Improving Insight into Radiobiology and Radionuclide Therapy

large quantities of similar nonlabeled type of emission, and energy of emis- In 1969, Edith Quimby, ScD, one of compounds. sion) of a radionuclide and the radio- the founders of modern radionuclide do- In kidneys removed from 3 patients biologic response elicited. This issue simetry, concluded her presentation at an with primary renal tumors, de Jong et al. goes beyond the specific application of Atomic Energy Commission symposium (2) have demonstrated by autoradiogra- radiolabeled peptides in the treatment at the Oak Ridge Associated Universities phy a nonuniform distribution pattern for of neuroendocrine tumors. Currently, entitled “Medical Radionuclides: Radia- the radiolabeled peptide. The radiolabel the nuclear medicine community has tion Dose and Effects” with the state- is deposited in linear bands, most prom- available 2 radiolabeled antibodies ap- ment: “Radionuclide dosimetry is not a inently in the inner renal cortex and also proved by the U.S. Food and Drug in the renal medulla. Unfortunately, de Administration for the treatment of finished product, but it has come a long Jong’s group has not yet analyzed the non-Hodgkin’s lymphoma, one labeled way from the early empiric days. We precise histologic distribution on com- with 90Y and the other with 131I. At this must be grateful to the patient people panion sections stained with hematoxy- time, there has not been a randomized who have spent untold hours on these lin and eosin, but the autoradiographs comparison of the 2 agents. Given the developments.” (1). demonstrate the highest deposition of ra- numerous variables in patient selec- Thirty-five years later, this statement dionuclide in a well-defined pattern that tion, one wonders if a clinical trial will is still relevant. It has been confirmed by is sure to correlate with specific struc- resolve the question of therapeutic su- the efforts of Marion de Jong et al. from tures. Although drawing conclusions periority. My own group has been The Netherlands, as reported on pages would be premature, I find the pattern evaluating the relative merits of 90Y- 1168–1171 of this issue of The Journal quite suggestive of deposition in the and 177Lu-labeled monoclonal antibod- of Nuclear Medicine (2). de Jong et al. proximal and perhaps distal convoluted ies in the therapy of metastatic pros- have convincingly demonstrated that, in tubules. The proximal convoluted tubule tatic cancer (7). radionuclide dosimetry, it is not valid to is the site of reabsorption of amino acids The observations and subsequent dis- assume a uniform distribution of radia- from the glomerular filtrate and, so, is cussion of de Jong et al. (2) reinforce the tion sources in a target organ and, hence, likely also the site of reabsorption of a notion that one must consider microdo- that it is not appropriate to compare ra- small peptidelike octreotide and other simetry in order to understand the radio- diation effects from absorbed doses de- somatostatin analogs. biology of antitumor effects and organ or livered by external-beam sources with Accurate demonstration of the pre- tissue toxicity. The early Quimby–Ma- doses from injected radionuclides. cise localization of the site of reabsorp- rinelli formulation and the subsequent The radiation-absorbed dose to the tion may assist in identifying drugs or MIRD formulation enable us to deter- kidneys is a particular problem in the other compounds that would be more mine the radiation-absorbed dose to or- clinical assessment of peptide-based effective in blocking or inhibiting the gans and tissues independent of the ra- targeted radionuclide therapy of islet tubular reabsorption and subsequent dionuclide. These formulations account cell adenocarcinoma, malignant carci- deposition of the radiolabel. for differences in the administered dose, noid tumors, and other somatostatin- Even while de Jong et al. (2) and the physical and biologic half-life of the others (3–5) have been trying to better different radionuclides, and the specific receptor–positive tumors. The fraction relate the renal radiation-absorbed type and energy of the emission after of an injected dose of radiolabeled dose, as it is currently measured, to each nuclear disintegration. The MIRD peptide retained in the kidneys can be nephrotoxicity from 90Y-labeled pep- formulation also incorporates Monte reduced by amino acid infusions when tide therapy and to take measures to Carlo statistics to further rationalize the a labeled peptide or antibody fragment reduce that dose, the Rotterdam group randomness of the radiation emission has been administered. This practice is has been trying also to determine the and the distance and direction between a now standard in clinical protocols relative therapeutic merits and poten- source and target organ or tissue. Never- evaluating radiolabeled somatostatin tial toxicity of 90Y and 177Lu as labels theless, compared with the absorbed analogs as therapeutic agents. The for therapeutic uses (6). dose for uniform external-beam radia- logic behind this approach is to inhibit It is desirable from a scientific, di- tion therapy, the overall radiation-ab- reabsorption of the radiolabeled pep- dactic, and clinical perspective to un- sorbed dose calculated for radionuclide tide that appears in the glomerular fil- derstand the relationship between the therapy often does not correlate with the trate by administering comparatively physical properties (physical half-life, therapeutic or toxic effects observed.

