177Lu-octreotate治疗神经内分泌胃肠胰腺肿瘤的SPECT显像研究

目前对于转移性神经内分泌胃肠胰腺肿瘤（NET）没有很好的治疗方法。分化良好的神经内分泌肿瘤多过度表达生长抑素受体（SSTR），尤其是亚型SSTR2。人工合成生长抑素衍生物如奥曲肽（octreotide）能治疗激素过度表达的症状，而采用放射性核素标记octreotide及其衍生物对NET进行靶向治疗效果更好，称为肽类受体介导的放射性核素治疗（PRRT），早期主要应用^111In-octreotide，     

生长抑素受体显像剂在神经内分泌肿瘤中的临床研究进展

神经内分泌肿瘤（NETs）是一类起源于神经内分泌细胞的异质恶性肿瘤,分化良好的NETs可过度表达生长抑素受体（SSTR）。放射性同位素标记的生长抑素类似物与SSTR的特异性结合可实现NETs的功能成像,对NETs的诊断及其患者的临床管理具有重要意义。近年来,研究者已成功研发出多种靶向SSTR的示踪剂并应用于临床,笔者总结了用于SPECT和PET的SSTR显像剂在NETs中的临床应用及其研究进展。     

90Y-DOTATOC对人胰腺神经内分泌瘤BON-1细胞的抑制作用

目的探讨90Y-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-酪氨酸3-奥曲肽(DOTATOC)对人胰腺神经内分泌瘤细胞BON-1的抑制作用。方法 (1)采用90Y对DOTATOC进行标记, 然后纯化90Y-DOTATOC;(2)考察90Y-DOTATOC的体外稳定性;(3)采用噻唑蓝(MTT)法, 分别考察90Y、DOTATOC、90Y-DOTATOC对人胰腺神经内分泌瘤细胞BON-1和人胰腺胆管瘤细胞PANC-1的抑制作用, 并分别计算细胞增殖抑制率。设立阴性对照组、阳性对照组(长春新碱, 50 μmol/L)、DOTATOC组(25 μmol/L)、90Y组(1.8 MBq/ml)、90Y-DOTATOC高剂量组(90Y的放射性浓度为1.8 MBq/ml, DOTATOC的浓度为25 μmol/L)、90Y-DOTATOC中剂量组(90Y的放射性浓度为0.37 MBq/ml, DOTATOC的浓度为25 μmol/L)、90Y-DOTATOC低剂量组(90Y的放射性浓度为0.074 MBq/ml, DOTATOC的浓度为25 μmol/L)。组间比较采用独立样本t检...     

生长抑素受体显像和治疗研究进展

神经内分泌源性及一些非神经内分泌源性的肿瘤细胞表面均有SSTR高表达,利用放射性核素标记的生长抑素类似物（somatostatin analog,SSA）与SSTR特异性结合可使肿瘤显像,并可通过内吞作用进入细胞溶酶体内,进行靶向放疗;细胞毒素与SSA的偶联物同样可以与SSTR特异性结合,通过内吞作用进入细胞,起到靶向化疗的作用。     

核素标记的生长抑素受体拮抗剂在神经内分泌肿瘤显像和治疗中的研究进展

生长抑素受体（SSTR）特别是SSTR2过表达是神经内分泌肿瘤（NEN）的共同特征,也是NEN分子显像和核素靶向治疗的理想靶点。过去,研究者们一直致力于核素标记的SSTR激动剂的研究,并成功将其应用于NEN的临床显像和治疗。近年来的研究结果表明,核素标记的SSTR拮抗剂比激动剂具有更好的药代动力学特性,其肿瘤摄取率更高、滞留时间更长,且所获得的影像对比度更高,故其在NEN的分子显像和核素靶向治疗中更具优越性。笔者就核素标记的SSTR拮抗剂在NEN显像和治疗中的研究进展进行综述,以期为NEN的临床诊疗提供参考。     

99Tcm-octreotide在荷H22肝癌小鼠体内的分布和显像

^111In-DTPA-octreotide已被临床常规用于探测生长抑素受体（SSTR）阳性肿瘤,但其受核素费用高的限制.本研究拟评价^99Tc^m-octreotide在荷H22肝癌小鼠体内的分布特性,探讨其作为临床SSTR阳性肿瘤显像剂的可能性.     

