Jeffry A. Siegel

Physical models and dose factors for use in internal dose assessment

Abstract— Internal dose assessment depends on the use of mathematical formulas for dose calculation and models of the human body and its organs. A simple, unified method for internal dose calculations is described, which brings together and simplifies concepts used in nuclear medicine and occupational internal dose systems previously described. Using the best current decay data and phantoms for internal dose calculations, dose factors for internal dose assessment are provided. Decay data for over 800 radionuclides from the data service at Brookhaven National Laboratory were combined with absorbed fraction data from a number of currently available mathematical whole body and organ models to provide the dose factors. This represents the first published update on nuclear medicine dose factors since MIRD Pamphlet No. 11 in 1975; in this paper, dose factors for many more nuclides are given (816 vs. 117 in MIRD 11), including some alpha emitters. New models are also employed, and dose factors for bone and marrow have been updated with recently suggested corrections. The good agreement of the new dose factors with previously published values for several of the models gives good confidence in their accuracy. This article gives an overview of the technical basis for these dose factors and some example tables of data, but the bulk of the data files will be distributed electronically. The use of an “electronic publishing” approach permits the publication of this kind of voluminous information in mainstream journals while facilitating rapid access and use without the need to purchase often expensive and bulky paper documents.

Overcoming the nephrotoxicity of radiometal-labeled immunoconjugates†

Elevated renal uptake and extended retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. However, cationic amino acids have been shown to reduce renal accretion. The aims of the current study were to evaluate whether this methodology would benefit therapy with yttrium 90 (90Y)‐labeled antibody fragments (Fab, F(ab)2), to establish the relationship between radiation dosimetry and observed biologic effects, and to compare the antitumor efficacy of antibody fragments with that of whole immunoglobulin (Ig)G.

Clinical evaluation of tumor targeting with a high-affinity, anticarcinoembryonic-antigen-specific, murine monoclonal antibody, MN-14

Background. The authors previously reported that an anticarcinoembryonic antigen antibody against a carcinoembryonic antigen (CEA)‐specific epitope is preferred for clinical investigations. They developed a second generation, CEA‐specific murine monoclonal antibody (MoAb), MN‐14 (IMMU‐14), that has a tenfold higher affinity. This report summarizes the initial clinical experience with the new MoAb.

Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen.

PURPOSE This investigation was undertaken to assess the targeting of established and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). PATIENTS AND METHODS Twenty-six assessable patients with known (n = 17) or occult (n = 9) MTC were studied with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine targeting of tumor lesions. RESULTS The targeting results of technetium 99m (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies (all directed against the same epitope of CEA) indicated that all these reagents were capable of detecting established and occult MTC. The sensitivity for detection of known sites of disease ranged from 76% to 100% for the various anti-CEA MAbs used, when compared with computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody scan was positive in seven of nine patients with occult disease (patients with negative conventional imaging studies, but who had elevated calcitonin and/or CEA levels). Three of seven patients underwent surgery and the disease was confirmed by histopathology in all three. CONCLUSION Anti-CEA MAbs are excellent agents for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease pretherapy or posttherapy, and especially for evaluating patients with recurrent or persistent hypercalcitonemia or CEA elevations after primary surgery. Analogous to radioiodine in the evaluation of patients with differentiated thyroid cancer, radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and monitoring patients with MTC.

Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: A phase I study

PURPOSE Selective high-dose radiation of solid tumors has been a goal of radiation oncology. The physiological barriers of solid tumors (high interstitial tumor pressure, reduced tumor vascularity, and poor perfusion) have been major barriers in achieving significant tumor dose of systemically infused radioconjugates. Direct tumor infusional brachytherapy overcomes these barriers and leads to selective high tumor doses. METHODS AND MATERIALS The development of interstitial tumor infusion of macroaggregated albumin (MAA) followed by colloidal chromic phosphate 32P has overcome solid tumor obstacles in 47 patients with nonresectable pancreatic cancer in a Phase I dose escalation study. The colloidal 32P infusion was followed by external radiation and five fluorouracil. RESULTS Of the 28 patients with cancer limited to the pancreas, 15 of 16 patients retained 86-100% (mean 96%) of the infused colloidal 32P isotope. While the other 12 patients had partial shunting to the liver, shunting to the liver was due to high interstitial resistance with tumor dose deposition of 17-88% (mean 52 %). Of the 19 patients with metastatic pancreas cancer, colloidal 32P tumor deposition ranged from 22 to 100% of the infused dose (mean 79%). The less than optimal tumor deposition led to our increasing the MAA from 600,000 to 1.5-2.5 million particles. Interstitial dexamethasone 2 mg and later 4 mg was infused first and prevented liver shunting by somehow reducing tumor resistance. The median survival in 28 Phase I patients with nonresectable pancreas cancer without metastasis, was 12 months. No significant toxicity occurred when treatment was limited to two infusions with as much as 30 mCi each. The maximum tumor dose was 17,000 Gy (1.700,000 cGy). In 19 nonresectable pancreatic cancer patients with metastasis, a 6.9 months median survival was observed. CONCLUSIONS Infusional brachytherapy is an outpatient procedure that delivers high-dose radiation selectively to pancreatic cancer. Results of the Phase I study in nonresectable pancreas cancer has led to a national multiinstitutional Phase II trial.

Subjecting Radiological Imaging to the Linear No-Threshold Hypothesis: A Non Sequitur of Non-Trivial Proportion

Radiologic imaging is claimed to carry an iatrogenic risk of cancer, based on an uninformed commitment to the 70-y-old linear no-threshold hypothesis (LNTH). Credible evidence of imaging-related low-dose (<100 mGy) carcinogenic risk is nonexistent; it is a hypothetical risk derived from the demonstrably false LNTH. On the contrary, low-dose radiation does not cause, but more likely helps prevent, cancer. The LNTH and its offspring, ALARA (as low as reasonably achievable), are fatally flawed, focusing only on molecular damage while ignoring protective, organismal biologic responses. Although some grant the absence of low-dose harm, they nevertheless advocate the “prudence” of dose optimization (i.e., using ALARA doses); but this is a radiophobia-centered, not scientific, approach. Medical imaging studies achieve a diagnostic purpose and should be governed by the highest science-based principles and policies. The LNTH is an invalidated hypothesis, and its use, in the form of ALARA dosing, is responsible for misguided concerns promoting radiophobia, leading to actual risks far greater than the hypothetical carcinogenic risk purportedly avoided. Further, the myriad benefits of imaging are ignored. The present work calls for ending the radiophobia caused by those asserting the need for dose optimization in imaging: the low-dose radiation of medical imaging has no documented pathway to harm, whereas the LNTH and ALARA most assuredly do.

Epidemiology Without Biology: False Paradigms, Unfounded Assumptions, and Specious Statistics in Radiation Science (with Commentaries by Inge Schmitz-Feuerhake and Christopher Busby and a Reply by the Authors)

Radiation science is dominated by a paradigm based on an assumption without empirical foundation. Known as the linear no-threshold (LNT) hypothesis, it holds that all ionizing radiation is harmful no matter how low the dose or dose rate. Epidemiological studies that claim to confirm LNT either neglect experimental and/or observational discoveries at the cellular, tissue, and organismal levels, or mention them only to distort or dismiss them. The appearance of validity in these studies rests on circular reasoning, cherry picking, faulty experimental design, and/or misleading inferences from weak statistical evidence. In contrast, studies based on biological discoveries demonstrate the reality of hormesis: the stimulation of biological responses that defend the organism against damage from environmental agents. Normal metabolic processes are far more damaging than all but the most extreme exposures to radiation. However, evolution has provided all extant plants and animals with defenses that repair such damage or remove the damaged cells, conferring on the organism even greater ability to defend against subsequent damage. Editors of medical journals now admit that perhaps half of the scientific literature may be untrue. Radiation science falls into that category. Belief in LNT informs the practice of radiology, radiation regulatory policies, and popular culture through the media. The result is mass radiophobia and harmful outcomes, including forced relocations of populations near nuclear power plant accidents, reluctance to avail oneself of needed medical imaging studies, and aversion to nuclear energy—all unwarranted and all harmful to millions of people.

