Abstract 1 of 25

Department of Radiology, Harvard Medical School, Boston, Massachusetts

Although the general radiobiologic principles underlying external beam therapy and radionuclide therapy are the same, there are significant differences in the radiobiologic effects observed in mammalian cells. External beam and brachytherapy emissions are composed of photons, whereas radiations of interest in radionuclide therapy are particulate. The special features that characterize the biologic effects consequent to the traversal of charged particles through mammalian cells are explored with respect to DNA lesions and cellular responses. Information about the ways in which these radionuclides are used to treat cancers in experimental models are highlighted.

Key Words: -particle emitters " Auger-electron emitters " ß-particle emitters " radiobiology " radionuclide therapy

[Full Text of Kassis and Adelstein] [Reprint (PDF) Version of Kassis and Adelstein]

Abstract 2 of 25

Department of Nuclear Medicine, Erasmus Medical College, Rotterdam, The Netherlands

Peptide receptor-targeted radionuclide therapy of somatostatin receptor-expressing tumors is a promising application of radiolabeled somatostatin analogs. Suitable radionuclides are ⁹⁰Y, a pure, high-energy ß-emitter (2.27 MeV), and ¹⁷⁷Lu, a medium-energy ß-emitter (0.5 MeV) with a low-abundance . Methods: Lewis rats, each bearing both a small (approximately 0.5 cm²) and a large (79 cm²) somatostatin receptor-positive rat pancreatic CA20948 tumor in their flanks, were used. We investigated the radiotherapeutic effects of [⁹⁰Y-tetraazacyclododecanetetraacetic acid (DOTA),Tyr³]octreotide, [⁹⁰Y-DOTA,Tyr³]octreotate, [¹⁷⁷Lu-DOTA,Tyr³]octreotate, and the combination of ⁹⁰Y- and ¹⁷⁷Lu-labeled analogs at the same tumor radiation dose (60 Gy). Results: Radiotherapeutic effects of the ⁹⁰Y- and ¹⁷⁷Lu-labeled analogs were found in the rat tumor model. In these animals bearing tumors of different sizes, the antitumor effects of the combination of 50% ¹⁷⁷Lu- plus 50% ⁹⁰Y-analogs were superior to those in animals treated with either ⁹⁰Y- or ¹⁷⁷Lu- analog alone. In smaller tumors, the ⁹⁰Y radiation energy was not completely absorbed in the tumor, whereas in larger tumors the increased number of clonogenic tumor cells at the fixed level of absorbed dose may account for the failure of ¹⁷⁷Lu alone to go completely into remission. Conclusion: This study shows the superior antitumor effects of the combination of ¹⁷⁷Lu- and ⁹⁰Y-somatostatin analogs when compared with either ⁹⁰Y- or ¹⁷⁷Lu-analog alone in animals bearing tumors of various sizes.

Key Words: ⁹⁰Y " ¹⁷⁷Lu " somatostatin analogs " tumor size " peptide-receptor radionuclide therapy

[Full Text of de Jong et al.] [Reprint (PDF) Version of de Jong et al.]

Abstract 3 of 25

Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Response and toxicity prediction is essential to rational implementation of cancer therapy. The biologic effects of radionuclide therapy are mediated via a well-defined physical quantity, the absorbed dose, which is defined as the energy absorbed per unit mass of tissue. The concepts, basic definitions, and different approaches to the clinical implementation of absorbed dose estimation are reviewed in this article. Ongoing efforts to improve the accuracy of dosimetry calculations are discussed, as well as studies examining the relationship between absorbed dose and response. Particular attention is placed on the marrow and kidney as dose-limiting organs. Finally, the potential role of radiobiologic modeling in helping to account for differences in dose rate and spatial distribution are reviewed. A treatment planning approach to radionuclide therapy will eventually require incorporation of biologic and radiobiologic considerations. Until such methods are developed and validated, absorbed dose remains an important variablebut still one of several likely to predict response in an individual patient.

Key Words: radionuclide therapy " radiobiologic modeling " absorbed dose " treatment planning

[Full Text of Sgouros] [Reprint (PDF) Version of Sgouros]

Abstract 4 of 25

¹ Endocrine Service, Division of General Medicine, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
² Service de Medecine Nucleaire, Institut Gustave Roussy, Villejuif, France

The use of radioactive iodine (¹³¹I) for the treatment of thyroid carcinoma has changed over the past 50 y. These changes are based on increasing awareness of the biophysical properties of ¹³¹I and new discoveries concerning the biology of iodine handling by thyroid cells. The therapeutic administration of ¹³¹I for thyroid remnant ablation and for metastases requires an appreciation of iodine clearance kinetics, of factors that can alter the occupancy time of ¹³¹I within lesions, and of the role of thyroid-stimulating hormone in stimulating the sodium-iodide symporter. The potential complications and adverse events associated with ¹³¹I are discussed. ¹³¹I will continue to be a major weapon in the fight against metastatic thyroid carcinoma. Its future role will be modified by expanding knowledge of its relative risks and benefits.