^68Ga-SSA/^18F-FDG PET/CT联合显像在神经内分泌肿瘤诊治中的应用价值

神经内分泌肿瘤(NEN)是起源于神经内分泌细胞或肽能神经元的一类肿瘤,可原发于全身多种脏器。NEN病理异质性大,患者预后差异大。常规影像学检查及病理学活组织检查对该病有重要意义,但均存在一定的局限性。NEN细胞常高度表达生长抑素受体(SSTR),且部分NEN因有高度增殖活性而表现出较高的葡萄糖代谢活性,这为核医学SSTR显像及葡萄糖代谢显像提供了分子基础。^68Ga-生长抑素类似物(SSA)/^18F-脱氧葡萄糖(FDG)PET/CT联合显像可从受体表达及糖代谢活性方面综合评估NEN生物学特性,为NEN的病灶筛查、分级分期、治疗选择、疗效监测及预后判断等提供有效信息。该文总结了上述联合显像应用于NEN诊治的研究现况。     

放射性核素标记奥曲肽诊断小细胞肺癌的研究进展

小细胞肺癌是神经内分泌肿瘤，起源于APUD（胺前体摄取脱羧化）细胞。其细胞表达高水平表达SSTR（生长抑素受体）。奥曲肽是SST（生长抑素）的八肽类似物，它保留了SST类似的活性结构而且有更强的生物学效应和更长的生物半衰期，不易被降解。用放射性核素标记奥曲肽来诊断小细胞肺癌是一种较为理想的无创伤性检查方法。     

^131I-酪氨酸-奥曲肽对荷人非小细胞肺癌小鼠的抑瘤效果

目的探讨^131I标记酪氨酸一奥曲肽（^131I-Tyr-octreotide）对荷人非小细胞肺癌（NSCLC）小鼠的抑瘤效果。方法经氯胺T法标记Tyr-octreotide,测其放化纯及其在小鼠体内的生物分布;建立荷人NSCLC小鼠模型,分为尾静脉注射^131I-Tyr-octreotide组、肿瘤间质注射^131I-Tyr-octreotide组、肿瘤间质单纯注射^131I组和间质注射生理盐水组,观察肿瘤部位的放射性摄取,勾画感兴趣区（ROI）,计算肿瘤与对侧正常组织（T／NT）放射性比值,并对肿瘤进行细胞周期检测和免疫组织化学检测,观察癌细胞的凋亡。采用SPSS 11.0软件进行统计学处理,组间两两比较行单因素方差分析。结果标记产物放化纯为（95．23±1．67）％,比活度为3．5×10^6 Bq／μg。小鼠体内放射性分布示肾摄取最高,肝、脾摄取较少;荷瘤鼠显像示：间质注射^131I-Tyr-octreotide组肿瘤放射性浓聚较尾静脉注射和间质单纯注射^131I明显,放射性滞留较久;其24h的T／NT比值最高,为52．74±0．13,明显高于其他2组（8．90±0．23,6．42±0．02,q=628．81和664．33,P均〈0．05）;流式细胞检测可见经间质给药组较尾静脉给药组和单纯注射^131I组G．期细胞阻滞明显[各组G1期肿瘤细胞占总细胞的百分比分别为（83．17±6．86）％、（57．02±18．81）％、（49．29±7．80）％,q=1．56～6．86,P均〈0．05],免疫组织化学检查结果示肿瘤细胞大量凋亡,可见凋亡小体形成。结论^131I-Tyr-octreotide易于标记且与生长抑素受体（SSTR）表达阳性的NSCLC有较高的亲和力,对肿瘤组织有较强的促凋亡和抑瘤作用。     

^90Sr敷贴治疗局限性神经性皮炎46例的疗效观察

目的观察^90Sr敷贴治疗局限性神经性皮炎的临床疗效。方法对46例经临床诊断为局限性神经性皮炎的患者^90Sr敷贴治疗的疗效情况进行观察。结果46例患者中痊愈17例（36．96％）,显效24例（52．17％）,无效5例（10．87％）,总有效率89．13％。结论^90Sr敷贴治疗局限性神经性皮炎临床疗效显著。     

Clinical results of radionuclide therapy of neuroendocrine tumours with <Superscript>90</Superscript>Y-DOTATATE and tandem <Superscript>90</Superscript>Y/<Superscript>177</Superscript>Lu-DOTATATE: which is a better therapy option?

Purpose  

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). A combination treatment using the high-energy ⁹⁰Y beta emitter for larger lesions and the lower energy ¹⁷⁷Lu for smaller lesions has been postulated in the literature.The aim of the study was to evaluate combined ⁹⁰Y/¹⁷⁷Lu-DOTATATE therapy in comparison to ⁹⁰Y-DOTATATE alone.     

Gelatin-based plasma expander effectively reduces renal uptake of 111In-octreotide in mice and rats.

