Future of radionuclide therapy

International Congress Series 1228 (2002) 129 – 137

Future of radionuclide therapy M. Fischer a,*, W. Becker b a

Stadische Kliniken, Zentral Rontgen Institut, Monchebergstrasse 41/43, 3500 Kassel, Germany b Go¨ttingen, Germany

‘‘Nuclear Oncology: a growth industry’’. This was the headline of The Journal of Nuclear Medicine, volume 36, 5 May, 1995. About 1/3 of the presentations of the European Association of Nuclear Medicine Congress in Paris 2000 were focused on diagnostic and therapeutic procedures in nuclear oncology. That same year H. N. Wagner jr. showed in his ‘‘Highlights 2000 Lecture’’ in St. Louis a slide with increasing numbers of presentations about radionuclide therapy during the Society of Nuclear Medicine Meeting (SNM) 2000. In 1997 and 1998, about 95– 100 presentations were given whereas the number increased from about 125 in 1999 up to 150 in 2000. For more than 60 years radionuclide, therapy is used for systemic, non-invasive treatment of benign and malignant diseases. There are a number of advantages and limitations for the use of radionuclide therapy [6] (Table 1). Many of these limitations have to be and will be overcome in the next future. The number of patients treated with radionuclides differs from country to country. Following a first questionnaire sent to all member states of the European Association of Nuclear Medicine (EANM) in 1993, the Committee Radionuclide Therapy EANM sent another questionnaire to 23 member states to get information about the number of therapy facilities, isolation beds, and patients treated by radionuclide therapy and amount of administered activity per year in these countries 5 years later [12]. In 20 European countries a total of 630 centers are involved in radionuclide therapy (RNT). About 1520 isolation beds are available for RNT in 18 of these countries, i.e. one isolation bed per 285,526 inhabitants. This is much less than calculated according to German legislation by the year 2000: one isolation bed per 40,000 inhabitants. In these 18 countries, 82,892 patients were treated with radionuclides in 1998. Indications for RNT are shown in Tables 2 and 3, whereas Table 4 shows the cumulative amounts of activities administered in 13 countries for RNT of benign and malignant diseases.

*

Corresponding author. Tel.: +49-561-9806459; fax: +49-561-9806975. E-mail address: [email protected] (M. Fischer).

0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 5 6 4 - 7

130

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

Table 1 Advantages and disadvantages of RNT (6) Advantages

Disadvantages

specificity due to radiation dose limited to target systemic or locoregional application low toxicity efficacy and/or good palliation limited long-term side effects multiple treatments possible exact measurement of uptake and tracer retention multidisciplinary approach required

isolation of patients for high dose therapy high costs for waste material storage availability of nuclides or radiopharmaceutical agents high costs of some newer agents mechanism poorly understood need for dosimetry calculations

The results of the EANM questionnaire show the wide variation in utilization of RNT, the availability of isolation facilities and probably different training of physicians and physicists responsible for RNT in the centers. These variations are even more obvious in comparison to developed and developing countries in the world. This is the present status of radionuclide therapy in the world, but what is the future? Development of RNT during the last decade was rather rapidly progressive, but prediction for the future may be speculative. In my opinion, there are different aspects for a positive trend for RNT in the near future: 1. 2. 3. 4. 5.

new radionuclides, new radiopharmaceutical agents, new indications for known nuclides and/or agents, new applications for known nuclides and/or agents, combination therapy (RNT + other modelities).

