Post-prostatectomy image-guided radiation therapy: evaluation of toxicity and inter-fraction variation using online cone-beam CT.

PURPOSE: The purpose of this study is to assess the acute and late genitourinary (GU) and gastrointestinal (GI) toxicities of cone-beam computed tomography (CBCT) guided conformal adjuvant and salvage post-prostatectomy radiotherapy (RT) compared with RT with port films. MATERIALS AND METHODS: Sixty-eight patients (group 1) were treated with RT following radical prostatectomy (RP) using CBCT-guided conformal RT to a median dose of 68.4Gy. CBCT images were acquired three to five times weekly and were automatically co-registered to a reference CT. A comparative group (group 2) included 150 patients who received post-RP RT with weekly port films to a median dose of 64.8Gy. GU and GI toxicities were graded in both the acute and late settings using Radiation Therapy Oncology Group criteria. Associations between toxicity and study variables were evaluated by odds ratios (ORs) estimated by logistic regression. RESULTS: Grades 2 and 3 acute GU toxicity were experienced by 13% (n=9) and 2% (n=1) of patients in group 1, respectively, while 13% (n=19) had grade 2 acute GU toxicity in the control group (group 2). Grade 2 acute GI toxicity was experienced by 13% (n=9) and 15% (n=23) in groups 1 and 2, respectively. Acute GU (P=0.67) and GI (P =0.84) toxicities were not significantly different between the two groups. There were no associations detected between CBCT and acute GI toxicity (OR 0.76, P=0.57) or acute GU (OR 1.16, P=0.75). Increased odds of acute GU toxicity were observed for doses>68.4Gy (OR 12.81, P=0.04), which were only delivered in the CBCT group. CBCT mean variations (standard deviation) for 1053 fractions were 2.8mm (2.8), 2.0mm (2.4) and 3.1mm (2.9) in the left-to-right, anterior-to-posterior (AP) and superior-to-inferior (SI) axes, respectively. Corrective shifts for variance≥5mm were required for 15%, 6% and 19% of fractions in the left-to-right, anterior-to-posterior and superior-to-inferior axes, respectively. CONCLUSIONS: Rates of acute toxicity with CBCT-guided post-RP RT to 68.4Gy were similar to treatment to 64.8Gy without image-guidance RT. Acceptable early toxicity profiles suggest that CBCT is a reasonable strategy for image guidance, but the value of CBCT must be weighed against potential increased risk of secondary cancers due to increased radiation exposure.

Protein binding to lanthanide(III) complexes can reduce the water exchange rate at the lanthanide.

The GdIII-based magnetic resonance imaging contrast agent MS-325 targets the blood protein serum albumin, resulting in an increased efficacy (relaxivity) as a relaxation agent. MS-325 showed different relaxivities when bound to serum albumin from different species, e.g., r1=30.5 mM-1 s-1 (rabbit) vs 46.3 mM-1 s-1 (human) at 35 degrees C and 0.47 T. To investigate the mechanism for this difference, surrogate complexes were prepared where the GdIII ion was replaced by other LnIII ions. Fluorescence lifetime measurements of the EuIII analogue indicated that the hydration number was q=1 and did not change when bound to either human, rat, rabbit, pig, or dog serum albumin. The YbIII analogue, YbL1, was prepared and characterized by 1H NMR. Line-shape analysis of the paramagnetic-shifted 1H NMR resonances in the presence of increasing amounts of human (HSA) or rabbit (RSA) serum albumin allowed estimation of the transverse relaxation rate, R2, of these resonances for the protein-bound YbL1. The rotational correlation time of YbL1 was calculated from R2, and the Yb-H distance and was tauR=8+/-1 ns when bound to HSA and 13+/-2 ns when bound to RSA. The water exchange rate at the DyIII analogue, DyL1, was determined from variable-temperature R2 measurements at 9.4 T when DyL1 was bound to either HSA or RSA. At 37 degrees C, water exchange at DyL1 was (31+/-5)x10(6) s-1 when bound to HSA but (3.8+/-0.2)x10(6) s-1 when bound to RSA. Slower water exchange upon RSA binding explains the differences in relaxivity observed. The approach of using surrogate lanthanides to identify specific molecular parameters influencing relaxivity is applicable to other protein-targeted GdIII contrast agents.

Species dependence on plasma protein binding and relaxivity of the gadolinium-based MRI contrast agent MS-325.

RATIONALE AND OBJECTIVES: We sought to determine whether there is a species dependence on plasma protein and serum album binding and/or relaxivity of the MR contrast agent MS-325. METHODS: Equilibrium binding of MS-325 to plasma proteins or purified serum albumin was determined as a function of chelate concentration. T1 and T2 values were determined at 0.47 and 1.41 T, and NMRD profiles were measured to determine the changes in relaxivity over varying field strengths from 0.002 to 1.2 T. RESULTS: The binding of MS-325 to either animal plasma or serum albumin plateaus at chelate concentrations less than 0.1 mM with human, pig, and rabbit plasmas showing maximum binding. Human and pig plasmas show the greatest observed relaxivity enhancement in the presence of MS-325. CONCLUSIONS: MS-325 exhibits increased relaxivity in blood plasma as the result of plasma protein binding. Binding ranged from 64% to 91% and was species dependent: human > pig approximately rabbit > dog approximately rat approximately mouse.