High-dose 166Ho-DOTMP in myeloablative treatment of multiple myeloma: pharmacokinetics, biodistribution, and absorbed dose estimation.

Thirty-two patients with multiple myeloma were treated with high doses of 166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid (DOTMP) and were a subset of patients enrolled in a multicenter phase I/II dose escalation myeloablative trial. 166Ho with beta-emission (half-life, 26.8 h; beta-particle energies, 1.85 MeV [51%] and 1.77 MeV [48%]; gamma-photons, 80.6 keV [6.6%] and 1.38 MeV [0.9%]) was complexed to DOTMP, a macrocyclic tetraphosphonate. Pharmacokinetics, dosimetry, and biodistribution were studied. METHODS: Patients were treated at escalating dose levels of 20, 30, and 40 Gy to the bone marrow in combination with high-dose melphalan, with or without total-body irradiation, to evaluate toxicity and efficacy. After infusion with 1,110 MBq (30 mCi) of 166Ho-DOTMP for evaluation of biodistribution and dosimetry calculation, patients received the calculated amount of radioactivity for therapy in a single administration based on estimated dose calculations. RESULTS: Thirty-two patients participated in the study and were then treated. The average amount of administered radioactivity was 74.3 GBq (2,007 mCi) (range, 21.5-147.5 GBq [581-3,987 mCi]) of 166Ho-DOTMP. CONCLUSION: 166Ho-DOTMP has physical and pharmacokinetic characteristics compatible with high-dose myeloablative treatment of multiple myeloma.     

俄歇电子发射核素靶向治疗中细胞平均吸收剂量的计算

目的 给出一种新的方法,计算俄歇电子发射核素在细胞中均匀分布和非均匀分布时细胞和细胞核的平均吸收剂量以吸引剂量在细胞内的分布。方法 俄歇电子单位路径的能量损失用多项式拟合,用解析方法给出点源在细胞或细胞核内的能量沉积,从而得到不同源－靶组合的S值。放射性核素在细胞中径向线性分布和指数分布,分别计算了细胞和细胞核的平均吸收剂量;以及放射源距细胞中心不同距离时对细胞吸收剂量的影响。光子对细胞或细胞核的剂量贡献忽略不计。结果 平均吸收剂量及其在细胞内的分布和细胞的大小、俄歇电子能谱、核素的空间分布密切相关。细胞核内的核素对细胞核吸收剂量的贡献远大于细胞质中的核素。结论 俄歇电子在生物组织中的射程短,单位路径的能量损失高,能产生非常高的局部能量沉积。我们给出的细胞平均吸收剂量的解析计算方法计算速度快,结果可靠。     

Normalized data for the estimation of fetal radiation dose from radiotherapy of the breast

There can be several reasons why a pregnant patient may receive a radiological examination. It could have been a planned exposure, or the exposure might have resulted from an emergency when a thorough evaluation of pregnancy was impractical. Sometimes the pregnancy was unsuspected at the time of the examination and, with younger women being diagnosed with breast cancer, the likelihood of this will increase in radiotherapy departments. Whatever the reason, when presented with a pregnant patient who has received a radiological examination involving ionizing radiation, the dose to the fetus should be assessed based on the patient's treatment plan. However, a major source of uncertainty in the estimation of fetal absorbed dose is the influence of fetal size and position as these change with gestational age. Consequently, dose to the fetus is related to gestational age. Various studies of fetal dose during pregnancy have appeared in the literature. Whilst these papers contain many useful data for estimating fetal dose, they usually contain limited data regarding the depth and size of the fetus within the maternal uterus. We have investigated doses to the fetus from radiation therapy of the breast of a pregnant patient using an anthropomorphic phantom. Normalized data for estimating fetal doses that takes into account the fetal size (gestational age: 8-20 weeks post-conception) and depth within the maternal abdomen (4-16 cm) for different treatment techniques have been provided. The data indicate that fetal dose is dependent on both depth within the maternal abdomen and gestational age, and hence these factors should always be considered when estimating fetal dose. The data show that fetal dose can be underestimated up to about 10% or overestimated up to about 30% if the dose to the uterus is assumed instead of the actual fetal dose. It can also be underestimated up to about 23% or overestimated up to about 12% if a mean depth of 9 cm is assumed, instead of using the actual depth of the fetus within the maternal abdomen. Multi-segments sMLC technique showed consistently lower fetal doses compared with all the wedged plans employed.     

