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Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs

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Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs Dik J. Kwekkeboom, MD1; Jan Mueller-Brand, MD2; Giovanni Paganelli, MD3; Lowell B. Anthony, MD4; Stanislas Pauwels, MD5; Larry K. Kvols, MD6; Thomas M. O’Dorisio, MD7; Roelf Valkema, MD1; Lisa Bodei, MD3; Marco Chinol, PhD3; Helmut R. Maecke, PhD2; and Eric P. Krenning, MD1 1Department of Nuclear Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, The Netherlands; 2Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland; 3Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy; 4Division of Hematology and Oncology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; 5Department of Nuclear Medicine, Universitaire Catholique Louvain, Brussels, Belgium; 6Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida; and 7Division of Endocrinology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa Key Words: somatostatin; somatostatin receptor; radionuclide A new treatment modality for inoperable or metastasized gas- therapy; gastroenteropancreatic tumors troenteropancreatic tumors is the use of radiolabeled soma- J Nucl Med 2005; 46:62S–66S tostatin analogs. Initial studies with high doses of [111In-diethyl- enetriaminepentaacetic acid (DTPA)0]octreotide in patients with metastasized neuroendocrine tumors were encouraging, al- though partial remissions were uncommon. Another radiola- beled somatostatin analog that is used for peptide receptor Neuroendocrine gastroenteropancreatic (GEP) tumors, radionuclide therapy (PRRT) is [90Y-1,4,7,10-tetraazacyclodode- which comprise pancreatic islet cell tumors, nonfunctioning -cane-N,NЈ,NЉ,Nٞ-tetraacetic acid (DOTA)0,Tyr3]octreotide. Vari- neuroendocrine pancreatic tumors, and carcinoids, are usu ous phase 1 and phase 2 PRRT trials have been performed with ally slow growing. When these tumors have metastasized, this compound. Despite differences in the protocols used, com- treatment with somatostatin analogs results in reduced hor- 90 plete and partial remissions in most of the studies with [ Y- monal overproduction and symptomatic relief in most cases. DOTA0,Tyr3]octreotide were in the same ranges, 10%–30%; 111 Treatment with somatostatin analogs, whether or not in these ranges were higher than those obtained with [ In- ␣ DTPA0]octreotide. Treatment with the newest radiolabeled so- combination with -interferon, however, is seldom success- matostatin analog, [177Lu-DOTA0,Tyr3]octreotate, which has a ful in terms of CT- or MRI-assessed tumor size reduc- higher affinity for the subtype 2 somatostatin receptor, resulted tion (1). in complete or partial remissions in 30% of 76 patients. Tumor A new treatment modality for inoperable or metastasized regression was positively correlated with a high level of uptake GEP tumors is the use of radiolabeled somatostatin analogs. on OctreoScan imaging, a limited hepatic tumor mass, and a The majority of GEP tumors possess somatostatin receptors high Karnofsky performance score. Treatment with radiolabeled and therefore can be visualized in vivo with the radiolabeled somatostatin analogs is a promising new tool in the manage- 111 ment of patients with inoperable or metastasized neuroendo- somatostatin analog [ In-diethylenetriaminepentaacetic 0 crine tumors. Symptomatic improvement may occur with all acid (DTPA) ]octreotide (OctreoScan; Mallinckrodt Medi- 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have cal). A logical extension of this tumor visualization in been used for PRRT. The results obtained with [90Y-DOTA0,Tyr3]- patients therefore is to try to treat these patients with radio- octreotide and [177Lu-DOTA0,Tyr3]octreotate are very encourag- labeled somatostatin analogs. ing in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and 111 0 mild, and the duration of the therapy response for both radio- STUDIES WITH [ IN-DTPA ]OCTREOTIDE pharmaceuticals is more than 2 y. These data compare favor- Initial studies with high doses of [111In-DTPA0]octreotide ably with those for the limited number of alternative treatment in patients with metastasized neuroendocrine tumors were approaches. encouraging, although partial remissions (PRs) were un- common. Two of 26 patients who had GEP tumors, who 111 0 Received May 11, 2004; revision accepted Aug. 13, 2004. were treated with high doses of [ In-DTPA ]octreotide, For correspondence or reprints contact: Dik J. Kwekkeboom, MD, Depart- and who received total cumulative dosages of more than 20 ment of Nuclear Medicine, Erasmus Medical Center, University Hospital Rot- terdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. GBq (550 mCi) had decreases in tumor size of 25%–50%, E-mail: [email protected] as measured on CT scans (2). None, however, had PRs 62S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 46 • No. 1 (Suppl) • January 2005 (Table 1). In another study of patients with GEP