IPEM topical report: the first UK survey of dose indices from radiotherapy treatment planning computed tomography scans for adult patients.

CT scans are an integral component of modern radiotherapy treatments, enabling the accurate localisation of the treatment target and organs-at-risk, and providing the tissue density information required for the calculation of dose in the treatment planning system. For these reasons, it is important to ensure exposures are optimised to give the required clinical image quality with doses that are as low as reasonably achievable. However, there is little guidance in the literature on dose levels in radiotherapy CT imaging either within the UK or internationally. This IPEM topical report presents the results of the first UK wide survey of dose indices in radiotherapy CT planning scans. Patient dose indices were collected for prostate, gynaecological, breast, lung 3D, lung 4D, brain and head and neck scans. Median values per scanner and examination type were calculated and national dose reference levels and 'achievable levels' of CT dose index (CTDIvol), dose-length-product (DLP) and scan length are proposed based on the third quartile and median values of these distributions, respectively. A total of 68 radiotherapy CT scanners were included in this audit. The proposed dose reference levels for CTDIvol and DLP are; prostate 16 mGy and 570 mGy · cm, gynaecological 16 mGy and 610 mGy · cm, breast 10 mGy and 390 mGy · cm, lung 3D 14 mGy and 550 mGy · cm, lung 4D 63 mGy and 1750 mGy · cm, brain 50 mGy and 1500 mGy · cm and head and neck 49 mGy and 2150 mGy · cm. Significant variations in dose indices were noted, with head and neck and lung 4D yielding a factor of eighteen difference between the lowest and highest dose scanners. There was also evidence of some clustering in the data by scanner manufacturer, which may be indicative of a lack of local optimisation of individual systems to the clinical task. It is anticipated that providing this data to the UK and wider radiotherapy community will aid the optimisation of treatment planning CT scan protocols.

Targeted Molecular Radiotherapy of Pediatric Solid Tumors Using a Radioiodinated Alkyl-Phospholipid Ether Analog.

External-beam radiotherapy plays a critical role in the treatment of most pediatric solid tumors. Particularly in children, achieving an optimal therapeutic index to avoid damage to normal tissue is extremely important. Consequently, in metastatic disease, the utility of external-beam radiotherapy is limited. Molecular radiotherapy with tumor-targeted radionuclides may overcome some of these challenges, but to date there exists no single cancer-selective agent capable of treating various pediatric malignancies independently of their histopathologic origin. We tested the therapeutic potential of the clinical-grade alkyl-phospholipid ether analog CLR1404, 18-(p-iodophenyl)octadecyl phosphocholine, as a scaffold for tumor-targeted radiotherapy of pediatric malignancies. Methods: Uptake of CLR1404 by pediatric solid tumor cells was tested in vitro by flow cytometry and in vivo by PET/CT imaging and dosimetry. The therapeutic potential of 131I-CLR1404 was evaluated in xenograft models. Results: In vitro, fluorescent CLR1404-BODIPY showed significant selective uptake in a variety of pediatric cancer lines compared with normal controls. In vivo tumor-targeted uptake in mouse xenograft models using 124I-CLR1404 was confirmed by imaging. Single-dose intravenous injection of 131I-CLR1404 significantly delayed tumor growth in all rodent pediatric xenograft models and extended animal survival while demonstrating a favorable side effect profile. Conclusion:131I-CLR1404 has the potential to become a tumor-targeted radiotherapeutic drug with broad applicability in pediatric oncology. Because 131I-CLR1404 has entered clinical trials in adults, our data warrant the development of pediatric clinical trials for this particularly vulnerable patient population.

Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404.