Foetal radiation dose in radiotherapy for breast cancer.

Management of breast cancer during pregnancy is complicated by the high risks of abortion and foetal malformation from the use of radiotherapy and chemotherapy. A case of breast cancer during pregnancy, treated with radiotherapy, and the estimated foetal dose is reported.     

166Ho and 90Y labeled 6D2 monoclonal antibody for targeted radiotherapy of melanoma: Comparison with 188Re radiolabel

IntroductionAn approach to radioimmunotherapy (RIT) of metastatic melanoma is the targeting of melanin pigment with monoclonal antibodies (mAbs) to melanin radiolabeled with therapeutic radionuclides. The proof of principle experiments were performed using a melanin-binding antibody 6D2 of IgM isotype radiolabeled with a β emitter ¹⁸⁸Re and demonstrated the inhibition of tumor growth. In this study we investigated the efficacy of 6D2 antibody radiolabeled with two other longer lived β emitters ⁹⁰Y and ¹⁶⁶Ho in treatment of experimental melanoma, with the objective to find a possible correlation between the efficacy and half-life of the radioisotopes which possess high energy β (E_max > 1.5 MeV) emission properties.Methods6D2 was radiolabeled with longer lived β emitters ⁹⁰Y and ¹⁶⁶Ho in treatment of experimental melanoma in A2058 melanoma tumor-bearing nude mice. The immunoreactivity of the radiolabeled 6D2 mAb, its in vitro binding to the MNT1 human melanoma cells, the biodistribution and therapy in A2058 human melanoma bearing nude mice as well as dosimetry calculations were performed.ResultsWhen labeled with the longer lived ⁹⁰Y radionuclide, the 6D2 mAb did not produce any therapeutic effect in tumor bearing mice while the reduction of the tumor growth by ¹⁶⁶Ho-6D2 was very similar to the previously reported therapy results for ¹⁸⁸Re-6D2. In addition, ¹⁶⁶Ho-labeled mAb produced the therapeutic effect on the tumor without any toxic effects while the administration of the ⁹⁰Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect.Conclusions¹⁶⁶Ho-labeled mAb to melanin produced some therapeutic effect on the tumor without any toxic effects while the administration of the ⁹⁰Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. We concluded that the serum half-life of the 6D2 carrier antibody matched well the physical half-life of ¹⁶⁶Ho to deliver the tumoricidal absorbed dose to the tumor. Further investigation of this radionuclide for RIT of melanoma is warranted.     

Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy

INTRODUCTION: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of beta-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells. METHODS: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for (99m)Tc and (90)Y chelation and was further conjugated to a alpha(V)beta(3) integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma. RESULTS: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P < .01) over time from 1.05 +/- 0.03 % injected dose (%ID)/g tissue at 1 h to 4.32 +/-0.32% at 72 h. The activity in major normal tissues significantly decreased (P < .05) during that period. At 21 days, the control tumors increased 442% in volume from baseline. In contrast, a 7% and a 63% decrease of tumor volume were observed for the 100- and 250-microCi (90)Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs. CONCLUSION: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth.     

The midline dose distribution for a three-field radiotherapy technique.

