Examining Absorbed Doses of Indigenously Developed 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Patients at Baseline and During Course of Peptide Receptor Radioligand Therapy.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.

Dosimetric Considerations for Ytterbium-169, Selenium-75, and Iridium-192 Radioisotopes in High-Dose-Rate Endorectal Brachytherapy.

PURPOSE: To investigate differences between prescribed and postimplant calculated dose in 192Ir high-dose-rate endorectal brachytherapy (HDR-EBT) by evaluating dose to clinical target volume (CTV) and organs at risk (OARs) calculated with a Monte Carlo-based dose calculation software, RapidBrachyMC. In addition, dose coverage, conformity, and homogeneity were compared among the radionuclides 192Ir, 75Se, and 169Yb for use in HDR-EBT. METHODS AND MATERIALS: Postimplant dosimetry was evaluated using 23 computed tomography (CT) images from patients treated with HDR-EBT using the 192Ir microSelectron v2 (Elekta AB, Stockholm, Sweden) source and the Intracavitary Mold Applicator Set (Elekta AB, Stockholm, Sweden), which is a flexible applicator capable of fitting a tungsten rod for OAR shielding. Four tissue segmentation schemes were evaluated: (1) TG-43 formalism, (2) materials and nominal densities assigned to contours of foreign objects, (3) materials and nominal densities assigned to contoured organs in addition to foreign objects, and (4) materials specified as in (3) but with voxel mass densities derived from CT Hounsfield units. Clinical plans optimized for 192Ir were used, with the results for 75Se and 169Yb normalized to the D90 of the 192Ir clinical plan. RESULTS: In comparison to segmentation scheme 4, TG-43-based dosimetry overestimates CTV D90 by 6% (P = .00003), rectum D50 by 24% (P = .00003), and pelvic bone D50 by 5% (P = .00003) for 192Ir. For 169Yb, CTV D90 is overestimated by 17% (P = .00003) and rectum D50 by 39% (P = .00003), and pelvic bone D50 is significantly underestimated by 27% (P = .007). Postimplant dosimetry calculations also showed that a 169Yb source would give 20% (P = .00003) lower rectum V60 and 17% (P = .00008) lower rectum D50. CONCLUSIONS: Ignoring high-Z materials in dose calculation contributes to inaccuracies that may lead to suboptimal dose optimization and disagreement between prescribed and calculated dose. This is especially important for low-energy radionuclides. Our results also show that with future magnetic resonance imaging-based treatment planning, loss of CT density data will only affect calculated dose in nonbone OARs by 2% or less and bone OARs by 13% or less across all sources if material composition and nominal mass densities are correctly assigned.

Monitoring the Response of PD-L1 Expression to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Nonsmall-Cell Lung Cancer Xenografts by Immuno-PET Imaging.

Accumulating evidence has suggested that the tumor microenvironment of nonsmall-cell lung cancer (NSCLC) may be impacted by chemotherapy, radiotherapy, or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). PD-L1 is an important biomarker in the tumor microenvironment that can predict patient response to immunotherapies. Therefore, it is highly desirable to achieve a real-time, noninvasive assessment of PD-L1 expression, which can provide critical information for recruiting patients as well as monitoring therapeutic efficacy. We herein studied the EGFR-TKI-induced effects on PD-L1 levels in NSCLC tumor models using immuno-PET imaging with 89Zr-Df-KN035, an imaging tracer previously established by our group. A549 human NSCLC xenografts were established in BALB/c nude mice and treated with different doses of an EGFR-TKI gefitinib. PET imaging with 89Zr-Df-KN035 was performed before and after the treatment to evaluate PD-L1 expression, which was further verified by immunohistochemical staining. Our results demonstrate that 89Zr-Df-KN035 can specifically evaluate PD-L1 levels in NSCLC tumor models. Compared to the untreated control, the high dose of gefitinib inhibited tumor growth and lowered the tumor uptake of 89Zr-Df-KN035. In comparison, the low dose of gefitinib did not affect tumor growth, although the extensive tumor necrosis also led to the lower uptake of 89Zr-Df-KN035. In conclusion, our results demonstrate that immuno-PET imaging with 89Zr-Df-KN035 is a promising tool to noninvasively monitor PD-L1 expression in NSCLC treated with EGFR-TKIs and can be used to optimize treatment plans for immunotherapy.