Table 2 Indications for RNT in 15 European countriesa Country

Benign thyroid disease

Joint diseases

Malignant diseases

Austria Czech Republic + Slovakia Germany Greece Hungary Ireland Israel Italy The Netherlands Norway Portugal Slovenia Switzerland Turkey United Kingdom

1400 (10) 550 (6) 22,890 (115) 850 (n.a.) 1023 (10) n.a. n.a. 1400 (55) 3318 (27) 796 (21) 295 (4) 393 (5) 896 (23) 750 (11) 9059 (88)

20 (4) 242 (6) 1388 (51) 115 20 (4) 4 (1) 1 (1) – 369 (20) 4 (1) 4 (1) 32 (1) 188 (11) – 321 (37)

217 (13.3%) 1011 (56.1%) 7524 (23.7%) 663 (40.7%) 79 (7%) 20 6 2800 (66.7%) 976 (20.9%) 220 (21.6%) 383 (56.2%) 90 (17.5%) 261 (19.4%) 490 (39.5%) 2055 (18.0%)

Total

43,620 (69%)

2708 (4.3%)

16,795 (26.6%)

a

The numbers of centers performing a particular type of therapy are added in parentheses in the first two columns. In the last column, treatments for oncologic indications are given as a percentage of all therapies [12].

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

131

Table 3 Oncological indications for RNT in 16 European countriesa Country

Thyroid Ca (I-131)

Haematology (P-32)

Bone palliation (bone therapy)

Neural crest tumors (I-131-MIBG)

Other incicationsb,c

Austria Czech Republic + Slovakia France Germany Greece Hungary Ireland Israel Italy The Netherlands Norway Portugal Slovenia Switzerland Turkey United Kingdom

145 (8) 700 (5)

5 (3) 7 (2)

60 (6) 300 (6)

2 (1) 4 (2)

5 (3) –

n.a. 6388 (79) 489 (n.a.) 61 (1) 20 (2) 4 (7) 1800 (31) 484 (16) 145 (8) 349 (4) 67 (1) 165 (8) 470 (7) 911 (50)

n.a. 150 (46) – – – (4) – – 91 (16) 3 (1) 5 (2) – 10 (5) 5 (3) 569 (59)

500 (60) 717 (45) 174 (n.a.) 10 (4) – (4) 1 (4) 700 (30) 296 (24) 63 (7) 26 (3) 19 (3) 77 (10) 15 (2) 425 (49)

n.a. n.a. (6) – 8 (1) – (1) 1 (3) 200 (5) 92 (7) 3 (1) 3 (2) 2 (1) 5 (2) – 76 (11)

n.a. 269b (26) – – – – 100c (2) 13b (6) 6 (1) – 2 (1) 4 (2) – 56b (12)

Total

12,198

845

3383

396

455

a b c

The number of centres performing a particular type of RNT is given in parentheses. Other indications include: intracavitary therapy. Other indications include: direct intratumoral administration [12].

For each of these aspects, only few examples will be given. ad 1. As shown from the results of the European questionnaire, there are few radionuclides used for routine therapy in nuclear medicine up until now. But there are Table 4 Cumulative amounts of radioactivities (GBq) administered for RNT in 13 European countries Country Austria Czech Republic + Slovakia Germany Hungary Israel The Netherlands Norway Portugal Slovenia Spain Switzerland Turkey United Kingdom

131-I 3500 4000 41,426 951 1000 2900 932 1194 582 10,000 1690 2080 16,695

n.a. = not available [12].