At the University of Florida, head and neck cancer often is irradiated using parallel opposed lateral fields (with inferior borders slanted superiorly) and an anterior low neck field. A common criticism is that overlap may occur at the match-line junction of the three fields, resulting in an increased risk of radiation myelitis. One setup for treatment of the oropharynx and two for the larynx were irradiated in an anthropomorphic head and neck phantom made of tissue-equivalent polyacrylamide gel with a two-dimensional thermoluminescent dosimeter array in its sagittal midplane. The results showed that no excess radiation dose was measured at the junction of the three fields. The "spinal cord dose," as percentage of dose to the central axis of the primary field, was as follows: oropharynx setup, 15% to 100%; larynx setup with midline tracheal block, 10% to 90%; larynx setup without tracheal block, 10% to 90%. In conclusion, the University of Florida three-field technique for head and neck cancer produces no measured increase in dose at field junctions.     

Trifunctional somatostatin-based derivatives designed for targeted radiotherapy using auger electron emitters.

Auger electron-emitting radionuclides have potential for the therapy of small-size cancers because of their high level of cytotoxicity, low-energy, high linear energy transfer, and short-range biologic effectiveness. Biologic effects are critically dependent on the subcellular (and even subnuclear) localization of these radionuclides. Our goals were the design, synthesis, and in vitro preclinical assessment of new trifunctional conjugates of somatostatin that should aim at the nucleus and, therefore, ensure a longer retention time in the cell, a close approximation to the DNA, and the success of Auger electron emitters in targeted radionuclide therapy as well as also improve other targeted therapy strategies. METHODS: Three trifunctional derivatives of [(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)0,Tyr3]octreotide (DOTA-TOC) bearing the nuclear localization signal (NLS) (of simian virus 40 large-T antigen) PKKKRKV in 3 different positions relative to the somatostatin analog sequence were synthesized using solid and solution phase peptide synthesis. These compounds together with DOTA-TOC and DOTA-NLS derivatives were labeled with 111In and tested for binding affinity, internalization, externalization, and nuclei localization on AR4-2J cells and on human embryonic cells stably transfected with sst2A. RESULTS: The two N-terminal derivatives preserved the sstr2A binding affinity. Their rate of internalization in all tested sstr-expressing cell lines was always superior for the trifunctional derivatives in comparison with the parent compound. A 6-fold increase in cellular retention from the total internalized activity and a 45-fold higher accumulation in the cell nuclei were found for one of the N-terminally modified compounds compared with [111In]-DOTA-TOC. The C-terminal conjugate was inferior in all tests compared with the parent compound. CONCLUSION: These encouraging results support our hypothesis that an additional NLS sequence to the DOTA-TOC could not only provide a better carrier for Auger electron-emitting radionuclides but also ensure a longer radioactivity retention time in the tumor cell.     

Whole-body biodistribution and estimation of radiation-absorbed doses of the dopamine D1 receptor radioligand 11C-NNC 112 in humans.

The present study estimated radiation-absorbed doses of the dopamine D(1) receptor radioligand [(11)C]((+)-8-chloro-5-(7-benzofuranyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (NNC 112) in humans, based on dynamic whole-body PET in healthy subjects. METHODS: Whole-body PET was performed on 7 subjects after injection of 710 +/- 85 MBq of (11)C-NNC 112. Fourteen frames were acquired for a total of 120 min in 7 segments of the body. Regions of interest were drawn on compressed planar images of source organs that could be identified. Radiation dose estimates were calculated from organ residence times using the OLINDA 1.0 program. RESULTS: The organs with the highest radiation-absorbed doses were the gallbladder, liver, lungs, kidneys, and urinary bladder wall. Biexponential fitting of mean bladder activity demonstrated that 15% of activity was excreted via the urine. With a 2.4-h voiding interval, the effective dose was 5.7 microSv/MBq (21.1 mrem/mCi). CONCLUSION: (11)C-NNC 112 displays a favorable radiation dose profile in humans and would allow multiple PET examinations per year to be performed on the same subject.     

Surface and build-up region dose analysis for clinical radiotherapy photon beams.