Key Words: thyroid carcinoma " radioactive iodine " dosimetry " metastases " adverse effects " carcinogenesis

[Full Text of Robbins and Schlumberger] [Reprint (PDF) Version of Robbins and Schlumberger]

Abstract 5 of 25

Royal Marsden Hospital, Sutton, England, United Kingdom

Systemic therapy using bone-seeking radiopharmaceuticals has clear advantages for the treatment of multisite metastatic pain. Evidence supporting the use of ß-particle, electron, and -particleemitting radiopharmaceuticals is reviewed here. Appropriate patient selection relies on correlating clinical symptoms with focal abnormalities on conventional bone scintigraphy. Time to symptom relief and response duration vary with the physical half-life and dose rate of the radionuclide used, offering the opportunity to tailor radiopharmaceutical choice to individual patient circumstances. Toxicity is limited to temporary myelosuppression, governed by the administered activity and underlying bone marrow reserve. Optimal responses are achieved in patients with a modest skeletal tumor burden, suggesting that targeted therapy should be considered early in the management of bone metastases. The development of reliable dosimetric models will facilitate patient-specific prescribing to deliver enhanced symptom response within acceptable toxicity limits. It is likely that targeted therapy will be most effective in the context of multimodality tumor management. Further research is required to examine the potential of radionuclides in combination with external-beam irradiation, bisphosphonates, or chemotherapy. This approach might allow targeted therapy to progress beyond symptom palliation to early intervention for survival gain.

Key Words: bone pain palliation " metastasis " targeted radionuclide therapy " dosimetry

[Full Text of Lewington] [Reprint (PDF) Version of Lewington]

Abstract 6 of 25

¹ Clinic for Nuclear Medicine, University of Würzburg, Würzburg, Germany
² Department for Nuclear Medicine, Bethesda Clinics, Essen, Germany

Radiosynovectomy (RSV) is a local intraarticular injection of radionuclides in colloidal form for radiotherapy. First used by Fellinger et al. in 1952, the technique has now been applied for more than 50 y for treatment of resistant synovitis of individual joints after failure of long-term systemic pharmacotherapy and intraarticular steroid injections. RSV relieves pain and inflammation from rheumatoid arthritis (RA), for which it initially was used, and is accepted as an alternative to surgical synovectomy in cases of RA or other inflammatory arthropathies such as osteoarthritis and hemophiliac arthropathy. A good understanding of the clinical pathophysiology of the disease processes is mandatory, and close interdisciplinary collaboration with other clinicians who diagnose and treat patients is strongly suggested. Reported success rates range from 40% to 90% for the different joints and underlying diseases. A few well-designed prospective double-blind trials have evaluated the efficacy of RSV and justified the procedure as a viable option for treating chronic synovitis in RA or secondary to inflammatory arthropathies. In comparison with surgical synovectomy, RSV produces equivalent results, costs less, allows the patient to remain ambulatory, and is repeatable. RSV has to be considered the initial procedure of choice for the treatment of patients with hemarthrosis in hemophilia. In addition, local instillation of radiopharmaceuticals can effectively reduce effusions after implantation of a prosthesis.

Key Words: radionuclide therapy " radiopharmaceuticals " radiosynovectomy " rheumatoid arthritis

[Full Text of Schneider et al.] [Reprint (PDF) Version of Schneider et al.]

Abstract 7 of 25

¹ Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa
² Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa

Nuclear imaging techniques such as bone scans, metaiodobenzylguanidine (MIBG) scans, and ¹¹¹In-diethylenetriaminepentaacetic acid-octreotide scans have greatly increased the sensitivity and specificity of both diagnostic and follow-up protocols for pediatric solid tumors. Molecular targets that are specific for certain pediatric tumors are now being developed. Targets include cell membrane receptors targeted by specific ligands, subcellular organelles targeted by false transmitters, and cellular proteins targeted by antibodies. This review focuses on the use of MIBG (which is a false transmitter) and octreotide (which is a ligand for G protein receptor) in the diagnosis and treatment of solid tumors that affect children and young adults.

Key Words: metaiodobenzylguanidine " molecular targets " pediatric tumors

[Full Text of Pashankar et al.] [Reprint (PDF) Version of Pashankar et al.]