Remission and survival following monthly intraarterial cisplatinum in nonresectable hepatoma.

Precis: Intraarterial delivery of 50 mg/m2 cisplatinum on a monthly basis is a well-tolerated regimen for patients with nonresectable hepatoma. The selective uptake of cisplatinum delivered intraarterially suggests other selective intraarterial protocols would be of use in regional cancers treated with cisplatinum. Background: Sixty-seven patients with nonresectable hepatoma were treated with hepatic artery infusions (HAI) of 50 mg/m2 cisplatinum on a monthly basis. Methods: Forty-eight patients received an initial course of whole liver external radiation with intravenous (IV) cisplatinum 50 mg/m2. Nineteen patients did not receive radiation and received HAI cisplatinum only. All patients then received HAI cisplatinum at 50 mg/m2 on a monthly basis. Six patients were given a tracer dose of radioactive 195mcisplatinum for quantitation by the HAI and IV routes. Results: Monthly HAI cisplatinum was well tolerated and could be repeated indefinitely. Median survival for primarily treated nonresectable hepatomas was 12 months [alpha fetoprotein (AFP) elevated] and 17.5 months (AFP negative). Radioactive cisplatinum given by HAI yielded 34–55% tumor uptake of cisplatinum vs. <5% by IV delivery. Conclusions: Hepatic intraarterial cisplatinum at 50 mg/m2 is a well-tolerated monthly regimen for patients with nonresectable hepatoma.

Clinical evaluation of tumor targeting with the anticarcinoembryonic antigen murine monoclonal antibody fragment, MN-14 F(ab)2

The initial clinical experience with the second‐generation, high‐affinity, MN‐14 immunoglobulin (IgG) anticarcinoembryonic antigen (CEA) monoclonal antibody (MoAb) in patients with CEA‐producing tumors was reported previously. A bivalent fragment of this MoAb, MN‐14 F(ab)2, was prepared, and its pharmacokinetics, targeting properties, dosimetry, and immunogenicity were investigated.

Posttherapy Radiation Safety Considerations in Radiomicrosphere Treatment with 90Y-Microspheres

Radiomicrosphere treatment involves the intrahepatic arterial administration of 90Y-resin or 90Y-glass microspheres. The microspheres are biocompatible, but not biodegradable, and little to no 90Y leaches from the microspheres. Without any bioelimination, the β-dose delivery is generally confined to the liver. Although U.S. Nuclear Regulatory Commission requirements permit patients treated with these microspheres to be released without the need for dose determination or patient instructions, there are important radiation safety issues that need scientific clarification. We carefully evaluated the radiation exposure mechanisms, including the bremsstrahlung radiation doses to others, for a variety of lifestyle behaviors. Dose estimates were also made for several practical and theoretic situations involving the patients gonads, an embryo or fetus, and a nursing infant. For the infant, we evaluated the potential β-dose that might be introduced via breast milk ingestion. The bremsstrahlung component of the decay scheme of the pure β-emitter 90Y has traditionally been ignored in internal and external dose calculations. Because the production of in vivo bremsstrahlung with the high-energy pure β-particle–emitting radionuclides used for therapeutic purposes is sufficient to permit external detection and imaging, we believe that the contribution of such radiation should be considered with regard to patient release; we therefore chose to evaluate this potential external radiation hazard. In all cases, the estimated doses were very small, indicating that no patient restrictions are required for radiation safety purposes after the release of a patient who has been treated with 90Y-microspheres.