tumors, treated either with 6 GBq (160 mCi)/m2 (5) or, in a later PRs were reported in 2 of 26 patients with measurable study, with 7.4 GBq (200 mCi)/m2 in 4 doses (6), was 24% disease (Table 1) (3). Both series included relatively high (Table 1). In a subsequent study, with the same dosage of numbers of patients who were in poor clinical condition on 7.4 GBq (200 mCi)/m2 administered in 2 sessions, complete study entry. Also, many had progressive disease (PD) on remission (CRs) and PRs were found in 33% of 36 patients study entry. The most common type of toxicity in both (Table 1) (7). It should be emphasized, however, that this series was bone marrow suppression (Table 2). Serious side trial was not a randomized trial comparing 2 dosage effects consisted of leukemia and myelodysplastic syn- schemes. drome (MDS) in 3 patients who had been treated with total Chinol et al. (8) described dosimetric and dose-escalating cumulative dosages of Ͼ100 GBq (2.7 Ci) (and an esti- studies with [90Y-DOTA0,Tyr3]octreotide with and without mated bone marrow radiation dosage of about 3 Gy) (2). the administration of kidney-protective agents. No major One of these patients had also been treated with chemother- acute reactions were observed up to an administered dose of apy, which may have contributed to or caused this grave 5.6 GBq (150 mCi) per cycle. Reversible grade 3 hemato- complication. Anthony et al. (3) reported renal insufficiency logic toxicity was found in 43% of patients injected with 5.2 in 1 patient; this effect probably was not treatment related GBq (140 mCi), which was defined as the maximum toler- but likely was attributable to preexisting retroperitoneal ated dose per cycle. None of the patients developed acute or fibrosis. Transient liver toxicity was observed in 3 patients delayed kidney nephropathy, although follow-up was short. with widespread liver metastases. Although in both series PRs and CRs were reported by the same group for 28% of favorable effects on symptomatology were reported, CT- 87 patients with neuroendocrine tumors (9). assessed tumor regression was observed only in rare cases. In a more detailed publication, Bodei et al. (10) reported This finding is not surprising, as 111In-coupled peptides are the results of a phase 1 study of 40 patients with somatosta- not ideal for peptide receptor radionuclide radiotherapy tin receptor–positive tumors, of whom 21 had GEP tumors. (PRRT) because of the small particle range and therefore Cumulative total treatment dosages ranged from 5.9 to 11.1 the lower tissue penetration range. GBq (from 160 to 300 mCi) given in 2 treatment cycles. Six of 21 patients (29%) had tumor regression (Table 1). The STUDIES WITH [90Y-DOTA0,TYR3]OCTREOTIDE median duration of the response was 9 mo. Another radiolabeled somatostatin analog that is used for Another study with [90Y-DOTA0,Tyr3]octreotide was a PRRT is [90Y-1,4,7,10-tetraazacyclododecane-N,NЈ,NЉ,Nٞ- multicenter phase 1 study performed in Rotterdam, The tetraacetic acid (DOTA)0,Tyr3]octreotide. Various phase 1 Netherlands; Brussels, Belgium; and Tampa, Florida, in and phase 2 PRRT trials have been performed with this which 60 patients received escalating doses of up to 14.8 compound. GBq (400 mCi)/m2 in 4 cycles or up to 9.3 GBq (250 Otte et al. (4) and Waldherr et al. (5,6) reported on mCi)/m2 in a single dose, without the maximum tolerated various phase 1 and phase 2 studies in patients with neu- single dose being reached (11). The cumulative radiation roendocrine GEP tumors. In their first reports, with a dose- dosage to the kidneys was limited to 27 Gy. All patients escalating scheme of 4 treatment sessions up to a cumula- received amino acids concomitantly with [90Y-DOTA0,Tyr3]- tive dosage of 6 GBq (160 mCi)/m2 and without renal octreotide for kidney protection. Three patients had dose- protection with amino acid infusion for half of the patients, limiting toxicity: 1 had liver toxicity, 1 had grade 4 throm- renal insufficiency developed in 4 of 29 patients (Table 2). bocytopenia (Ͻ25 ϫ 109/L), and 1 had MDS. Four of 54 The overall response rate in GEP tumor patients who were patients (8%) who received their maximum allowed dose TABLE 1 Tumor Responses in Patients with GEP Tumors and Treated with Various Radiolabeled Somatostatin Analogs No. of Tumor response Center (reference) Ligand patients CR* PR* MR* SD* PD* CR ϩ PR† Rotterdam (2)[111In-DTPA0]octreotide 26 0 0 5 (19) 11 (42) 10 (38) 0 New Orleans (3)[111In-DTPA0]octreotide 26 0 2 (8) NA 21 (81) 3 (12) 8 Milan (10)[90Y-DOTA0, Tyr3]octreotide 21 0 6 (29) NA 11 (52) 4 (19) 29 Basel (5,6)[90Y-DOTA0, Tyr3]octreotide 74 3 (4) 15 (20) NA 48 (65) 8 (11) 24 Basel (7)[90Y-DOTA0, Tyr3]octreotide 33 2 (6) 9 (27) NA 19 (57) 3 (9) 33 Rotterdam (11)[90Y-DOTA0, Tyr3]octreotide 54 0 4 (7) 7 (13) 33 (61) 10 (19) 7 Rotterdam (18)[177Lu-DOTA0, Tyr3]octreotate 76 1 (1) 22 (29) 9 (12) 30 (39) 14 (18) 30 *Reported as number (percentage) of patients.
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