Abstract 8 of 25

¹ Department of Nuclear Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, The Netherlands
² Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
³ Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy
⁴ Division of Hematology and Oncology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana
⁵ Department of Nuclear Medicine, Universitaire Catholique Louvain, Brussels, Belgium
⁶ Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida
⁷ Division of Endocrinology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa

A new treatment modality for inoperable or metastasized gastroenteropancreatic tumors is the use of radiolabeled somatostatin analogs. Initial studies with high doses of [¹¹¹In-diethylenetriaminepentaacetic acid (DTPA)⁰]octreotide in patients with metastasized neuroendocrine tumors were encouraging, although partial remissions were uncommon. Another radiolabeled somatostatin analog that is used for peptide receptor radionuclide therapy (PRRT) is [⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)⁰,Tyr³]octreotide. Various phase 1 and phase 2 PRRT trials have been performed with this compound. Despite differences in the protocols used, complete and partial remissions in most of the studies with [⁹⁰Y-DOTA⁰,Tyr³]octreotide were in the same ranges, 10%30%; these ranges were higher than those obtained with [¹¹¹In-DTPA⁰]octreotide. Treatment with the newest radiolabeled somatostatin analog, [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, which has a higher affinity for the subtype 2 somatostatin receptor, resulted in complete or partial remissions in 30% of 76 patients. Tumor regression was positively correlated with a high level of uptake on OctreoScan imaging, a limited hepatic tumor mass, and a high Karnofsky performance score. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all ¹¹¹In-, ⁹⁰Y-, or ¹⁷⁷Lu-labeled somatostatin analogs that have been used for PRRT. The results obtained with [⁹⁰Y-DOTA⁰,Tyr³]octreotide and [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the duration of the therapy response for both radiopharmaceuticals is more than 2 y. These data compare favorably with those for the limited number of alternative treatment approaches.

Key Words: somatostatin " somatostatin receptor " radionuclide therapy " gastroenteropancreatic tumors

[Full Text of Kwekkeboom et al.] [Reprint (PDF) Version of Kwekkeboom et al.]

Abstract 9 of 25

¹ Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland
² Radiopharmacy, Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
³ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

Regulatory peptide receptors are overexpressed in numerous human cancers. These receptors have been used as molecular targets by which radiolabeled peptides can localize cancers in vivo and, more recently, to treat cancers with peptide receptor radiation therapy (PRRT). This review describes the candidate tumors eligible for such radiotherapy on the basis of their peptide receptor content and discusses factors in PRRT eligibility. At the present time, PRRT is performed primarily with somatostatin receptor- and cholecystokinin-2 (CCK2)-receptor-expressing neuroendocrine tumors with radiolabeled octreotide analogs or with radiolabeled CCK2-selective analogs. In the future, PRRT may be extended to many other tumor types, including breast, prostate, gut, pancreas, and brain tumors, that have recently been shown to overexpress several other peptide receptors, such as gastrin-releasing peptide-, neurotensin-, substance P-, glucagon-like peptide 1-, neuropeptide Y-, or corticotropin-releasing factor-receptors. A wide range of radiolabeled peptides is being developed for clinical use. Improved somatostatin or CCK₂ analogs as well as newly designed bombesin, neurotensin, substance P, neuropeptide Y, and glucagon-like peptide-1 analogs offer promise for future PRRT.

Key Words: tumor targeting " radiopeptides " receptors " peptide receptor radiation therapy " tumor selection

[Full Text of Reubi et al.] [Reprint (PDF) Version of Reubi et al.]

Abstract 10 of 25

¹ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
³ Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
⁴ Department of Nuclear Medicine, Université Catholique de Louvain, Brussels, Belgium
⁵ Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern, Switzerland

Peptide receptor scintigraphy in combination with anatomic imaging methods such as CT can be regarded as molecular imaging. It offers insight into the variability of somatostatin receptor expression in neuroendocrine tumor lesions within a patient. The somatostatin receptor status of all tumors in a patient is an important issue, because receptor-negative lesions may be poorly differentiated and characterized by aggressive growth and poor prognosis, with consequences for the choice of therapy. Methods: Follow-up studies of 3 patients with gastroenteropancreatic neuroendocrine tumors who had been previously treated with peptide receptor radionuclide therapy (PRRT) are presented. Results: Patient 1 had a mixed response after treatment with ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid⁰ (DOTA),Tyr³-octreotide. The response included fibrosis and a low rate of mitosis in receptor-positive lesions that had decreased in volume after treatment and vital tumor cells and a high rate of mitosis in receptor-negative lesions that had grown since the start of treatment. Patient 2 had a good clinical and biochemical response after PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-DOTATATE), with disappearance of ¹¹¹In-pentetreotide uptake on follow-up scans, whereas on CT the size of the lesions remained unchanged, possibly indicating tumor necrosis. Patient 3 had a complete remission after PRRT with ¹⁷⁷Lu-DOTATATE but subsequently relapsed with many receptor-negative metastases, requiring intensive chemotherapy. Conclusion: Although biopsy is required for initial diagnosis and treatment planning, noninvasive molecular imaging may evolve into in vivo molecular pathology in selected groups of patients, especially in treatment follow-up.

Key Words: neuroendocrine tumor " pathology " peptide " peptide receptor radiation therapy

[Full Text of Krenning et al.] [Reprint (PDF) Version of Krenning et al.]