Radium-223 Dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases.

Purpose: This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases.Patients and Methods: Fifteen treatment-naïve patients (n = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed.Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time.Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. Clin Cancer Res; 24(17); 4081-8. ©2018 AACR.

Pilot study of parathyroid glands in adult and pediatric subjects exposed to ionizing radiation after the ChNPP accident, methodology of parathyroid diagnostic ultrasound. / PILOTNE DOSLIDZhENNIa STANU PRYShchYTOPODIBNYKh ZALOZ OSIB, OPROMINENYKh VNASLIDOK AVARIÏ NA ChAES DOROSLOGO TA DYTIaChOGO VIKU, METODOLOGIIa ÏKh UL'TRAZVUKOVOGO DOSLIDZhENNIa.

OBJECTIVE: Estimation of the parathyroid hyperplasia prevalence after the ChNPP accident in adults exposed to ion izing radiation and their descendants using the diagnostic ultrasound and its methodology elaboration. MATERIALS AND METHODS: The pilot prospective study of the prevalence of parathyroid hyperplasia among the Chornobyl Nuclear Power Plant (ChNPP) accident adult survivors (n=686) and their descendants (54 children) was performed using diagnostic ultrasound examination of thyroid and parathyroids. Among the study subjects there were 339 ChNPP accident clean up workers (ACUW), 32 persons were evacuated from the 30 km exclusion zone and 224 ones were included to the control group. Diagnostic ultrasound of thyroid and parathyroids was performed according to the standard method. Additionally, in children with parathyroid hyperplasia an additional assay of 25 hydroxyvitamin D levels in serum was performed. In calculating the statistical significance, its level p < 0.05 was considered statistically significant. RESULTS: Parathyroids are a few small but critically important endocrine glands that synthesize parathyroid hormone, regulating mainly phosphoric calcium metabolism. Insufficient (hypoparathyroidism) or excessive (hyperparathy roidism) function of parathyroids is harmful to the patients affecting the state of nervous and cardiovascular sys tem. Parathyroidss can accumulate isotopes of cesium, strontium and radioactive iodine. The available data testify to an increased incidence of clinically significant hyperplasia of parthyroids (more than 9 mm in adults and more than 5 mm in children) among persons exposed toionizng radiation as a result of the accident at the ChNPP (28.64%) and their descendants (23.8-70.6%). First of all are concerned those adults who live in contaminated areas in comparison with the control group (24.15% in not irradiated). Evacuees from the 30 km exclusion zone being the category of people who were exposed to the absorbed iodine isotopes in the first days of the Chernobyl accident are the another risk group. These data demonstrate sensitivity of parathyroidss to the impact of incorpo rated isotopes (iodine, cesium and strontium), which in the long term exposure create conditions for structural and functional changes in regulation of phosphorous calcium metabolism being the basis for a significant prevalence of osteopenia and osteoporosis in irradiated individuals and their descendants. A number of further studies are required to clarify the findings and to disclose the hormonal mechanisms of radiation effects on parathyroids. CONCLUSIONS: Parathyroid glands are radiosensitive and susceptible to effects of strontium, cesium and iodine iso topes, which cause parathyroid irradiation and subsequent structural and functional changes, being a prerequisite for development of osteopenia and osteoporosis in the ChNPP accident survivors and their descendants. High inci dence of parathyroid hypertrophy is found in the inhabitants of the radiation contaminated territories (long term irradiation by cesium isotopes), as well as in evacuated from the 30 km exclusion zone (irradiation by iodine iso topes in the early days of the accident).

Do androgen deprivation and the biologically equivalent dose matter in low-dose-rate brachytherapy for intermediate-risk prostate cancer?