90-Y

186-Re

32-P

131-I-MIBG

89-Sr

Others

10 55

– 12

0.2 15

3.3 12

7.5 15

52 8

1025 9.3 740 75 1.9 0.74 7.59 n.a. 31 – 88

113 – – 2 – – – n.a. n.a. – –

23 – – 18 0.33 1.66 1.3 n.a. 11 0.45 94.96

477 24.9 7.4 510 11.1 18.5 15 n.a. 1 14.8 646

13 1.5 – 42 9.4 3 2 n.a. 8 2.22 57.06

324 – 37 60 – – – n.a. – – 207

132

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

more nuclides available and probably some of them are more suitable. One aim of RNT is a dose of maximal radiation to affected tissue and a minimal radiation dose to normal tissue. As we know from radiosynovectomy, we have to use different radionuclides for different joints depending on the physical characteristics of the nuclide and the joint volume: the smaller the joint volume, the shorter the maximal range of the nuclide should be. In Table 5, more nuclides are shown than really used routinely. Since more than 50 years ago, 89-Sr was used for palliation of painful bone metastases. More recently, new agents (186-Re HEDP and 153-Sm EDTMP) were introduced for pain palliation. The response rate for these nuclides is about 80% in osteoblastic metastases, in patients with prostate and breast cancers. There are ongoing clinical trials with two other nuclides: 188Re HEDP and 117 m-Sn DTPA. The advantages of 188-Re may be the permanent availability because it is eluted from a generator system, low cost and physical characteristics, whereas 117 m-Sn is emitting conversion electrons causing less myelotoxocity than beta-emitting nuclides used for treating patients with pain from osteoblastic bone metastases. 188-Re is also used for irradiation after angioplasty to prevent restenoses [15]. 224-Ra was used during the early 1960s and 1970s for the treatment of spondylitis ankylosans but then taken from the market. Since 1999, it is available again in several European countries. Another alpha particle-emitting nuclide 213-Bi was used for labeling of numerous monoclonal antibodies. Treating patients in a phase I trial: individual doses of 148 –814 MBq were administered without complication. As shown in a clinical trial treating lymphoma patients with the radioimmunogate 67-Cu-2IT-BAT-Lym-1 achieved tumor radiation doses were significantly higher than with 131-I-Lym-1 due to longer residence time in the tumor [8]. A patch contaminated with 166-Ho was recommended for treatment of the intradermal, squamous cell carcinoma (Bowen’s disease) an often multilocular disease. A 30– 60 min application may apply a total radiation dose to the cancer of 35 Gy [7]. Table 5 Radionuclides used for radionuclide therapy in routine or trials Nuclide

Half life

Emission

Maximum range

Br-80m I-125 At-211 Sn-117m Ra-224 Er-169 Cu-67 I-131 Sm-153 Au-198 Re-186 Dy-165 Sr-89 P-32 Ho-166 Re-188 Y-90

4.42 h 60.0 d 7.2 d 13.6 d 3.64 d 9.5 d 2.58 d 8.04 d 1.95 d 2.7 d 3.77 d 2.33 h 50.5 d 14.3 d 1.1 d 0.71 d 2.67 d

Auger Auger alpha conversion electrons alpha beta beta/gamma beta/gamma beta/gamma beta/gamma beta/gamma beta/gamma beta beta beta beta/gamma beta

! < 10 nm ! 10 nm ! 65 nm ! 30 mm ! 50 mm ! 1 mm ! 2.2 mm ! 2.4 mm ! 3 mm ! 4.4 mm ! 5.0 mm ! 6.4 mm ! 8.0 mm ! 8.7 mm ! 8.7 mm ! 11 mm ! 12 mm