Abstract 11 of 25

¹ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
² Service de Medecine Nucleaire, Cliniques Universitaires Saint-Luc, Universite Catholique Louvain, Brussels, Belgium
³ Gastrointestinal Tumor Program, H. Lee Moffitt Cancer Hospital, University of South Florida, Tampa, Florida
⁴ Novartis Pharmaceuticals Corp., East Hanover, New Jersey

The kidneys are critical organs in peptide receptor radiation therapy (PRRT). Renal function loss may become apparent many years after PRRT. We analyzed the time course of decline in creatinine clearance (CLR) in patients during a follow-up of at least 18 mo after the start of PRRT with ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA),Tyr³-octreotide (⁹⁰Y-DOTATOC) or ¹⁷⁷Lu-DOTA⁰,Tyr³-octreotate (¹⁷⁷Lu-DOTATATE). Methods: Twenty-eight patients with metastasized neuroendocrine tumors received 15 cycles of ⁹⁰Y-DOTATOC, leading to renal radiation doses of 5.926.9 Gy per cycle and a total of 18.338.7 Gy. Median follow-up was 2.9 y (range, 1.55.4 y), with a median of 16 measurements (range, 553) per patient. Thirty-seven patients with metastasized neuroendocrine tumors received 37 cycles of ¹⁷⁷Lu-DOTATATE, leading to renal radiation doses of 1.87.8 Gy per cycle and a total of 7.326.7 Gy. Median follow-up was 2.4 y (range, 1.74.0 y), with a median of 10 (range, 627) measurements per patient. All renal dose estimates were calculated with the MIRDOSE3 model. All patients were infused with renoprotective amino acids during the administration of the radioactive peptides. The time trend of CLR was determined by fitting a monoexponential function through the data of individual patients, yielding the decline in CLR in terms of percentage change per year. Results: The median decline in CLR was 7.3% per y in patients treated with ⁹⁰Y-DOTATOC and 3.8% per y in patients treated with ¹⁷⁷Lu-DOTATATE (P = 0.06). The time trend of decline in CLR was sustained during the follow-up period. Eleven patients had a >15% per y decline in CLR. Cumulative renal radiation dose, per-cycle renal radiation dose, age, hypertension, and diabetes are probable contributing factors to the rate of decline in CLR after PRRT. Conclusion: This study showed that the time course of CLR after PRRT was compatible with the pattern of sustained CLR loss in progressive chronic kidney disease.

Key Words: ⁹⁰Y-DOTA⁰,Tyr³-octreotide " ¹⁷⁷Lu-DOTA⁰,Tyr³-octreotate " peptide receptor radiation therapy " radiation nephropathy " chronic kidney disease

[Full Text of Valkema et al.] [Reprint (PDF) Version of Valkema et al.]

Abstract 12 of 25

¹ Centre de Médecine Nucléaire, Université Catholique de Louvain, Brussels, Belgium
² Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
³ Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida

The challenge for internal therapy is to deliver the highest possible dose to the tumor while sparing normal organs from damage. Currently, the potential risk of kidney and red marrow toxicity limits the amount of radioactivity that may be administered. An accurate dosimetry method that would provide reliable dose estimates to these critical organs and to tumors before therapy would allow the clinician to plan a specific therapeutic regimen and also select those patients who would benefit the most from treatment. The dosimetry for ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-D-Phe¹-Tyr³-octreotide is usually based on quantitative imaging at different time points that provides information on activity retention in organs over time and on stylized models representing average individuals. Because the therapeutic agent labeled with ⁹⁰Y is not suitable for quantitative imaging, the peptide surrogate labeled with the positron emitter ⁸⁶Y can be considered the most appropriate tracer for measuring distribution and retention of the radiopharmaceutical over time. Dose calculations in target organs are generally performed using the MIRDOSE program, in which S values from source to target are integrated. Significant improvement of dose estimates may be achieved by introducing patient-specific adjustments to the standard models. The use of individual kidney volumes assessed by CT instead of the use of a fixed volume for males and females may significantly improve the determination of kidney radiation doses. The use of actual CT-derived tumor volumes has also shown a doseefficacy relationship. Additional improvements in this field include the validation and use of an ¹¹¹In surrogate to avoid the complexity of ⁸⁶Y use and the consideration of radiobiologic parameters, such as fractionation effects and the specific biologic efficacy of internally deposited radiation, which are probably underestimated using currently available methods.

Key Words: dosimetry " ⁹⁰Y-DOTA-Tyr³-octreotide " radionuclide therapy " oncology

[Full Text of Pauwels et al.] [Reprint (PDF) Version of Pauwels et al.]