The objective of this study was to investigate the impact of the biologically equivalent dose (BED) on treatment outcomes after iodine-125 low-dose-rate brachytherapy (LDR-BT) with or without supplemental external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for intermediate-risk prostate cancer (PCa). We retrospectively evaluated 292 Japanese patients. The impact of the BED and ADT on treatment outcomes was investigated. Cox proportional hazard models were used for univariate and multivariate analysis with biological progression-free survival (bPFS) and clinical progression-free survival (cPFS) as the primary outcome measures. The median follow-up was 66 months. The bPFS and cPFS rates at 5-/7-years were 91.6/87.7% and 95.9/94.0%, respectively. When stratified by BED levels, the bPFS rates at 5-/7-years were 92.1/89.3% for <178.0 Gy2, and 91.2/86.0% for ≥178.0 Gy2 , respectively (P > 0.05). Based on ADT duration, the bPFS rates at 5-/7-years were 89.8/83.5%, 89.7/89.7%, and 97.5/97.5% for none, 1-3 months, and 4-12 months, respectively (P = 0.03). For the univariate analysis, the use of ADT and its duration were significant predictors for bPFS, whereas BED was not significant. A multivariate analysis did not indicate the use of ADT itself was significant, however, when covariates were accounted for by the duration of ADT, the longer use of ADT was found to significantly improve bPFS. Although cPFS was associated neither with the BED levels nor ADT duration (P > 0.05), ADT duration had a trend of improving cPFS (P = 0.053). The higher levels of BED did not significantly impact bPFS for intermediate-risk PCa after LDR-BT with or without supplemental EBRT and ADT. The longer duration of ADT could provide an additional benefit in the context of high-dose irradiation generated by LDR-BT.

Study of the radiation effect of 99Mo/99mTc generator on Bacillus subtilis and Bacillus pumilus species.

In this work, molybdenum-99 loaded columns were challenged with Bacillus subtilis vegetative cells and Bacillus pumilus spores inside and outside the alumina column, and microbial recovery and radiation effect were assessed. Alumina was a barrier for the passage of microorganisms regardless the species, whilst spores were more retained than vegetative cells with a lower microbial recovery, without significant differences between 9.25 and 74 GBq generators. Bacillus pumilus biological indicator showed lower recoveries, suggesting a radiation inactivating effect on microorganisms.

177Lu-EC0800 combined with the antifolate pemetrexed: preclinical pilot study of folate receptor targeted radionuclide tumor therapy.

Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with (177)Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of (177)Lu-EC0800 with PMXther resulted in a two- to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of (177)Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using (99m)Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity.

Continuing pursuit for ideal systemic anticancer radiotherapeutics.

Cancer is one of the major causes of death for non-transmissible chronic diseases worldwide. Conventional treatments including surgery, chemotherapy and external beam radiotherapy are generally far from curative. Complementary therapies are attempted for achieving more successful treatment response. Systemic targeted radiotherapy (STR) is a radiotherapeutic modality based on systemic administration of radioactive agents for selectively delivering high doses of energy to destroy cancer cells. For this purpose, diverse tumour-target specific agents including monoclonal antibodies (MoAb), MoAb fragments and peptides have been tested and some of them have already got FDA approval for clinical use. However, MoAbs and their tailored analogues have shown non-homogeneous tumour distribution, limited diffusion, insufficient intratumoral accumulation and retention, unwanted uptake in normal tissues and scarcity of identified cancer antigens for generating new MoAbs. Similarly, peptides have also exhibited retention in normal organs, lacks of favourable membrane permeability or drug cell internalization and short-term residence in cancer cells. Recently, a new category of target-specific agent with strong affinity for necrosis has emerged as an excellent option for developing targeted radiotherapeutic agents to be used after necrosis-inducing treatments (NITs). The combination of their high, specific and long-term accumulation and retention at necrotic sites with the crossfire effect of ionizing particle-emitters allows irradiating adjacent residual viable tumour cells during a prolonged period of time. It may considerably enhance the therapeutic response and open a new horizon for improved cancer treatability or curability.

The role of brachytherapy in the definitive management of prostate cancer.

Over the past two decades, brachytherapy has played an ever expanding role in the definitive radiotherapy of prostate cancer. Brachytherapy surpasses external beam radiotherapy in its ability to deliver intense intraprostatic dose escalation. Although initially low dose rate permanent seed brachytherapy was favored for favorable risk prostate cancers, and high dose rate temporary brachytherapy for intermediate and advanced disease, both types of brachytherapy now have a place across all the risk groups of localized prostate cancer. This article will review indications and patient selection, planning and technical aspects, toxicity and efficacy for both low and high dose rate prostate brachytherapy.

Preclinical animal research on therapy dosimetry with dual isotopes.