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

133

ad 2. Shortly after the development of monoclonal antibodies in 1976, the first diagnostic trials were performed with 131-I labeled monoclonal antibodies directed against various antigenes associated with specific tumor types. These diagnostic procedures progressed to radioimmunotherapy during the last few years. Most promising results are published using radiolabeled monoclonal antibodies for treatment of malignant lymphomas. Non-Hodgkin’s lymphomas (NHL) are a frequent malignancy with increasing incidence with a high economic impact. NHLs are the fifth leading cause of cancer morbidity and mortality in the US. An overview of the different therapeutic modalities was published in a supplement to the Journal of Nuclear Medicine 39 (1998). A great variety of radiolabeled monoclonal antibodies was studied for the treatment of NHL. Only some examples will be mentioned here. After the administration of 1.7– 7.4 GBq (45 –198 mCi) 131-I anti-B1 antibody a response rate of 63% ( 23% complete remission) were reported in patients with low-grade and transformed low-grade Non-Hodgkin’s lymphoma [3]. Another 90-Y labeled monoclonal antibody (IDEC-Y2B8) was used for the treatment of B-cell Non-Hodgkin’s lymphoma after dosimetry with a 111-In labeled compound [25]. Different murine monoclonal antibodies labeled with either 131-I or 90-Y were administered intraperitoneally in patients with ovarian cancer. Response rate in patients with small lesions or no clinical or radiological signs of tumor but increased levels of hematological tumor markers was 76.4% or 100%, respectively, whereas the response rate in patients with bulky disease was poor (9.3%) [22]. Murine anti-CEA antibody (F023C5) and a humanized high-affinity anti CEA antibody (hMN-14) are used in phase I/II trials with quite encouraging results [1]. Biokinetical studies with iodine labeled diethylstilbestrol show high potential for therapy of breast cancer [24]. DeNardo et al. [9] observed less toxicity and better tumor response by linking a macrocyclic chelator (DOTA) to a monoclonal antibody (ChL6) by a catabolizable peptide (90-Y-DOTA-peptide-ChL6) compared to 131-I-ChL6 for therapy of an incurable breast cancer. The affinity of monoclonal antibodies to tumor antigens may be improved by two- or three-step targeting techniques. A new promising area of RNT involves radiolabeled low-molecular-weight peptides. Natural peptides like somatostatin have a short biological half-life but receptor scintigraphy with 111-In labeled somatostatin-analogue octreotide has proven high specificity and sensitivity. Analogues (octreotide and lanreotide) labeled with 90-Y were administered successfully to patients suffering from carcinoid tumors. Another somatostatin-analogue (RC-160) labeled to 188-Re may be useful in somatostatin receptors overexpressing tumors for direct intralesional, intracavitary, and intraarterial administration [2]. Several radiolabeled monoclonal antibodies and peptides are described to be suitable for scintigraphic imaging of neurocrest tumors. Their use for treatment has to be studied. ad 3. The first clinical trials are ongoing treating patients with primary bone tumors (osteosarcoma) with radionuclides with a short physical half-life, only used for palliative therapy of painful bone metastases up until now [4]. In trials, some nuclides are administered in patients with rheumatoid arthritis systemically. ad 4. For neuroblastoma patients the results of 131-I-MIBG therapy indicate an impressive palliative effect and an overall objective response rate of about 35%. These results were published using protocols administering therapeutic doses of 131-I-MIBG in progressive and intensively pretreated neuroblastoma stage IV patients. Introducing 131-I-

134

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

MIBG as a first-line therapy just after diagnosis objective response rate could be improved. In about 70% of patients after first-line therapy complete tumor resection became possible [11,13]. High grade malignant brain tumors (anaplastic astrocytoma, glioblastoma) have a poor prognosis. Intratumoral administration of radiolabeled monoclonal antibodies (131-I-and 90-Y antitenascin) demonstrated a high response rate in oligodendroglioma (100%), anaplastic astrocytoma (72.7%), and glioblastoma (45.7%). Even in patients with bulky glioblastoma survival time and quality of life significantly improved [21]. Several groups, mainly in Asia, France and Germany published results about treatment of patients with hepatocellular cancer with intra-arterial administration of 131-I-Lipiodol [17]. Using 90-Y labeled glass microspheres in liver tumor bearing rats a significant difference in survival time and tumor response between intra-arterially or intra-tumorally treated animals was observed versus non-treated rats. No significant difference was seen between both treatment modalities. The intra-tumoral approach may be of an advantage in patients with a singular lesion whereas in patients with a multilocular lesion in the intraarterial approach is preferable [16]. Mainly hematotoxicity is the limiting factor for quantity of radiolabeled agents that can be administered for RNT. Comparing multiple injections and continuous infusion of radiolabeled CC49 in a human cancer xenograft model the three-time bolus injection was clearly superior to infusion administration regarding survival, tumor growth inhibition, tumor absorbed dose and bone marrow dose [5]. ad 5. The administration of radiolabeled monoclonal antibody (125-I-A33) with or without time interval to external beam radiotherapy showed different results. Maximum tracer uptake was observed in the group with radiolabeled antibodies administered just prior to radiation therapy. The authors suggest that transient increase of capillary leakage may be the reason [23]. Another promising procedure is the enhancement of tumor/ background ratio with a avidin– biotin pretargeting approach treating patients with high doses of 90-Y-biotin after surgery and conventional radiotherapy. A significant improvement of disease free interval was observed in glioblastoma ( > 16 months) [10]. A Japanese group [14] combined radioimmunotherapy with local hyperthermia and chemotherapy. Hyperthermia did not effect antigene expression on cells soon after hyperthermia, only after 48 h by factor 2.7. The combined therapy with radiolabeled monoclonal antibodies (125-I A7 a murine IgG1), hyperthermia and 5-Fluorouracil improved mean tumor doubling time from 12.1 to 41.0. The mechanism of hyperthermia may be explained by vascular and immunological effects in the tumor. Recently cloned and characterized human Na+/I-symporter (hNIS), responsible for iodine uptake in the thyroid gland, may be transfected into non-thyroidal cells. Preliminary results of an in vitro/in vivo study with breast cancer cells indicate that NIS based gene therapy may cause high intracellular I-131 concentrations inducing cell death [18].