Abstract 13 of 25

¹ Centre of Nuclear Medicine and Laboratory of Positron Emission Tomography; Université Catholique de Louvain, Brussels and Louvain-la-Neuve, Belgium
² Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
³ Department of Biostatistics, Centre Léon Bérard, Lyon, France
⁴ H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida

Nephrotoxicity is the major limiting factor during therapy with the radiolabeled somatostatin analog ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-D-Phe¹-Tyr³-octreotide (DOTATOC). Pretherapeutic assessment of kidney absorbed dose could help to minimize the risk of renal toxicity. The aim of this study was to evaluate the contribution of patient-specific adjustments to the standard dosimetric models, such as the renal volume and dose rate, for estimating renal absorbed dose during therapy with ⁹⁰Y-DOTATOC. In particular, we investigated the correlation between dose estimates and effect on renal function after therapy. Methods: Eighteen patients with neuroendocrine tumors (9 men and 9 women; median age, 59 y) underwent treatment with ⁹⁰Y-DOTATOC (8.122.9 GBq) after pretherapeutic biodistribution study with ⁸⁶Y-DOTATOC. Kidney uptake and residence times were measured and the absorbed dose (KAD) was computed using either the MIRDOSE3.1 software assuming a standard kidney volume (KAD_StdVol) or the MIRD Pamphlet 19 values and the actual kidney cortex volume determined by pretherapeutic CT (KAD_CTVol). For each patient, the biologic effective dose (BED) was calculated according to the linear quadratic model to take into account the effect of dose rate and fractionation. Renal function was evaluated every 6 mo by serum creatinine and creatinine clearance (CLR) during a median follow-up of 35.5 mo (range, 1865 mo). The individual rate of decline of renal function was expressed as CLR loss per year. Results: KAD_CTVol ranged between 19.4 and 39.6 Gy (mean, 28.9 ± 5.34 Gy). BED, obtained from KAD_CTVol, ranged between 27.7 and 59.3 Gy (mean, 40.4 ± 10.6 Gy). The CLR loss per year ranged from 0% to 56.4%. In 12 of 18 patients, CLR loss per year was <20%. No correlation was observed between CLR loss per year and the KAD_StdVol or the KAD_CTVol. In contrast, BED strongly correlated with CLR loss per year (r = 0.93; P < 0.0001). All 5 patients with CLR loss per year >20% received a BED >45 Gy. Patients who were treated with low fractionation were those with the highest rate of renal function impairment. Conclusion: Radiation nephrotoxicity after ⁹⁰Y-DOTATOC therapy is dose dependent. Individual renal volume, dose rate, and fractionation play important roles in an accurate dosimetry estimation that enables prediction of risk of renal function impairment.

Key Words: kidney dosimetry " ⁹⁰Y-DOTA-Tyr³-octreotide " radionuclide therapy " radiation nephropathy

[Full Text of Barone et al.] [Reprint (PDF) Version of Barone et al.]

Abstract 14 of 25

¹ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

In patients with progressive metastatic (or recurrent) differentiated thyroid carcinoma (DTC) who do not respond to radioiodine therapy or do not show uptake on radioiodine scintigraphy, treatment options are few. Because these tumors may express somatostatin receptors, peptide receptor radionuclide therapy might be effective. We evaluated the therapeutic efficacy of the radiolabeled somatostatin analog ¹⁷⁷Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid⁰ (DOTA), Tyr³-octreotate (¹⁷⁷Lu-DOTATATE) in patients with DTC. The uptake of radioactivity in tumors was also studied in relation to treatment outcome. Methods: Five patients with DTC (3 with Hürthle cell thyroid carcinoma [HCTC], 1 with papillary thyroid carcinoma [PTC], and 1 with follicular thyroid carcinoma [FTC]) were treated with 22.430.1 GBq of ¹⁷⁷Lu-DOTATATE. Response to therapy was evaluated with CT. Uptake on ¹⁷⁷Lu-DOTATATE scintigraphy (24 h after treatment), expressed as percentage of injected dose, was compared with uptake on pretherapy ¹¹¹In-octreotide scintigraphy (24 h after injection). Results: After the last treatment with ¹⁷⁷Lu-DOTATATE, 1 patient with HCTC had stable disease as a maximum response, 1 patient with HCTC had minor remission (tumor shrinkage between 25% and 50%), and 1 patient with HCTC had partial remission (shrinkage 50%). The responses in PTC and FTC were stable disease and progressive disease, respectively. A decrease in serum thyroglobulin level was found in patients with HCTC. Patients with minor and partial remissions had the highest ¹⁷⁷Lu-DOTATATE-to-¹¹¹In-diethylenetriamine pentaacetic acid⁰-octreotide (¹¹¹In-octreotide) uptake ratios (3.2 and 2.4, respectively) whereas the other patients had uptake ratios smaller than 1.5. Conclusion: ¹⁷⁷Lu-DOTATATE therapy can be effective in patients with progressive DTC who have no therapeutic options and sufficient uptake of ¹¹¹In-octreotide in tumor lesions as shown on ¹¹¹In-octreotide scintigraphy. This finding is especially important in patients with HCTC, because they cannot benefit from radioiodine therapy because of non-iodine-avid lesions at diagnosis.

Key Words: differentiated thyroid carcinoma " radionuclide therapy " ¹⁷⁷Lu " somatostatin receptor " octreotate

[Full Text of Teunissen et al.] [Reprint (PDF) Version of Teunissen et al.]