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray-emitting radionuclides for a chemically comparable beta-particle-emitting paired isotope for therapy evaluation would be feasible.

[Radioembolisation for hepatocellular carcinoma]. / Traitement des carcinomes hépatocellulaires par injection intra-artérielle de radio-isotopes.

Hepatocellular carcinoma is now a major public health concern. In intermediate stages (one third of hepatocellular carcinoma patients), chemoembolization is the standard of care despite a poor tolerance and a moderate efficacy. Moreover, despite recent improvements, this technique seems in a dead end. Radioembolization could be an excellent tool for such patients. Currently (131)I-Lipiodol, (188)Re-Lipiodol, (90)Y-glass or resin microspheres are available. More recent and promising data come from microspheres, but phase II and III studies are needed before drawing any conclusion. In the future, the combination of radioembolization with systemic chemotherapy or targeted agents (particularly antiangiogenic drugs) seems very promising.

Treatment of hepatocellular carcinoma with intra-arterial injection of radionuclides.

Hepatocellular carcinoma (HCC) is becoming an important public health concern. Current therapeutic options are limited and new treatments are therefore being developed. The intra-arterial treatment chemoembolization has limited efficacy and few prospects for further progress. One particularly promising, though little used, alternative to chemoembolization is radioembolization with iodine-131 ((131)I) or rhenium-188 labeled lipiodol or yttrium-90 labeled microspheres (glass or resin beads). Three randomized studies have proven the effectiveness of (131)I-lipiodol in patients with HCC-as adjuvant therapy after surgery, compared with chemoembolization, and also in patients who have portal vein thrombosis. Microspheres enable the delivery of high-dose radiation (>200 Gy) to the tumor while sparing the neighboring hepatic tissue from overexposure. Overall, the efficacy of radioembolization has been good and toxic effects have been low. These results are comparable to those obtained with chemoembolization but further improvement can be expected by combining radioembolization with standard chemotherapy or with targeted therapies, such as anti-angiogenic drugs.

Use of the Oak Ridge National Laboratory tungsten-188/rhenium-188 generator for preparation of the rhenium-188 HDD/lipiodol complex for trans-arterial liver cancer therapy.

This work describes the installation, use, and quality control (QC) of the alumina-based tungsten-188 ((188)W)/rhenium-188 ((188)Re) generators provided by the Oak Ridge National Laboratory (ORNL). In addition, methods used for concentration of the (188)Re-perrhenate bolus and preparation of (188)Re-labeled HDD (4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) for trans-arterial administration for therapy of nonresectable liver cancer also are described. The (188)W/(188)Re generator has a long useful shelf-life of several months and is a convenient on-site (188)Re production system. (188)Re has excellent therapeutic and imaging properties (T(1/2) 16.9 hours; E(betamax) 2.12 MeV; 155-keV gamma ray, 15%) and is cost effectively obtained on demand by saline elution of the generator. The clinical efficacy of a variety of (188)Re-labeled agents has been demonstrated for several therapeutic applications. Because of the favorable physical properties of (188)Re, several (188)Re-labeled agents are being developed and evaluated for the treatment of nonresectable/refractory liver cancer. (188)Re-labeled HDD has been the most widely studied of these agents for this application and has been introduced into clinical trials at a number of institutions. The trans-arterial administration of (188)Re-labeled agents for treatment of inoperable liver cancer requires use of high-level (1-2 Ci) (188)W/(188)Re generators. The handling of such high levels of (188)Re imposes radiological precautions normally not encountered in a radiopharmacy and adequate care and ALARA (ie, "As Low As Reasonably Achievable") principles must be followed. The ORNL generator provides consistently high (188)Re yields (>75%) and low (188)W parent breakthrough (<10(-3)%) over an extended shelf-life of several months. However, the high elution volumes (20-40 mL for 1-2 Ci generators) can require concentration of the (188)Re bolus by postelution passage through silver cation chloride trapping columns used in the cost-effective tandem cation/anion column system. The silver column removes the high levels of chloride anion as insoluble AgCl, thus allowing subsequent specific trapping of the perrhenate anion on the small (QMA SeaPak) anion column. This method permits subsequent elution of (188)Re-perrhenate with a small volume of saline, providing a very high activity-concentration solution. Because the (188)Re-specific volume-activity concentration continually decreases with time, the tandem system is especially effective method for extending the useful generator shelf-life. Low elution flow rates (<1 mL/min) minimize any high back pressure which may be encountered during generator/tandem column elution when using tightly packed, small-particle-size commercial columns. In-house preparation of silver cation columns is recommended since the chloride trapping capacity is essentially unlimited, it is inexpensive and not limited in availability to any one supplier, and back pressure can be eliminated by the use of larger particles. Methods for the preparation of (188)Re-HDD have been optimized and this agent can be obtained in high yield (80%).