1. Conclusions For today’s radionuclide therapy, there are many radionuclides, radiopharmaceutical agents and different approaches available. But in their conclusion to the monograph

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

135

‘‘Radionuclide therapy: from palliation to cure’’, the Committee Radionuclide Therapy of the EANM stated: ‘‘For many indications radionulcide therapy still finds itself in last position among other treatment modalities. The response to date can certainly be considered as promising. In addition the invasiveness and toxicity compare favorably with that of chemotherapy, immunotherapy and external beam radiotherapy. By moving radionuclide therapy forward in treatment protocols, the efficacy of this modality in the perspective of the overall management of (benign and) oncological diseases can be optimized. This can provide significant improvements in the management of the cancer patient.’’ The near future of radionuclide therapy, we expect a lot of new radiopharmaceutical agents, labeled with other nuclides than used routinely today, and combined with new approaches and other treatment modalities, but my vision goes still further. I strongly believe that in the future one may use a tailored nuclide or radiopharmaceutical agent per lesion or patient to be treated. The aim of RNT is to reach maximal radiation dose to tumor tissue but minimal radiation dose to normal tissue. The efficacy of radiopharmaceutical agents may depend on the characteristics of the radionuclide used for labeling the agent (i.e. physical half-life, penetration, specific activity, and stability of the complex). And as shown for SST receptor subtypes their definite role is not yet fully established. Also small changes in the radioligand molecule, the introduction of different radiometals or chelators may provoke alterations in the binding affinity for selected SST subtypes. Such changes must be identified for newly developed radiotracers for somatostatin receptor therapy and also for other peptide radioligands [20]. The same is also true for the monoclonal antibodies and antigens. Additionally autoradiography of tumor tissue normally shows inhomogeneous intratumoral tracer distribution due to increasing interstitial pressure. Therefore, larger intact monoclonal antibodies may need several days for homogeneous distribution whereas fragments or peptides only need hours or even a few minutes. This will influence the selection of nuclides for labelling procedures. Other factors influencing intra-tumoral tracer distribution are non-uniform blood flow, necrotic areas, and absent of receptors or antigenic targets on some of the tumor cells. For intratumoral administration of tracers intact monoclonal antibodies may be advantageous because their longer residence time in the tumor. These facts may lead not only to a tailored nuclide or radiopharmaceutical agent but to a tailored cocktail directed against multiple receptors and/or antigens within a tumor and also against lesions of different sizes. Also, the application of radiopharmaceutical agents for RNT has to be evaluated per patient and tumor. A large single dose of a short-range emitting nuclide is probably more appropriate in minimal disease whereas fractionated administrations of smaller doses of long-range emitting nuclides are more appropriate in macroscopic tumors. If there is a slowly growing macroscopic part and a rapidly growing microscopic part in one single tumor a combination of both application modalities could be optimal [19]. Important steps towards future of RNT are: (1) improvements at RNT facilities in developing countries, (2) closer collaboration with other medical specialities, radiochemists, biologists and others, (3) better positioning of radionuclide therapy in treatment protocols, and (4) better dissemination of nulcear medicine in clinical journals and meetings. Today RNT is an integral part of nuclear medicine. In the future, it will be part of a multidisciplinary therapy of patients with benign and malignant diseases. To