Abstract 15 of 25

¹ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey

With the approval of 2 radiolabeled antibody products for the treatment of non-Hodgkins lymphoma (NHL), radioimmunotherapy (RIT) has finally come of age as a new therapeutic modality, exemplifying the collaboration of multiple disciplines, including immunology, radiochemistry, radiation medicine, medical oncology, and nuclear medicine. Despite the many challenges that this new therapy discipline has encountered, there is growing evidence that RIT can have a significant impact on the treatment of cancer. Although follicular NHL is currently the only indication in which RIT has been proven to be effective, clinical trials are showing usefulness in other forms of NHL as well as in other hematologic neoplasms. However, the treatment of solid tumors remains a formidable challenge, because the doses shown to be effective in hematologic tumors are insufficient in the more common epithelial cancers. Nevertheless, there has been progress in locoregional applications and in the treatment of minimal residual disease. There is also optimism that pretargeting procedures, including new molecular constructs and targets, will improve the delivery of radioactivity to tumors, do so with less hematologic toxicity, and become the next generation of RIT.

Key Words: Antibodies " colorectal cancer " non-Hodgkins lymphoma " pretargeting " radioimmunotherapy

[Full Text of Sharkey and Goldenberg] [Reprint (PDF) Version of Sharkey and Goldenberg]

Abstract 16 of 25

Division of Nuclear Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Tositumomab and ¹³¹I-tositumomab constitute a relatively new radioimmunotherapeutic regimen for patients with CD20+ follicular non-Hodgkins lymphoma (NHL). Currently, it is approved for use in patients whose disease has relapsed after chemotherapy and is refactory to rituximab, including patients whose tumors have transformed to a higher histologic grade. This review outlines the current and evolving status of this therapeutic regimen at nonmyeloablative doses. Methods: Clinical data from multiple published studies and preliminary communications encompassing more than 1,000 patients were reviewed to describe the current status of tositumomab and ¹³¹I-tositumomab therapy. The therapy is delivered in 2 parts, a dosimetric dose and a therapeutic dose. The therapeutic radioactivity millicurie dose is calculated on a patient-individualized ("tailored") basis. A series of 3 total-body -camera scans are used to determine the patient-specific pharmacokinetics (total-body residence time) of the radiolabeled antibody conjugate required to deliver the desired total-body radiation dose, typically 75 cGy. Results: In clinical trials, objective response rates in patients who had been extensively pretreated with chemotherapy ranged from 47% to 68%. Tositumomab and ¹³¹I-tositumomab therapy also was effective in patients who had failed to respond to or who had relapsed after rituximab therapy, with a 68% overall response rate. Thirty percent of such patients achieved complete responses that were generally of several years duration. Single-center trials using tositumomab and ¹³¹I-tositumomab therapy alone or after chemotherapy in previously untreated patients have shown response rates in excess of 90%, with most responses complete. Retreatment with tositumomab and ¹³¹I-tositumomab and use of lower total-body radiation doses of tositumomab and ¹³¹I-tositumomab to treat patients who have relapsed after stem cell transplantation have been shown feasible in limited clinical studies. Toxicity is predominately hematologic; however, human antimouse antibodies, hypothyroidism, and myelodysplastic syndrome have been reported in a small fraction of patients. Conclusion: Tositumomab and ¹³¹I-tositumomab therapy at patient-specific, nonmyeloablative doses is safe and effective in treatment of relapsed and refractory follicular NHL. Toxicity is mainly hematologic and reversible. Tositumomab and ¹³¹I-tositumomab therapy is assuming a growing role in this common malignancy.

Key Words: tositumomab and ¹³¹I-tositumomab therapy " radioimmunotherapy " non-Hodgkins lymphoma

[Full Text of Wahl] [Reprint (PDF) Version of Wahl]

Abstract 17 of 25

Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York

The recent approval of 2 radiolabeled antibodies against cluster designation 20positive lymphoma has led to a resurgence of interest in radioimmunotherapy. As was the case with chemotherapy development, progress has been most marked in the hematologic neoplasms, both in myeloablative and in nonmyeloablative therapeutic strategies. Success in the radioimmunotherapy of solid tumors has lagged because of the immunogenicity of murine proteins and the relatively slow clearance of humanized intact immunoglobulins. Genetic engineering has enabled the development of a variety of antigen-binding constructs of various sizes and immunobiologic characteristics. Developments in radiochemistry as well as production of an increasing number of radionuclides with therapeutic potential or optimal imaging characteristics have spurred tailored therapeutic strategies that include dosimetry and considerations of tumor burden. Such progress has generated pivotal studies that will establish the radiobiologic paradigms for successful radioimmunotherapy of solid tumors. This review will describe seminal studies that have paved the way to an understanding of radioimmunotherapy in solid tumors. Finally, the authors views of the future of this promising cancer therapy will be presented.