Variations in tumor volume segmentation methods in targeted radionuclide therapy (TRT) may lead to dosimetric uncertainties. This work investigates the impact of PET and MRI threshold-based tumor segmentation on TRT dosimetry in patients with primary and metastatic brain tumors. In this study, PET/CT images of five brain cancer patients were acquired at 6, 24, and 48 h post-injection of 124I-CLR1404. The tumor volume was segmented using two standardized uptake value (SUV) threshold levels, two tumor-to-background ratio (TBR) threshold levels, and a T1 Gadolinium-enhanced MRI threshold. The dice similarity coefficient (DSC), jaccard similarity coefficient (JSC), and overlap volume (OV) metrics were calculated to compare differences in the MRI and PET contours. The therapeutic 131I-CLR1404 voxel-level dose distribution was calculated from the 124I-CLR1404 activity distribution using RAPID, a Geant4 Monte Carlo internal dosimetry platform. The TBR, SUV, and MRI tumor volumes ranged from 2.3-63.9 cc, 0.1-34.7 cc, and 0.4-11.8 cc, respectively. The average ± standard deviation (range) was 0.19 ± 0.13 (0.01-0.51), 0.30 ± 0.17 (0.03-0.67), and 0.75 ± 0.29 (0.05-1.00) for the JSC, DSC, and OV, respectively. The DSC and JSC values were small and the OV values were large for both the MRI-SUV and MRI-TBR combinations because the regions of PET uptake were generally larger than the MRI enhancement. Notable differences in the tumor dose volume histograms were observed for each patient. The mean (standard deviation) 131I-CLR1404 tumor doses ranged from 0.28-1.75 Gy GBq-1 (0.07-0.37 Gy GBq-1). The ratio of maximum-to-minimum mean doses for each patient ranged from 1.4-2.0. The tumor volume and the interpretation of the tumor dose is highly sensitive to the imaging modality, PET enhancement metric, and threshold level used for tumor volume segmentation. The large variations in tumor doses clearly demonstrate the need for standard protocols for multimodality tumor segmentation in TRT dosimetry.

Acute myeloid leukemia therapy elicits durable complete response in chemoradio-resistant metastatic paraganglioma.

Few effective therapeutic options exist for patients with metastatic paraganglioma (PGL). We report the case of a 16-year-old male who developed acute myeloid leukemia (AML) 30 months following the treatment for metastatic PGL. PGL had been refractory to 131 I-meta-iodobenzylguanidine and temozolomide therapy. However, there was a major reduction in primary tumor allowing its gross total resection, and complete resolution of metastatic disease following AML-directed therapy that included daunorubicin, cytarabine, and etoposide. He remains in remission for both AML and PGL, 48 months post AML chemotherapy. Alternative chemotherapeutic agents should be considered for metastatic PGL resistant to conventional therapy.

A Phase 1, Multi-Center, Open-Label, Dose-Escalation Study of 131I-CLR1404 in Subjects with Relapsed or Refractory Advanced Solid Malignancies.

This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues' retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy.

A phase 1 study of 131I-CLR1404 in patients with relapsed or refractory advanced solid tumors: dosimetry, biodistribution, pharmacokinetics, and safety.

INTRODUCTION: (131)I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of (131)I-CLR1404. METHODS: Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of (131)I-CLR1404. Whole body planar nuclear medicine scans were performed at 15-35 minutes, 4-6, 18-24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on (127)I-CLR1404 mass measurements. To evaluate renal clearance of (131)I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. RESULTS: Single administrations of 370 MBq of (131)I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma (127)I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng • hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. CONCLUSIONS: Preliminary data suggest that (131)I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. TRIAL REGISTRATION: ClinicalTrials.gov NCT00925275.

Cytotoxic Effects of a Novel Thialo Benzene Derivative 2,4-Dithiophenoxy-1-iodo-4-bromobenzene (C18H12S2IBr) in L929 Cells.