Patient-specific radiation dosimetry for radionuclide therapy of liver tumors with intrahepatic artery rhenium-188 lipiodol.

A clinically practical algorithm has been developed for the treatment of liver cancer by the administration of rhenium-188 ((188)Re)-labeled lipiodol via the hepatic artery. This algorithm is based on the "maximum tolerated-activity" paradigm for radionuclide therapy. A small "scout" activity of (188)Re-labeled lipiodol is administered to the patient before the actual therapeutic administration. At approximately 3 hours after administration, the activities in the normal liver, liver tumors, lungs, and total body are measured by gamma camera imaging using the conjugate-view method, with first-order corrections for attenuation (using a (188)Re transmission scan) and scatter (using the "dual-window" method). At the same time, peripheral blood samples are counted, and the activity concentrations in whole blood are calculated. The blood activity concentrations are then converted to red marrow activity concentrations and then total red marrow activity using anatomic data from Standard Man anthropomorphic models. Next, the cumulated activities in the normal liver, liver tumors, lungs, red marrow, and total body are calculated using the measured activities in the respective source regions and conservatively assuming elimination of activity only by physical decay in situ. The absorbed doses to the therapy-limiting normal tissues, liver, lung, and red marrow, are then calculated using the Medical Internal Radiation Dose Committee schema, adjusting the pertinent S factors for differences in total body and organ masses between the patient and the anthropomorphic model and including the dose contribution from the liver tumors. Finally, based on maximum tolerated absorbed doses of 3,000, 1,200, and 150 rad (cGy) to liver, lung, and red marrow, the respective absorbed doses per unit administered activity are used to calculate the therapy activity. Although not required for treatment planning, tumor absorbed dose may also be estimated. This algorithm has been automated using an Excel (Microsoft, Redmond, WA) spreadsheet.

A report on the implementation aspects of the International Atomic Energy Agency's first doctoral coordinated research project, "Management of liver cancer using radionuclide methods with special emphasis on trans-arterial radio-conjugate therapy and internal dosimetry".

Liver cancer is one of the most dreaded cancers, and it is highly prevalent in the developing countries, where the resources are extremely scarce to deal with this disease using the current commercially available and expensive therapeutic radiopharmaceuticals. The International Atomic Energy Agency (IAEA), in pursuit of its mandate to promote the application of nuclear technology in the health care in its Member States, has developed and clinically evaluated a new and cost-effective therapeutic radio-conjugate, rhenium-188 ((188)Re)-lipiodol for the treatment of hepatocellular carcinoma through its first Doctoral Coordinated Research Project. The ready availability of no-carrier-added (188)Re from the tungsten-188/(188)Re generator represents a potentially important source of a therapeutic radioisotope for a broad range of therapeutic applications in nuclear medicine. The alumina-based tungsten-188/(188)Re generator system comes with reasonable cost and exhibits attractive therapeutic properties, excellent performance and very long useful shelf-life. Because of the long shelf-life of several months, the use of this generator offers a unique opportunity for the cost-effective and routine availability of a versatile therapeutic radioisotope on an on-demand basis. Further, using its extensive global network and outreach, the IAEA has also transferred the technology of the in-house preparation and use of (188)Re-labeled lipiodol to many institutions around the world, which can now prepare (188)Re-labeled lipiodol in their own radiopharmacy laboratories and treat patients. This effort of the IAEA in trying to address some of the challenges of liver cancer therapy in developing countries has been and truly a global venture with involvement and contributions from several organizations, institutions and numerous individuals. This article discusses some of the implementation aspects of this very important activity of the Agency.

International Atomic Energy Agency-sponsored multination study of intra-arterial rhenium-188-labeled lipiodol in the treatment of inoperable hepatocellular carcinoma: results with special emphasis on prognostic value of dosimetric study.