Key Words: radioimmunotherapy " solid tumors " antigen-binding construct " radionuclides

[Full Text of Jhanwar and Divgi] [Reprint (PDF) Version of Jhanwar and Divgi]

Abstract 18 of 25

Departments of Radiology and Biomedical Engineering, Duke University Medical Center, Durham, North Carolina

Treatment of malignant brain tumors with conventional approaches is largely unsuccessful because curative doses generally cannot be delivered without excessive toxicity to normal brain. Radioimmunotherapy is emerging as an attractive alternative for glioma therapy because of the potential for more selectively irradiating tumor cells while sparing normal tissues. Several institutions are engaged in phase I and phase II trials investigating the therapeutic potential of monoclonal antibodies (mAbs) labeled with the ß-emitters ¹³¹I and ⁹⁰Y and the -emitter ²¹¹At in patients with recurrent and newly diagnosed brain tumors. The current status of these trials will be discussed with regard to efficacy, toxicity, and future directions.

Key Words: brain tumor " glioma " ²¹¹At " radionuclide therapy " ¹³¹I

[Full Text of Zalutsky] [Reprint (PDF) Version of Zalutsky]

Abstract 19 of 25

Department of Pediatrics, Memorial SloanKettering Cancer Center, New York, New York

Radioimmunotherapy (RIT) for pediatric tumors remains in its infancy despite its potential as an attractive therapeutic modality. Most childhood tumors are radiation sensitive, but the side effects of external beam radiation are well recognized. Despite achieving complete remissions with sophisticated combination therapies, treatment failure primarily results from the inability to eradicate minimal residual disease, which is typically distant and occult. RIT can conceivably target such disease and improve cancer treatment. Because intensive chemotherapy regimens used in most childhood cancers are highly immunosuppressive, repeated administration of radiolabeled monoclonal antibodies is possible without the immediate induction of human antimouse or human antichimeric antibody responses. Despite the differences in biology between childhood and adult hematologic malignancies, they share several tumor antigens for which RIT agents are now available. However, safety and efficacy profiles in children remain to be defined. On the other hand, the antigen repertoire of pediatric solid tumors differs substantially from that in adults, partly because of differing lineages: pediatric solid tumors are typically of embryonal origin, whereas adult tumors are usually carcinomas of epithelial origin. Hence, RIT agents licensed for adult tumors are generally not applicable to pediatric solid tumors. Tumor-selective radioimmunoconjugates specific for embryonal tumors of childhood are currently being actively investigated. Without substantial policy changes in drug development for orphan indications, however, these agents are not likely to be widely available in the near future.

Key Words: pediatric cancer " radioimmunodetection " radioimmunotherapy

[Full Text of Modak and Cheung] [Reprint (PDF) Version of Modak and Cheung]

Abstract 20 of 25

¹ Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands
² Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, The Netherlands

Immuno-PET as a quantitative imaging procedure before or concomitant with radioimmunotherapy is an attractive option to improve confirmation of tumor targeting and especially assessment of radiation dose delivery to both tumor and normal tissues. General information about PET, PET systems, and quantification is provided in this review. The requirements for an appropriate positron emitter and characteristics of the most attractive candidate emitters for immuno-PET are discussed. An overview of preclinical and clinical immuno-PET studies reported in the literature is provided.

Key Words: immuno-PET " radioimmunotherapy " monoclonal antibodies " positron emitters " oncology

[Full Text of Verel et al.] [Reprint (PDF) Version of Verel et al.]

Abstract 21 of 25

¹ Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, Basel, Switzerland
² Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
³ Department of Nuclear Medicine, University of Heidelberg and Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany

Radiolabeled peptides are of increasing interest in nuclear oncology. Special emphasis has been given to the development of peptides labeled with positron emitters. Among these, ⁶⁸Ga deserves special attention, because it is available from an inhouse generator rendering ⁶⁸Ga radiopharmacy independent of an onsite cyclotron. ⁶⁸Ga has a half-life of 68 min and decays by 89% through positron emission. The parent, ⁶⁸Ge, is accelerator produced and decays with a half-life of 270.8 d by electron capture. Currently, at least 1 commercial and several in-house generators are available. ⁶⁸Ge is strongly absorbed on metal oxides or organic material, making a ⁶⁸Ge-breakthrough highly unlikely. Several groups continue to further develop generators to remove cationic impurities from the eluate. Several bifunctional chelators based on 1,4,7-triazacyclononane-N,N',N''-triacetic acid and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) macrocycles are available for coupling to peptides and other biomolecules. In addition to these hydrophilic chelators, a lipophilic tetradentate S₃N ligand was developed. Radiopeptides for ⁶⁸Ga labeling have been developed and tested preclinically for the targeting of somatostatin receptors, the melanocortin 1 receptor, and the bombesin receptor. Clinical studies were performed with ⁶⁸Ga-DOTA,Tyr³-octreotide, localizing neuroendocrine tumors with higher sensitivity than ¹¹¹In-diethylenetriaminepentaacetic acid-octreotide. In addition, ⁶⁸Ga-DOTA-based bombesin derivatives are being investigated with some success in patients with prostate cancer. Conclusion: Generator-produced ⁶⁸Ga and the development of small chelator-coupled peptides (and other small biomolecules) may open a new generation of freeze-dried, good manufacturing practiceproduced, kit-formulated PET radiopharmaceuticals similar to ⁹⁹Mo-/^99mTc-generatorbased, ^99mTc-labeled radiopharmaceuticals.