The aim of this study was to compare the cytotoxic effects of a newly synthesized thialo benzene derivative 2,4-dithiophenoxy-1-iodo-4-bromobenzene (C18H12S2IBr) and a well-known antifungal agent, fluconazole, in L929 cells. L929 cells were treated with 250, 500, or 1000 µg/mL of C18H12S2IBr and with the same doses of fluconazole. Cytotoxicity tests including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), lactate dehydrogenase (LDH) leakage, and protein content were compared. Glucose and lactate concentrations were measured to determine alterations in metabolic activity. Apoptosis was investigated by TUNEL test and results were supported with survivin enzyme-linked immunosorbent assay. Treatment with C18H12S2IBr resulted in a concentration-dependent cytotoxicity as indicated by MTT, LDH leakage assay, and decreased protein concentration. The loss of cell viability and the increased LDH leakage in 500 µg/mL and 1000 µg/mL C18H12S2IBr and fluconazole groups indicated cell membrane damage and necrotic cell death. In all groups, metabolic activities were altered but apoptosis was not induced. We have previously investigated lower doses of C18H12S2IBr; there was no cytotoxicity in L929 cells. In this study, higher doses caused cytotoxicity and alterations in metabolic activity . When we consider the similar results obtained from fluconazole and especially the lowest dose of C18H12S2IBr, this newly synthesized compound may be a good alternative antifungal agent.

Medical management of hyperthyroidism.

Radioiodine is considered the treatment of choice for hyperthyroidism, but in some situations, methimazole therapy is preferred, such as in cats with pre-existing renal insufficiency. Methimazole blocks thyroid hormone synthesis, and controls hyperthyroidism in more than 90% of cats that tolerate the drug. Unfavorable outcomes are usually due to side effects such as gastrointestinal (GI) upset, facial excoriation, thrombocytopenia, neutropenia, or liver enzyme elevations; warfarin-like coagulopathy or myasthenia gravis have been reported but are rare. Because restoration of euthyroidism can lead to a drop in glomerular filtration rate, all cats treated with methimazole should be monitored with BUN and creatinine, in addition to serum T4, complete blood count, and liver enzymes. Transdermal methimazole is associated with fewer GI side effects, and can be used in cats with simple vomiting or inappetance from oral methimazole. Hypertension may not resolve immediately when serum T4 is normalized, and moderate to severe hypertension should be treated concurrently with-atenolol, amlodipine, or an ACE inhibitor. Alternatives to methimazole include carbimazole, propylthiouracil, or iodinated contrast agents.

Scintigraphic localization of lymphatic leakage site after oral administration of iodine-123-IPPA.

UNLABELLED: Chylothorax can occur secondary to traumatic lesions of the thoracic duct caused by chest injuries, surgical procedures involving the pleural space, neoplasms or malformations of the lymphatics. METHODS: Lymphatic leakage sites were localized by scintigraphy after oral administration of the 123I-labeled long-chain fatty acid derivative iodophenyl pentadecanoic acid (IPPA). We report on three patients with different lymphatic leakage sites and on one normal control subject. RESULTS: IPPA scintigraphy localized the lymphatic leakage site correctly in all three patients. In two of them, the method even guided the successful surgical treatment of the leakage. CONCLUSION: This approach is suitable for detecting lymphatic leakages of intestinal origin.

Acute liver necrosis induced by iodine-131-MIBG in the treatment of metastatic carcinoid tumors.

Iodine-131-metaiodobenzylguanidine (MIBG) is used in the treatment of carcinoid tumors. Temporary palliation with complete subjective symptomatic response has been reported in these patients. This treatment is usually well tolerated and side-effects are generally limited to nausea, mild hepatic toxicity with spontaneous recovery and temporary myelosuppression. Our case report shows that repeated treatment with [131I]MIBG in a patient with extensive carcinoid liver metastasis may cause severe hepatic toxicity leading to death. Factors such as concomitant use of 5-fluorouracil and the progressive nature of the disease may have contributed to this event.

131I-MIBG therapy of neural crest tumours (review).