The standard clinical approach of dose measurement using a Farmer type fixed plane parallel cylindrical ionization chamber produces erroneous results in the build-up region. We studied dose distribution in this region using a Monte Carlo simulation technique and compared our results with data measured using extrapolation, parallel plate, and cylindrical farmer type ionization chambers for 6 and 10MV photon beams from two different accelerators. The extrapolation chamber data agreed favorably with the Monte Carlo results, suggesting that dose at the skin surface and a few mm beneath is significantly lower than conventionally accepted values.     

In vivo estimation of midline dose maps by transit dosimetry in head and neck radiotherapy

The aim of the present study is to compare the calculated midline dose map with the in vivo measured midline dose map, using portal detectors in conjunction with a pair of diodes. Measurements were performed in 10 patients treated for head/neck cancer and irradiated with lateral opposed 6 MV X-ray beams. The relative exit dose map, derived from transmission dose data of a portal film combined with the absolute entrance/exit dose measured by the diodes, can be used to derive the corresponding midline dose map by applying appropriate algorithms. Midplane dose values were estimated in eight relevant anatomic positions and compared with the corresponding calculated values with our three-dimensional (3D) treatment planning system using two-dimensional (2D) (Batho) and 3D (ETAR) inhomogeneity correction algorithms. In vivo estimated midplane doses agree within +/-3.5% relative to treatment planning calculations in 89 of 116 measurements points, with only 4 of 116 points outside +/-5%. A variation between measured and calculated dose can be found according to anatomical location. For air inhomogeneity, mean deviations were +2.2% (1 standard deviation (SD) approximately 1.7%) for both Batho and ETAR algorithms; for bone structures, mean deviations were approximately -0.6% (1 SD approximately 2.7%) for both algorithms. The worst agreement was found in the anterior neck where the mean deviation between measured and calculated midline dose was +3.1% (1 SD=1.4%) and +3.4% (1 SD= 2%) using Batho and ETAR, respectively. Sufficiently accurate 2D midplane dose maps may be simply obtained in vivo in the irradiation of head/neck cancer by using a portal detector in combination with a pair of diodes, in order to verify the dose actually delivered during treatment.     

Thrombin-soaked coils: estimation of thrombin dose.

Thrombin-soaked coils have been used as embolic agents for the treatment of various conditions. Intravascular injection of thrombin also has been used for thrombus formation; however, the effects of high doses of intravascular thrombin may be detrimental. In an in vitro experiment, the dose of thrombin associated with transcatheter use of thrombin-soaked steel coils was estimated. The 8 mm x 5 cm, 0.038-inch coils absorbed an overall average dose of 38.4 U (USP) of thrombin when soaked in a solution of 10,000 U of thrombin per 10 mL of saline. The same size coils absorbed an overall average dose of 71.6 U of thrombin when soaked in a concentration of 20,000 U of thrombin per 10 mL of solution. Maximum single-coil absorbed doses were 45.6 and 88.2 U for 1,000 and 2,000 U/mL, respectively. A plateau in thrombin absorption occurred after 1 minute of soaking. Absorption of thrombin was maximized by soaking the coils in a vertical orientation; almost no thrombin was absorbed when the coils were soaked in a horizontal position.     

Polymer gels for in-phantom dose imaging in radiotherapy

Normoxic polymer gel dosimeters are studied, with the aim of achieving a valid and advantageous method for in-phantom 3D dose determinations. Developments were carried out in the application of such dosimetric material to the method based on dosimeter gel layers that has shown good reliability for absorbed dose imaging in radiotherapy. The technique has been improved, in particular taking care of minimizing the oxygen infiltration into the gel matrix in order to suitably avoid its effect of inhibiting the polymerization process after exposure. A suitable choice of the material of dosimeter walls has brought to achieve good steadiness in time of dosimeter sensitivity and satisfactory results in dose imaging and depth-dose profiling.