Key Words: oncology " ⁶⁸Ga " peptides " tumor imaging

[Full Text of Maecke et al.] [Reprint (PDF) Version of Maecke et al.]

Abstract 22 of 25

¹ Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
² Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama
³ Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

The radiotargeted gene therapy approach to localizing radionuclides at tumor sites involves inducing tumor cells to synthesize a membrane-expressed receptor with a high affinity for injected radiolabeled ligands. A second strategy involves transduction of the sodium iodide symporter (NIS) and free radionuclide therapy. Using the first strategy, induction of high levels of human somatostatin receptor subtype 2 expression and selective tumor uptake, imaging, or growth inhibition with radiolabeled somatostatin analogs has been achieved in human tumor xenograft models. Therapy studies have been performed on several tumor xenograft models with various radionuclides using the NIS radiotargeted gene therapy approach. The use of gene transfer technology to induce expression of high-affinity membrane receptors or transporters can enhance the specificity and extent of radioligand or radionuclide localization in tumors, and the use of radionuclides with appropriate emissions can deliver radiation-absorbed cytotoxic doses across several cell diameters to compensate for limited transduction efficiency. Clinical studies are needed to determine the most promising of these new therapeutic approaches.

Key Words: human somatostatin receptor subtype 2 " sodium iodide symporter " gene therapy " radiopharmaceuticals " radiolabeled peptides

[Full Text of Buchsbaum et al.] [Reprint (PDF) Version of Buchsbaum et al.]

Abstract 23 of 25

H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida

The ideal radiation sensitizer would reach the tumor in adequate concentrations and act selectively in the tumor compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today. This review outlines the concept of combining 2 modalities of cancer treatment, radiation and drug therapy, to provide enhanced tumor cell kill in the treatment of human malignancies and discusses molecules that target DNA and non-DNA targets. Combining drugs that have unique mechanisms of action and absence of overlapping toxicities with systemically administered radiotherapy should be exploited in future clinical trials. This is an exciting time in clinical oncology research, because we have a plethora of new molecules to evaluate.

Key Words: radiation sensitizers " 5-fluorouracil " platinum " gemcitabine " topoisomerase " epidermal growth factor inhibitors " vascular endothelial growth factor inhibitors

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Abstract 24 of 25

¹ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
² Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
³ Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands

The presence of a high density of somatostatin receptors (SSRs) on human tumors forms the basis for the successful visualization of primary tumors and their metastases using radiolabeled somatostatin analogs. In recent years somatostatin analogs, coupled to ß-emitting radioisotopes, have been successfully applied in the treatment of patients with metastatic SSR-positive neuroendocrine tumors. This concept of targeting SSR-expressing tumors using peptide receptor radionuclide therapy may also apply to the use of somatostatin analogs coupled to chemotherapeutic compounds. Evidence for the effectiveness of such cytotoxic somatostatin analogs as antitumor agents has been provided in a significant number of studies in experimental tumor models. In addition to cytotoxic somatostatin analogs, somatostatin analogs coupled to peptides containing arginine, glycine, and aspartate and coupled to paclitaxel have been synthesized. Here we discuss the development of the different cytotoxic somatostatin analogs and their antitumor effects in vitro and in vivo in experimental models.

Key Words: somatostatin analogs " somatostatin receptors " apoptosis; cytotoxic agents

[Full Text of Hofland et al.] [Reprint (PDF) Version of Hofland et al.]

Abstract 25 of 25

The Promise of Targeted -Particle Therapy

¹ Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
² Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York

The use of monoclonal antibodies to deliver radioisotopes directly to tumor cells has become a promising strategy to enhance the antitumor effects of native antibodies. Since the - and ß-particles emitted during the decay of radioisotopes differ in significant ways, proper selection of isotope and antibody combinations is crucial to making radioimmunotherapy a standard therapeutic modality. Because of the short pathlength (5080 µm) and high linear energy transfer (100 keV/µm) of -emitting radioisotopes, targeted -particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissues than ß-emitters. These properties make targeted -particle therapy ideal for the elimination of minimal residual or micrometastatic disease. Radioimmunotherapy using -emitters such as ²¹³Bi, ²¹¹At, and ²²⁵Ac has shown activity in several in vitro and in vivo experimental models. Clinical trials have demonstrated the safety, feasibility, and activity of targeted -particle therapy in the treatment of small-volume and cytoreduced disease. Further advances will require investigation of more potent isotopes, new sources and methods of isotope production, improved chelation techniques, better methods for pharmacokinetic and dosimetric modeling, and new methods of isotope delivery such as pretargeting. Treatment of patients with less-advanced disease and, ultimately, randomized trials comparing targeted -particle therapy with standard approaches will be required to determine the clinical utility of this approach.

Key Words: targeted -particle therapy " radiolabeled monoclonal antibodies " radioimmunotherapy