¹³¹I-MIBG combined with pre-doses of MIBG. Based on the palliative effect observed for both ¹³¹I-MIBG and MIBG independently administered in carcinoid, the administration of ¹³¹I-MIBG dosages of 7.4 GBq shortly after the infusion of 20mg/ m² unlabelled MIBG resulted in the reduction of 5-HIAA in urine in 3 of 5 patients and 6-12 month symptom relief in 4 (21). The observation of an increase in the tumor/non-tumor ratio on diagnostic scintigraphy with ¹³¹I-MIBG combined with pre-dosing of unlabelled MIBG may help to select carcinoid patients for this therapy. By saturating sites of physiological uptake pre-dosing with MIBG does decrease ¹³¹I-MIBG uptake in organs such as salivary glands, heart and liver but apparently not in tumor. More recently, a pre-treatment with interferon alpha has been added to the MIBG/¹³¹I-MIBG schedule based on the observation that interferon applied as monotherapy may also lead to palliation and biochemical response in carcinoid patients (12).

¹¹¹In-DTPAOC. This Auger-emitting radiolabeled peptide, which binds to somatostatin receptors subtypes sst2 and sst5, was employed in a phase I study concerning 50 patients who received cumulative doses of 20-160 GBq. Therapeutic effect was observed in 21 patients. In 3 of 6 patients with more than 100 GBq a myelodysplastic syndrome or leukemia was observed. Short-term nephrotoxicity was not seen despite the high radiation dose to the kidneys calculated for patients receiving more than 100 GBq (22). In another study 2 doses of 180 mCi resulted in 62% symptom improvement, 81% hormonal marker decrease, 27% CT-documented tumor effect, and a median survival of 18 months (3-54 m) in a group of 27 patients (24 carcinoid, 3 pancreatic islet cells) (23). The limitation of ¹¹¹In is the short range of the Auger electrons, which cannot kill neighboring receptor-negative cells in tumors with receptor heterogeneity, and has reinforced the search to develop somatostatin analogs linked to "β-emitter" (24).

⁹⁰Y-DOTATOC. The development of DOTA as a chelating agent for complexing of ⁹⁰Y,  "pure β-emitter" with a 64 h physical half-life, has lead to the use of ⁹⁰Y-DOTATOC in the treatment of carcinoid and other neuroendocrine tumors. A dose-escalation study with cumulative doses ranging from 3.97 to 8.92 GBq/m² in 29 patients with neuroendocrine tumors (14 carcinoid) resulted in stable disease in 20 patients, > 50% tumor reduction in 4, partial remission in 2 and tumor progression in 3. Renal toxicity was observed in 4 patients, 2 of them requiring haemodyalisis (25). In another study concerning 30 patients, escalated doses in groups of 6 patients (3 cycles of 1.1 GBq ⁹⁰Y-DOTATOC containing 30 ìg octreotide and increases of 0.4 GBq per group) led to partial of complete tumor reduction in 23%, stable disease in 64% and progression in 13%. Only one patient developed nephrotoxicity at 6 months after a cumulative dose of 3.33 GBq (26).   Data of 92 patients of 3 different phase I studies showed 20% partial response and 60% stable disease with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative dose was about 26 GBq (27).

Other radiolabelled somatostatin analogues. Based on its high affinity for the somatostatin receptors subtypes sst2, 3, 4 and 5, a phase II trial with ⁹⁰Y-DOTA-lanreotide in cumulative doses up to 232 mCi led to 41% stable disease and 14% regression in 154 patients with different tumor entities expressing somatostatin receptors (28). Another somatostatin analog [DTPA⁰,Tyr³]octreotate (in which the C-terminal threoninol is replaced with threonine) has been labeled with the β- and γ-emitter ¹⁷⁷Lu and used in a phase I study. In 18 patients with neuroendocrine malignancies > 50% tumor reduction was obtained in 39%, 25%-50% in 6%, no changes in 44% and tumor progression in 11% (27).