136

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

consolidate the role of RNT in this concept, we need trials following guidelines of evidence based medicine.

References [1] T.M. Behr, T. Liersch, S. Gratz, S. Canelo, et al., Radioimmunotherapy of colo-rectal cancer patients with small volume disease: results of a clinical phase I/II trial, Eur. J. Nucl. Med. 26 (1999) 969, abstr. [2] H. Bender, P.O. Zamora, B.A. Rhodes, S. Guhlke, H.J. Biersack, Clinical aspects of local and regional tumor therapy, Anticancer Res. 17 (1997) 1705 – 1712. [3] A. Bhatnagar, S. Kroll, V. Langmuir, G. Tidmarsh, R. Wahl, Clinical experience with iodo-131 anti-B1 antibody for the treatment of low-grade and transformed low-grade Non-Hodgkin’s lymphoma, Eur. J. Nucl. Med. 26 (1999) 970, abstr. [4] O.S. Bruland, A. Skretting, O.P. Solheim, M. Aas, Targeted radiotherapy of osteosarcoma using Sm-153 EDTMP. A new promising approach, Acta Oncol. 35 (1996) 381 – 384. [5] D.J. Buchsbaum, M.B. Khazaeli, M.S. Mayo, P.C. Roberson, Comparison of multiple bolus and continuous injections of 131-I-labeled CC49 for therapy in a colon cancer xenograft model, Clin. Cancer Res. 5 (10 suppl.) (1999) 3153s – 3159s. [6] J.-F. Chatal, C.A. Hoefnagel, Radionuclide therapy, Lancet 354 (1999) 931 – 935. [7] Y.L. Chung, J.D. Lee, D. Bang, J.B. Lee, et al., Treatment of Bowen’s disease with a specially designed radioaktive skin patch, Eur. J. Nucl. Med. 27 (2000) 842 – 846. [8] S.J. DeNardo, G.J. DeNardo, D.L. Kukio, S. Shen, et al., 67 Cu2IT-BAT-Lym1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma, J. Nucl. Med. 40 (1999) 302 – 310. [9] G.J. DeNardo, C.M. Richman, D.S. Goldstein, S. Shen, et al., Yttrium-90/indium-111-DOTA-peptidechimeric L6: pharmacokinetics, dosimetry and initial results in patients with incurable breast cancer, Anticancer Res. 17 (1997) 1735 – 1744. [10] C. Grana, S. Zoboli, C. DeCicco, et al., Adjuvant radioimmunotherapy in glioma patients with 3-step 90-YBiotin, Eur. J. Nucl. Med. 26 (1999) 979, abstr. [11] C.A. Hoefnagel, Nuclear medicine therapy of neuroblastoma, Q. J. Nucl. Med. 43 (1999) 336 – 343. [12] C.A. Hoefnagel, S.E.M. Clarke, M. Fischer, J.F. Chatal, et al., Radionuclide therapy practice and facilities in Europe, Eur. J. Nucl. Med. 26 (1999) 277 – 282. [13] C.A. Hoefnagel, J. de Kraker, R.A. Valdes Olmos, P.A. Voute, I-131-MIBG as a first line treatment in high risk neuroblastoma patients, Nucl. Med. Comm. 15 (1994) 712 – 717. [14] S. Kinuya, K. Yokoyama, S. Konishi, T. Hiramatsu, et al., Multimodality radioimmunotherapy (RIT) in colon cancer xenografts, enhenced tumor dose by local hyperthermia and additive effect of 5-fluorouracil, Eur. J. Nucl. Med. 26 (1999) 968, abstr. [15] F.F. Knapp Jr., A.L. Beets, S. Guhlke, H.J. Biersack, et al., Liquid-filled balloons for coronary restenosis therapy — strategy and dosimetry for use of rhenium-188 (Re-188), Eur. J. Nucl. Med. 25 (1998) 883, abstr. [16] W.-Y. Lin, S.-C. Tsai, J.-F. Hsieh, S.-J. Wang, Effects of 90-Y-microsu¨heres on liver tumors: comparison of intratumoral injection method and intra-arterial injection method, J. Nucl. Med. 41 (2000) 1892 – 1897; M.R. McDevitt, R.D. Finn, D. Ma, S.M. Larson, D.A. Scheinberg, Preparation of alpha-emitting 213-Bilabeled antibody constructs for clinical use, J. Nucl. Med. 40 (1999) 1722 – 1727. [17] M. Nakajo, H. Kobayashi, K. Shimabukuro, K. Shirono, et al., Biodistribution and in vivo kinetics of iodine-131 lipiodol infused via hepatic artery of patients with hepatic cancer, J. Nucl. Med. 29 (1988) 1066 – 1077. [18] Y. Nakamoto, T. Saga, T. Misaki, H. Kobayashi, et al., Establishment and characterization of a breast cancer cell line expressing Na+/I-symporters for radioiodide concentrator gene therapy, J. Nucl. Med. 41 (2000) 1898 – 1904. [19] J.A. O’Donoghue, G. Sgouros, C.R. Divgi, J.L. Humm, Single-dose versus fractionated radioimmunotherapy: model comparisons for uniform tumor dosimetry, J. Nucl. Med. 41 (2000) 538 – 547. [20] J.C. Reubi, J.-C. Scha¨r, B. Waser, S. Wenger, et al., Affinity profiles for human somatostatin receptor subtype SST1 – SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use, Eur. J. Nucl. Med. 27 (2000) 273 – 282.

