Advancing Nuclear Medicine Through Innovation (2007) / Chapter Skim
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4 Targeted Radionuclide Therapy
4 Targeted Radionuclide Therapy
Pages 59-74
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From page 59... ...
There are currently hundreds of new pathway-targeted anticancer agents undergoing phase II and phase III clinical trials. Targeted radionuclide therapy is just one type within the category of "targeted therapies." At present, effective targeted radiopharmaceutical therapeutics have been developed and validated for a few tumor types, such as malignant lymphoma; for most other tumor types, the older nonspecific types of cancer treatments are still the dominant form of therapy.
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From page 60... ...
Whereas the radionuclides used for nuclear medicine imaging emit gamma rays, which can penetrate deeply into the body, the radionuclides used for targeted radionuclide therapy must emit radiation with a relatively short path length. There are three types of particulate radiation of consequence for targeted radionuclide therapy -- beta particles, alpha particles,1 and Auger An alpha particle is sub-atomic matter consisting of two protons and two 1 neutrons.
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From page 61... ...
. Moreover, within each of these categories, there are multiple radionuclides with a variety of tissue ranges, half-lives, and chemistries, offering the attractive possibility of tailor-making the properties of a targeted radionuclide therapeutic to the needs of an individual patient.
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From page 62... ...
4.2 Alpha Particle 50-80-micron range 5-8 MeV Beta Particle 1-10-mm range 0.1-1 MeV FIGURE 4.3 Penetrating power of alpha and beta particles. SOURCE: Courtesy of Joseph Jurcic, Memorial Sloan-Kettering Cancer Center.
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From page 63... ...
. Although the radiobiologic principles and dosimetric requirements for the effective use of these two agents are still not fully understood, the clinical response shows that a single cycle of treatment with either of these two radiopharmaceuticals can result in essentially the same level of tumor response as multiple cycles of conventional chemotherapy, generally with a fraction of the toxicity (Macklis 2004)
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From page 64... ...
FIGURE 4.4 Initial radionuclide scan of patient infused with indium-111 labeled anti-CD20 antibody in preparation for a subsequent therapeutic infusion with an yttrium-90-labeled antibody (ibritumomab tiuxetan or Zevalin®) of the same specificity.
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From page 65... ...
Other Antibodies and Radionuclides in Pre-Clinical and Early Clinical Phases of Testing Many of these classes of biologically targeted radiopharmaceuticals have shown clear objective responses with acceptable toxicity levels (DeNardo
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From page 66... ...
Translation of Alpha Particle-Emitting Radiotherapeutics from the Laboratory to the Clinical Setting Basic chemical advances in labeling molecules at high levels of radioactivity have led to the ability to assess the therapeutic potential of alphaemitting radionuclides in preclinical models of human malignancy. The predicted localized cytotoxicity of alpha particles has been demonstrated, providing compelling evidence for initiating clinical trials with monoclonal antibodies radiolabeled with an alpha-emitting radionuclide in patients with leukemia and brain tumors.
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From page 67... ...
It is this flexibility that makes this approach to cancer treatment attractive. Implicit in the above scenario is the availability of truly effective targeted radiotherapeutic agents for solid tumors, such as breast, colon, prostate, and lung cancers, that are less radiosensitive and less accessible than lymphomas, where targeted radionuclide therapy has already demonstrated meaningful results.
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From page 68... ...
Another attractive feature of alpha particles for targeted radionuclide therapy is that, as a consequence of their high linear energy transfer, they have greater biological effectiveness than either conventional external beam x-ray radiation or beta emitters. Studies performed in cell culture have demonstrated that human cancer cells can be killed even after being hit by only a few alpha particles (Akabani et al.
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From page 69... ...
Because most GBM kill through local invasion and rarely metastasize outside the cranium, the clinical potential of loco-regionally applied targeted radionuclide therapy is being evaluated for the treatment of this malignancy. More than 300 patients have been treated worldwide with radiolabeled monoclonal antibodies injected directly into
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From page 70... ...
Radiolabeled Small Molecules Radiolabeled monoclonal antibodies have been the most widely pursued approach to targeted radionuclide therapy; however, smaller molecular carriers, such as peptides that regulate the endocrine system, have been found to offer advantages for certain applications. The advantages of these smaller molecules include rapid accumulation in tumor and clearance from most normal tissues, which make them well-suited to use in tandem with some of the most promising radionuclides for targeted radionuclide therapy such as astatine-211 and rhenium-188, which have half lives of less than 24 hours.
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From page 71... ...
This is contrary to conventional radiation biological wisdom, which considers cell death to be a direct consequence of radiation traversal and energy deposition. These findings may have implications for targeted radionuclide therapy because if RIBBE could be harnessed, it could help compensate for variability in radiation dose deposition which is the bane of targeted radionuclide therapy (O'Donoghue et al.
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From page 72... ...
; and • strategies for reducing toxic effects to the kidneys from promising radiotherapeutics of lower molecular weight. 4.4 CURRENT IMPEDIMENTS TO FULL IMPLEMENTATION OF TARGETED RADIOPHARMACEUTICAL THERAPEUTICS The committee solicited input from individuals working in academia and in industry to identify current obstacles to the advancement of targeted radionuclide therapy.
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From page 73... ...
lack of a consensus for standardized image acquisition in nuclear medicine imaging procedures and protocols appropriate for multi-institutional clinical trials. The costs associated with meeting the FDA toxicology requirements for evaluating a new radiotracer in humans are beyond the budgets of academic institutions and are a major regulatory impediment to radiopharmaceutical development and translation to clinical practice.
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From page 74... ...
Recent experience in Europe demonstrates the appeal of targeted radionuclide therapy to patients. Patients increasingly go to Europe to receive targeted radionuclide therapy treatments that are not available domestically, and the gap in technology is increasing.
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