Due to its diagnostic application, consideration was given to the therapeutic potential of 131I-MIBG in neural crest tumours, mainly in malignant pheochromocytomas, paragangliomas, neuroblastomas (NB), carcinoids and medullary thyroid carcinomas (MTC). The therapeutic procedure consists of a) thyroid blockade; b) administration of high specific activity 131I-MIBG; c) single doses, varying from 3.7 to 9.5 GBq, given by slow i.v. infusion (2-3 hours); d) monitoring of the patient during the infusion of the tracer. Targeted radiotherapy with 131I-MIBG in malignant pheochromocytomas, paragangliomas, carcinoids and medullary thyroid carcinomas, was shown to be effective with partial reduction of tumoral lesions (mainly in pheochromocytomas with 58% of objective responses) and palliation in metastatic tumors; in a few pheochromocytomas also succeed in eradicating the residual/recurrent tumor. In patients with stage IV NB who failed to respond to or relapsed after conventional chemotherapy, MIBG therapy showed an important palliative role. A significant therapeutic improvement in the outcome of stage III and IV NB patients was obtained by introducing 131I-MIBG as a first line therapy, partial or even complete responses occurring in more than 60% of the cases treated. Experiences combining chemotherapeutic agents and 131I-MIBG are also in progress with encouraging results. MIBG therapy is well tolerated; toxicity is limited to minor hematologic toxicity and patients generally recover spontaneously. The risk of pancytopenia rises in patients with bone and/or bone marrow metastases; in these cases bone marrow harvesting is recommended. An alternative approach to 131I-MIBG therapy in MTC uses radiolabeled monoclonal antibodies. A novel immunotargeting method, which includes a bispecific antibody and 131I as a radiolabel, seems to be very promising.

No-carrier-added iodine-131-FIBG: evaluation of an MIBG analog.

UNLABELLED: The purpose of this study was to evaluate the properties of 4-fluoro-3-[131I]iodobenzylguanidine ([131I]FIBG), a potential neuroendocrine tumor and myocardial imaging radiopharmaceutical. METHODS: The binding of [131I]FIBG and [125I]MIBG was compared in vitro using the SK-N-SH human neuroblastoma cell line. The role of the active uptake-1 mechanism was investigated by determining the effect on cell binding of desipramine (DMI), ouabain, norepinephrine (NE), unlabeled MIBG and FIBG and by incubation at 4 degrees C. Finally, the tissue distributions of [131I]FIBG and [125I]MIBG were compared in normal mice. RESULTS: The specific binding of [131I]FIBG remained fairly constant (45%-60%) over a 2-3-log activity range and consistently was 11%-14% higher (p < 0.05) than that of [125I]MIBG. The uptake of [131I]FIBG was reduced to 13% of control values by 1.5 microM DMI, to 31% by 1 mM ouabain, to 8% by lower temperature, to 8% by 50 microM NE and to 6% and 5% by 10 microM each of unlabeled MIBG and FIBG, respectively. The amount of [131I]FIBG retained by SK-N-SH cells was significantly higher than that of [125I]MIBG with the maximum difference observed at 72 hr. In mice, the uptake of [131I]FIBG was higher than that of [125I]MIBG not only in target tissues (heart and adrenals) but also in many other normal tissues; conversely, thyroidal uptake of [131I]FIBG was 2-3-fold lower than that of [125I]MIBG. The uptake of [131I]FIBG in the heart and adrenals was reduced by DMI. CONCLUSION: Iodine-131-FIBG is an analog of MIBG with prolonged binding to neuroblastoma cells in vitro and retention in the myocardium in vivo.

[Therapeutic possibilities in metastatic pheochromocytoma]. / Die therapeutischen Möglichkeiten bei metastasiertem Phäochromozytom.

Malignant pheochromocytomas are rare. Although 5-year survival is less than 50%, the prognosis varies. Some patients, even those with extensive metastases, have been followed up for many years. If the tumor tissue's uptake is adequate (> 5 Gy/100 mCi) the therapeutic use of 131I-meta-iodobenzylguanidin (131I-MIBG) is at present the therapy of first choice. The use of cytostatic chemotherapy should be limited to patients with rapidly progressive disease.

Improved detection of disseminated pheochromocytoma using post therapy I-131 MIBG scanning.

A 50-year-old man had metastatic pheochromocytoma to the left frontal bone. The primary adrenal tumor was removed 12 years previously. Bone scanning and diagnostic I-131 and I-123 MIBG imaging showed metastatic lesions in the right femur and midthoracic spine. However, post-therapy I-131 MIBG scanning showed extensive and widespread metastatic disease. Post-therapeutic I-131 MIBG whole-body scanning was necessary to more fully assess the extent of metastatic pheochromocytoma.