1104 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 45 • No. 7 • July 2004 Questions remain about the differences gan or tissue refocuses the spotlight on from the early empiric days. We must in therapeutic and toxic effects from dif- differences between radionuclides in be grateful to the patient people who ferent radionuclides despite administra- terms of pathlength and linear energy have spent untold hours on these de- tion of similar radiation-absorbed doses. deposition, both functions of the en- velopments.” (1). Are these differences due to dose ergy of the specific emission. Until rate effects? This possibility was en- now, in Quimby–Marinelli and MIRD thusiastically considered a few years formulations, in contrast to ␥-radiation Stanley J. Goldsmith, MD ago, when the radionuclide therapy of and x-rays (penetrating radiation), we New York Weill Cornell Medical Center painful bone metastases was attracting have assigned a uniform absorbed- New York, New York attention. Because clinical trials vary fraction value to all nonpenetrating ra- so much in patient demographics, it diation (␣, ␤, and Auger). If the source REFERENCES was desirable to identify a scientific and target were the same, it was as- 1. Quimby E. The development of radiation dosimetry basis for selection among the several sumed that 100% of the energy from in nuclear medicine. In: Medical Radionuclides: Ra- diation Dose and Effects. Washington, DC: U.S. 89 153 166 radionuclides ( Sr, Sm, Re, and nonpenetrating emissions was ab- Atomic Energy Commission; 1970:7–15. AEC Sym- 87mSn) available for clinical trials. To sorbed (absorbed fraction ϭ 1.0); if the posium Series 20. date, no convincing evidence exists target was distant from the source, ab- 2. de Jong M, Valkema R, van Gameren A, et al. that differences in the physical half- sorbed fraction was assigned a value of Inhomogeneous localization of radioactivity in the human kidney after injection of [111In-DTPA]oct- lives of these radionuclides have an 0. It seems more appropriate now to reotide. J Nucl Med. 2004;45:1168–1171 impact. consider the distribution of energy de- 3. Otte A, Herrmann R, Heppeler A, et al. Yttrium-90 Several years ago, O’Donoghue et posited over the pathlength of an emit- DOTATOC: first clinical results. Eur J Nucl Med. 1999;26:1439–1447. al. determined the optimal tumor cure ted particle on a microscopic scale 4. Paganelli G, Zoboli S, Cremonesi M, et al. Receptor- diameter (lethal dose delivered) as a (even as we have done on a larger scale mediated radiotherapy with 90Y-DOTA-D-Phe1- function of ␤-particle energy (8). They for ␥-radiation) and to relate this dis- Tyr3-octreotide. Eur J Nucl Med. 2001;28:426–434. demonstrated that lower-energy emit- tribution to the histopathology for tu- 5. Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]- ters are more appropriate for the treat- mors and normal tissues in order to D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the ment of micrometastases, whereas determine the effective radiation-ab- treatment of neuroendocrine tumors: a clinical phase higher-energy ␤-emissions are less ef- sorbed dose on a microscopic anatomic II study. Ann Oncol. 2001;12:941–945. fective in that situation. Given that level. 6. Kwekkeboom DJ, Bakker WH, Kam BL, et al. ␤ Treatment of patients with gastro-entero-pancreatic -labeled carriers (peptides and mono- To understand the relationship be- (GEP) tumours with the novel radiolabelled soma- clonal antibodies) cannot be assumed tween radiation-absorbed dose and ra- tostatin analog [(177)Lu-DOTA(0), Tyr(3) oct- to be uniformly distributed, higher-en- diobiologic response in both tumors reotate. Eur J Nucl Med Mol Imaging. 2003;30:417– 422. ergy radionuclides may be more effec- and normal tissues and organs, we 7. Bander NH, Trabulsi EJ, Kostakoglu L, et al. Tar- tive in larger tumors. Bardies and must determine the microdosimetry; geting metastatic prostate cancer with radiolabeled Chatal (9) have calculated the ab- that is, we need to know the pattern of monoclonal antibody J591 to the extracellular do- sorbed fraction for ␤-emissions of dif- distribution of the radionuclide and ac- main of prostate specific membrane antigen. J Urol. 2003;170:1717–1721. ferent energies as a function of sphere count for the distribution of energy 8. O’Donoghue JA, Bardies M, Wheldon TE. Relation- diameter. deposition on a microscopic and his- ships between tumor size and curability for uni- We must be grateful to Marion de topathologic scale. It is appropriate to formly targeted therapy with beta-emitting radionu- Jong et al., because their observation repeat Dr. Quimby’s summation: “Ra- clides. J Nucl Med. 1995;36:1902–1909. 9. Bardies M, Chatal JF. Absorbed fractions of 22 of histopathologic differences in distri- dionuclide dosimetry is not a finished potential beta-emitting radionuclides for internal ra- bution of the radiolabel within an or- product, but it has come a long way diotherapy. Phys Med Biol. 1994;39:961–981.

IMPROVING INSIGHT INTO RADIOTHERAPY • Goldsmith 1105