Halperin7e_CH29

656

S E C T I O N I I  Techniques, Modalities, and Modifiers in Radiation Oncology

cell diameters). Although it has a short range, the α -particle is very destructive and has a high linear energy transfer (LET). Low-energy electron emitters also emit radiation that is high LET and have path lengths between 2 and 500 nm (width of a double-strand helix). Auger emitters, such as 111 In or 125 I, are most effective if delivered to the nucleus of a cell or incor- porated into the DNA. It has been mathematically postulated that it will only take 60 decays of 125 I, coupled to DNA, to reduce cell survival to 50%. For a patient with 1-g circulating micrometastatic disease, 1,000 decays in the malignant cells can produce a probable cure. This amount of radiation cor- responds to 0.1-MBq injected activity. This represents 5 mSv per 1 year of background radiation for the average human. 32 To further place this in perspective, Auger emitters can be safely injected into humans with an activity between 100 and 350 mCi, perhaps even at higher activities. It should be under- stood, 100 mCi = 3700 MBq; 1 MBq = 1,000,000 dps. Because radionuclides have different energy spectra for their emitted particulate radiation, they will each interact with tissue and deposit their energy over varying distances. There is therefore a relation between the type of radionuclide, tumor size, absorbed dose, and ultimately tumor cure prob- ability (TCP). If it is assumed that a tumor has a spherical volume and contains a uniform and identical activity concen- tration of a radionuclide, then the TCP can be calculated for different radionuclides and tumor size. 33 Figure 29.4 illus- trates the relation between tumor mass and TCP for asta- tine-211 [ 211 At], lutetium 177 [ 177 Lu], 131 I, and 90 Y. As can be seen, there is an optimum tumor size for the different energy spectra for each radionuclide such that the TCP is maximized. If the tumor is small relative to the emission range, then much of the energy will be lost to the surrounding tissue and the absorbed dose will be low. As the tumor size increases, more energy is absorbed until the maximum TCP is reached. As the tumor further increases in size, the absorbed energy remains high, although fewer cells are affected by the radiation and TCP begins to decrease. 33 These observations move forward the concept of using multiple radionuclides, in the RIT pro- cess, that deposit their energies over different ranges in tis- sue. As a result, more energy could then be deposited into tumors of various sizes, potentially improving the therapeutic ratio. Labeling the targeting construct with the appropri- ate radionuclide (radiochemistry) is exceedingly important and equally complex. Radionuclides are attached to target- ing constructs by either using a “linker” molecule, termed a FIGURE 29.4.  Tumor control probability (TCP) for various radionuclides. TCP = 0.9 versus tumor mass. The optimal TCP for various tumor masses when treated with 211 At, 177 Lu, 131 I, and 90 Y. This corresponds to approximately 10 − 5 , 10 − 2 , 0.1, and 10 g, respectively. (From Bernhardt P, Speer TW. Modeling the systemic cure with targeted radionuclide therapy. In: Speer TW, ed. Targeted radionuclide therapy . Philadelphia: Lippincott Williams & Wilkins, 2011:266. With permission.)

bifunctional chelating agent (BCA), or by a chemical reaction that forms a covalent bond between the radionuclide and the targeting construct. Three basic scientific fields converged to make radiochemistry a reality: coordination chemistry, directed biologic targeting, and the medical application of radiopharmaceuticals. 34 In general, metallic radionuclides will require a BCA for labeling, and radiohalogens will require a chemical reaction (halogenation). The most prevalent thera- peutic radionuclides used in RIT are 90 Y (metallic radionuclide) and 131 I (radiohalogen). One of the most commonly used BCAs is DTPA—a polyaminopolycarboxylate straight chain ligand. Tiuxetan, a modified DTPA molecule, is used as a linker mole- cule to chelate 90 Y to ibritumomab ( 90 Y ibritumomab tiuxetan; Zevalin, Spectrum Pharmaceuticals, Henderson, NV).Tiuxetan forms a urea-type bond to the antibody (ibritumomab), and its five carboxyl groups interact with and chelate 90 Y to form a stable coordination sphere. The halogenation reaction that bonds 131 I to a protein-targeting construct ( 131 I tositumomab; Bexxar, GlaxoSmithKline, Philadelphia, PA; discontinued 2013) is called iodination. Although there are many permuta- tions of the iodination reaction, it basically inserts 131 I into a tyrosine group on the mAb without the need for a chelation molecule. Regardless of the required labeling technique, it is incumbent that a reasonably high labeling yield, unaltered biodistribution, stability of the radionuclide, and immunore- activity are preserved. Historically, a single instillation or fraction of the RIT agent is delivered systemically (i.e., Zevalin and Bexxar). It is well known that although relatively effective for hemato- logic malignancies, RIT is much less effective for treating solid tumors. Therefore, a number of strategies are being devel- oped that will potentially increase the effectiveness of RIT. These strategies include modulating the tumor microenviron- ment; using pretargeting techniques, extracorporeal delivery, combined modality therapy (CMT), fractionation, and multiple radionuclides (radionuclide cocktail); increasing antibody mass (the amount of antibody delivered systemically); altera- tion of the physical properties (size and affinity) of the target- ing construct; and employing different types of LET radiation (i.e., β -emitter vs. α -emitter). These strategies are designed to deliver more radiation to the tumor, make the radiation more cytotoxic, or decrease the exposure of radiation to bone mar- row. As a result, the tumor to blood ratio will increase, and ultimately, the therapeutic ratio will increase. The pretarget- ing strategy warrants further discussion. 35,36 Because radiolabeled mAbs take 2 to 3 days to localize or accrete into tumors, antibody-based RIT results in a prolonged exposure of the bone marrow to radiation, causing hemato- logic toxicity and rendering the bone marrow as the dose- limiting normal tissue. Accordingly, the tumor/blood ratios of mAb will only slightly favor the tumor. This situation can seriously limit the successful prospects of antibody-based RIT, especially for treating solid tumors. Smaller targeting con- structs (antibody fragments, peptides, aptamers) can be used for RIT, and they will exhibit pharmacokinetics that result in a more rapid blood clearance allowing for the administration of higher activities. Unfortunately, because of the lower over- all tumor accretion and retention of smaller constructs, the advantage of a more rapid blood clearance is usually offset. Therefore, the ideal delivery construct would manifest the high-affinity targeting properties of an intact mAb but exhibit the blood clearance pattern of a small molecular weight con- struct. This conventional wisdom is based upon using beta and alpha radionuclides, both of which will be toxic with long circulation times. If targeting constructs using Auger emitters can be engineered, the circulation time becomes rather imma- terial as Auger radionuclides are only cytotoxic if internalized into cells. Because no known construct manifesting all of these attributes exists today, pretargeting strategies have been developed.The basic premise of pretargeting is to separate the