A multicenter study was sponsored by the International Atomic Energy Agency (IAEA) to assess the safety and efficacy of transarterial rhenium-188 ((188)Re) HDD lipiodol (radioconjugate to lipiodol using an HDD kit) in the treatment of unresectable hepatocellular carcinoma. During 5 years, 185 patients received at least 1 treatment of radioconjugate, and 51 were retreated. The level of radioconjugate administered was based on radiation-absorbed dose to critical normal organs, calculated after a "scout" dose of radioconjugate. The total injected activity, including the scout dose during the first treatment, ranged from 21 to 364 mCi (mean, 108 mCi/4 GBq). Immediate and late side-effects were minimal. Tumor size could be evaluated in 88 patients. Among these patients, the objective response rate was 25%; stable disease was observed in 53% and tumor progression in 22%. With a median follow-up of 455 days, the estimated 12- and 24-month overall survival was 46% and 23%. This multicenter study shows that (188)Re lipiodol is a safe and cost-effective method to treat primary hepatocellular carcinoma via the transarterial route and requires further evaluation by treatment of greater numbers of patients.

Intra-arterial rhenium-188 lipiodol in the treatment of inoperable hepatocellular carcinoma: results of an IAEA-sponsored multination study.

PURPOSE: Intra-arterial injections (IAI) of 131I-lipiodol is effective in treating hepatocellular carcinoma patients, but is expensive and requires a 7-day hospitalization in a radioprotection room. 188Re is inexpensive, requires no patient isolation, and can be used with lipiodol. METHODS AND MATERIALS: This International Atomic Energy Agency-sponsored phase II trial aimed to assess the safety and the efficacy of a radioconjugate 188Re + lipiodol (188Re-Lip) in a large cohort of hepatocellular carcinoma patients from developing countries. A scout dose is used to determine the maximal tolerated dose (lungs <12 Gy, normal liver <30 Gy, bone marrow <1.5 Gy) and then the delivery of the calculated activity. Efficacy was assessed using response evaluation criteria in solid tumor (RECIST) and alpha-feto-protein (alpha FP) levels and severe adverse events were graded using the Common Toxicity Criteria of the National Cancer Institute scale v2.0. RESULTS: The trial included 185 patients from eight countries. The procedure was feasible in all participating centers. One treatment was given to 134 patients; 42, 8, and 1 received two, three, and four injections, respectively. The injected activity during the first treatment was 100 mCi. Tolerance was excellent. We observed three complete responses and 19 partial responses (22% of evaluable patients, 95% confidence interval 16-35%); 1- and 2-year survivals were 46% and 23%. Some factors affected survival: country of origin, existence of a cirrhosis, Cancer of the Liver Italian Program score, tumor dose, absence of progression, and posttreatment decrease in alpha FP level. CONCLUSIONS: IAI of 188Re-Lip in developing countries is feasible, safe, cost-effective, and deserves a phase III trial.

Translation of dosimetric results of preclinical radionuclide therapy to clinical situations: influence of photon irradiation.

The radionuclide evaluation for therapy starts with preclinical studies in, for example, mice and rats, and various radionuclides have shown promising results. However, many radionuclides emit photons that will irradiate normal tissues. The risk of normal tissue toxicity in patients (e.g., bone marrow suppression) may be underestimated when relying on preclinical results. To illustrate the influence of photons in preclinical and clinical trials, the ratio between the tumor-to-normal tissue absorbed-dose rate ratio (TND) was calculated for humans, rats, and mice for 111In, 125I, 67Ga, 90Y, 131I, and 177Lu. The normal tissues were simulated by 70-kg, 300-g, and 20-g ellipsoids for humans, rats, and mice, respectively. It was assumed that the radionuclides were uniformly distributed, and that the activity concentration was 25 times higher in the tumor than in the normal tissue. There were only small differences between the TND values for the different species for 90Y and 177Lu. 131I showed similar TND values for rats and mice, whereas they were lower for humans. For 111In, 125I, and 67Ga, however, there were large differences between the different species. The influence of photons may thus be much lower in preclinical studies than in clinical situations. Therefore, translations of absorbed doses from animals to humans must be performed with caution.