M. Fischer, W. Becker / International Congress Series 1228 (2002) 129–137

137

[21] P. Riva, G. Franceschi, M. Frattarelli, N. Riva, et al., Effectiveness of Y-90 antitenascin Mabs loco-regional radioimmunotherapy of malignant gliomas: an ongoing phase II trial, Eur. J. Nucl. Med. 26 (1999) 969, abstr. [22] P. Riva, G. Franceschi, N. Riva, M. Casi, et al., Radioimmunotherapy of ovarian cancer with 131-I and 90-Y labelled monoclonal antibodies intraperitoneally admninistered: clinical experience in 62 cases, Eur. J. Nucl. Med. 26 (1999) 969, abstr. [23] S. Ruan, J.A. O’Donoghue, S.M. Larson, R.D. Finn, et al., Optimizing the sequence of combination therapy with radiolabeled antibodies and fractionated external beam, J. Nucl. Med. 41 (2000) 1905 – 1912. [24] K. Schoma¨ker, T. Fischer, B. Meller, D. Moka, H. Schicha, Biokiniteics of iodine labelled diethylstilbestrol (DES) with high specific activity, Eur. J. Nucl. Med. 26 (1999) 970, abstr. [25] G.A. Wiseman, R.B. Sparks, B.R. Leigh, W.D. Erwin, et al., Biodistribution and dosimetry results for 179 patients receiving Zevalin radioimmunotherapy RIT for B-cell Non-Hodgkin’s lymphoma (NHL), Eur. J. Nucl. Med. 27 (2000) 904, abstr.