Therapeutic effect of m-[131I]- and m-[125I]iodobenzylguanidine on neuroblastoma multicellular tumor spheroids of different sizes.

m-[l25I]iodobenzylguanidine (m-[125I]MIBG) has been suggested as an alternative to m-[131I]MIBG for the treatment of metastatic neuroblastoma to achieve a higher radiation dose in micrometastases. To compare these two radiopharmaceuticals, a mathematical model was developed in the present study that allows for the calculation of radiation dose rates within small spherical tumors for different distributions of 131I and 125I. Furthermore, the relationship between tumor size and the therapeutic effects of m-[131I]- and m-[125I]MIBG was studied in vitro using multicellular tumor spheroids of the neuroblastoma cell line SK-N-SH. According to the calculations, higher mean dose rates can be achieved by m-[125I]MIBG than by m-[131I]MIBG up to a tumor diameter of 100 microm when both substances are homogeneously distributed within the tumor. In larger tumors, however, mean dose rates achieved by 131I are up to 8-fold higher. Evaluation of various activity distributions demonstrated that even in tumors of less than 100 microm in diameter, marked heterogeneities of the dose rate can occur when m-[125I]MIBG is not distributed homogeneously. By treatment with m-[131I]MIBG, the growth of tumor spheroids ranging from 100 to 250 microm in diameter was inhibited more effectively in the larger than in the smaller spheroids. The growth inhibition of spheroids treated with m-[125I]MIBG was independent of the spheroid size. In consistency with the calculations, the therapeutic effect of m-[125I]- and m-[131I]MIBG was equal in spheroids with diameters of about 100 microm. In larger spheroids, m-[131I]MIBG induced a more pronounced delay in spheroid growth than m-[125I]MIBG. According to these calculations and in vitro data, m-[125I]MIBG as a single agent does not seem to be a promising alternative to m-[131I]MIBG for treatment of metastatic neuroblastoma. However, the combined use of m-[131I]- and m-[125I]MIBG may be more effective than treatment with m-[131I]MIBG alone.

The current status of targeted radiotherapy in clinical practice.

Biologically targeted radiotherapy in clinical practice requires a molecule which has a relative specificity for tumour tissue--the missile--coupled to a radionuclide with appropriate physical characteristics--the warhead. When administered to a patient this combination should result in selective irradiation of the target tumour cells with relative sparing of normal tissues. Simple ions and small molecules which follow physiological pathways as either the natural substrates or analogues form the best examples of biological targeting. Clinically valuable results are seen with, for instance, iodine uptake by normal and malignant thyroid cells, incorporation of the calci-mimetic element strontium in areas of increased bone metabolism and accumulation of the catecholamine analogue meta-iodobenzylguanidine in neuroblastoma. The use of monoclonal antibodies as targeting vehicles has not proved to be a panacea, yet some patients with lymphoma, hepatoma and ovarian carcinoma have obtained benefit. Current clinical studies in targeted radiotherapy focus on the integration of radionuclide treatment with conventional treatments, and the optimization of such combined approaches. The development of modifications to offset the limitations inherent in the use of crude antibodies also offers an opportunity for improved clinical outcomes.

Radiation dosimetry for 131I-mIBG therapy of neuroblastoma.

This paper describes the methodology which can be used to determine whole-body, red marrow, blood, bladder, liver, and tumour doses delivered during 131I-mIBG therapy of neuroblastoma. The methodology is based on the Physics Protocol used in a multi-centre study undertaken by the United Kingdom Children's Cancer Study Group (UKCCSG). In this study, the estimates of the doses delivered, using 2.4-12.1 GBq 131I-mIBG, were in the following ranges: whole body, 0.14-0.65 mGy MBq-1; red marrow, 0.17-0.63 mGy MBq-1; blood, 0.04-0.17 mGy MBq-1; bladder, 2.2-5.3 mGy MBq-1; liver, 0.3-1.9 mGy MBq-1; and tumour, 0.2-16.6 mGy MBq-1.