2IT 2.4 14.3 7.2 15.1 5.3 16.6 (1) 2.8 
2IT 2.4 15.8 5.9 19.1 6.8 34.2 (3) 2.8 
2IT 2.3 16.9 7.1 4.6 7.5 33.7 (1) 2.7 
10 2IT 2.3 15.7 6.6 12.4 6.4 44.6 (1) 2.9 
11 2IT 2.3 12.6 6.7 14.3 6.2 47.8 (1) 2.2 
12 2IT 2.2 13.9 15.2 14.6 6.4 21.4 (4) 2.9 
13 2IT 2.4 9.7 8.1 12.4 6.0 56.5 (2) 3.2 
14 2IT 2.4 14.6 12.2 6.5 7.2 na 1.8 
15 2IT 2.2 15.8 7.2 14.5 9.4 46.6 (2) 2.7 
16 2IT 2.2 18.5 7.7 10.2 8.5 51.6 (1) 2.0 
17 2IT 2.3 16.1 10.3 7.7 5.0 17.9 (2) 2.2 
18 pep 2.2 13.1 6.4 10.3 5.1 37.6 (5) 2.7 
19 pep 2.1 10.5 5.3 17.6 4.9 28.0 (2) 2.6 
20 pep 2.3 7.5 5.3 8.5 3.4 37.1 (4) 2.9 
21 pep 2.2 8.8 7.6 7.7 4.3 na 2.7 
22 pep 2.1 8.8 4.1 5.1 3.2 37.1 (4) 2.3 
23 pep 1.9 13.7 3.3 4.8 4.2 24.3 (4) 1.7 
24 pep 2.3 10.1 4.0 7.9 3.5 35.8 (2) 3.8 
25 pep 2.4 9.1 8.3 7.3 3.7 20.4 (2) 3.2 
PatientLinkerBodyLiverKidneySpleenLungTumor (n)aBld/Marb
2IT 2.4 17.3 6.1 14.7 6.0 26.8 (1) 2.4 
2IT 2.3 11.7 7.3 7.8 4.6 29.9 (3) 2.2 
2IT 2.3 12.0 5.6 17.8 4.3 41.1 (1) 2.9 
2IT 2.3 10.9 10.0 10.3 8.5 37.7 (4) 3.6 
2IT 2.2 15.9 6.0 4.8 6.4 35.8 (1) 2.1 
2IT 2.1 17.2 10.9 8.7 5.3 39.1 (3) 1.8 
2IT 2.4 14.3 7.2 15.1 5.3 16.6 (1) 2.8 
2IT 2.4 15.8 5.9 19.1 6.8 34.2 (3) 2.8 
2IT 2.3 16.9 7.1 4.6 7.5 33.7 (1) 2.7 
10 2IT 2.3 15.7 6.6 12.4 6.4 44.6 (1) 2.9 
11 2IT 2.3 12.6 6.7 14.3 6.2 47.8 (1) 2.2 
12 2IT 2.2 13.9 15.2 14.6 6.4 21.4 (4) 2.9 
13 2IT 2.4 9.7 8.1 12.4 6.0 56.5 (2) 3.2 
14 2IT 2.4 14.6 12.2 6.5 7.2 na 1.8 
15 2IT 2.2 15.8 7.2 14.5 9.4 46.6 (2) 2.7 
16 2IT 2.2 18.5 7.7 10.2 8.5 51.6 (1) 2.0 
17 2IT 2.3 16.1 10.3 7.7 5.0 17.9 (2) 2.2 
18 pep 2.2 13.1 6.4 10.3 5.1 37.6 (5) 2.7 
19 pep 2.1 10.5 5.3 17.6 4.9 28.0 (2) 2.6 
20 pep 2.3 7.5 5.3 8.5 3.4 37.1 (4) 2.9 
21 pep 2.2 8.8 7.6 7.7 4.3 na 2.7 
22 pep 2.1 8.8 4.1 5.1 3.2 37.1 (4) 2.3 
23 pep 1.9 13.7 3.3 4.8 4.2 24.3 (4) 1.7 
24 pep 2.3 10.1 4.0 7.9 3.5 35.8 (2) 3.8 
25 pep 2.4 9.1 8.3 7.3 3.7 20.4 (2) 3.2 
a

Mean tumor dose (no. of tumors per patient).

b

Blood to marrow.

Table 2

Mean radiation dose (rads/mCi) for each RIC

MeanSDP for difference between groups
2IT-BAD-m170    
 Kidney 8.2 2.6 0.02 
 Liver 14.7 2.5 <0.01 
 Marrow 6.2 1.3 0.12 
 Lung 6.4 1.4 <0.01 
 Spleen 11.5 4.4 0.16 
 Blood 2.5 0.5 0.58 
 Tumor (n = 32) 36.4 11.8 0.31 
 Tumor (n = 32)a 31.5 8.4 <0.30 
 Body 2.3 0.1 0.68 
DOTA-peptide-m170    
 Kidney 5.5 1.8  
 Liver 10.2 2.2  
 Marrow 7.1 1.9  
 Lung 4.1 0.7  
 Spleen 8.7 4.1  
 Blood 2.7 0.6  
 Tumor (n = 23) 31.7 7.4  
 Tumor (n = 23)a 28.7 7.8  
 Body 2.2 0.2  
MeanSDP for difference between groups
2IT-BAD-m170    
 Kidney 8.2 2.6 0.02 
 Liver 14.7 2.5 <0.01 
 Marrow 6.2 1.3 0.12 
 Lung 6.4 1.4 <0.01 
 Spleen 11.5 4.4 0.16 
 Blood 2.5 0.5 0.58 
 Tumor (n = 32) 36.4 11.8 0.31 
 Tumor (n = 32)a 31.5 8.4 <0.30 
 Body 2.3 0.1 0.68 
DOTA-peptide-m170    
 Kidney 5.5 1.8  
 Liver 10.2 2.2  
 Marrow 7.1 1.9  
 Lung 4.1 0.7  
 Spleen 8.7 4.1  
 Blood 2.7 0.6  
 Tumor (n = 23) 31.7 7.4  
 Tumor (n = 23)a 28.7 7.8  
 Body 2.2 0.2  
a

Tumor dose (rads/mCi) after the absorbed dose for each tumor was corrected for the absorbed fraction based on mass (46).

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