111In-Diethylenetriaminepentaacetic acid-octreotide generally is used for the scintigraphic imaging of neuroendocrine and other somatostatin receptor-positive tumors. On the basis of the successful targeting of octreotide, radiolabeled somatostatin analogs, such as 90Y-(1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid [DOTA])0-Tyr3-octreotide and 177Lu-DOTA0-Tyr3-octreotate, were developed for peptide receptor radionuclide therapy. However, the maximum tolerated doses of these analogs are limited because of the high and persistent renal uptake that leads to relatively high radiation doses in the kidneys. Renal uptake can be reduced by coinfusion of basic amino acids or polypeptides. However, high doses of basic amino acids can induce severe side effects. It was reported that the infusion of gelatin-based plasma expanders resulted in increased low-molecular-weight proteinuria, suggesting that these plasma expanders interfere with the tubular reabsorption of peptides and proteins. In the present study, we analyzed the effects of several plasma expanders on the renal uptake of 111In-octreotide in rats and mice. METHODS: Wistar rats and BALB/c mice were injected with 0.5 or 0.1 mL of plasma expander, respectively. Thereafter, the animals received 111In-octreotide intravenously. Animals were killed at 20 h after the injection of the radiopharmaceutical. Organs were dissected, and the amount of radioactivity in the organs and tissues was measured. RESULTS: The administration of 20 mg of Gelofusine in rats or 4 mg in mice was as effective in reducing the renal uptake of 111In-octreotide as the administration of 80 or 20 mg of lysine in rats or mice, respectively, without reducing 111In-octreotide uptake in receptor-positive organs. Plasma expanders based on starch or dextran had no effect on the renal uptake of 111In-octreotide. CONCLUSION: The gelatin-based plasma expander Gelofusine significantly reduced the kidney uptake of 111In-octreotide as effectively as did lysine. Because Gelofusine is a well-known and generally used blood volume substitute that can be applied safely without the induction of toxicity, evaluation of this compound for its potential to reduce the kidney uptake of radiolabeled peptides in patients is warranted.     

Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy

PURPOSE: To prospectively evaluate the safety and effectiveness of hepatic intraarterial injection of yttrium 90 ((90)Y) tetraazacyclododecane tetraacetic acid (DOTA) lanreotide as a treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors. MATERIALS AND METHODS: The study was local ethics committee approved, and all patients gave informed consent. Twenty-three patients (13 men, 10 women; age range, 21-69 years; median age, 57 years) with histologically proved large-volume liver metastases from neuroendocrine cancers were treated. All patients had radiologic evidence of liver disease progression and high uptake of indium 111 ((111)In) pentetreotide at scintigraphy. Selective hepatic intraarterial injection of (90)Y-DOTA-lanreotide (total of 36 treatments; median activity per dose, 1 GBq) was administered with or without embolization. Treatment cycles were performed in 8-week intervals. Clinical, biologic, and radiologic tumor responses were assessed 8-12 weeks after each treatment cycle. Objective tumor response was classified according to World Health Organization response criteria as complete regression, partial response, stable disease, or disease progression. Kaplan-Meier survival curves were used to calculate 1-year survivals. RESULTS: Partial response to treatment was achieved in three (16%) of 19 patients, and stable disease was achieved in 12 (63%). Four (21%) of 19 patients had continued disease progression. Clinical improvement was reported by 14 (61%) of the 23 patients, and a reduction in biologic marker levels was observed in nine (60%) of 15 patients. Reversible hematologic toxicity (National Cancer Institute common toxicity criteria grade > 2) occurred in three patients. The 1-year survival rate was 63% (median survival time, 15 months). CONCLUSION: Hepatic intraarterial injection of (90)Y-DOTA-lanreotide is a safe and effective palliative treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors.     

Evaluating the clinical effectiveness of 90Y-SMT 487 in patients with neuroendocrine tumors.

Because of the presence of cell membrane somatostatin receptors (SSTRs), many neuroendocrine tumors will bind analogs of somatostatin. (90)Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487) is an SSTR radiopharmaceutical currently under investigation as a therapeutic option for neuroendocrine tumors. Although there are a variety of methods for evaluating response to a given cancer therapy, an important indicator of success is the impact on the clinical status of the patient. The purpose of this work was to develop a semiquantitative method and assess the clinical effectiveness of (90)Y-SMT 487 therapy in patients with neuroendocrine tumors. METHODS: A scoring system was developed to evaluate clinical response that included the following parameters: weight, health status score (determined by the patient), Karnofsky score, and tumor-related symptoms. RESULTS: We applied this scoring system to 21 patients who had completed 3 cycles of therapy with (90)Y-SMT 487. Fourteen of the 21 showed a favorable clinical response, whereas 5 were clinically stable after treatment and 2 showed evidence of clinical progression. There was also a significant reduction in the amount of octreotide being used after completion of (90)Y-SMT 487 therapy in the 20 patients who were on this medication. CONCLUSION: Using this scoring method, (90)Y-SMT 487 appears effective in improving the clinical status of patients with (111)In-pentetreotide-positive neuroendocrine tumors.     

Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma.

Therapy using the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) has been used primarily in gastroenteropancreatic neuroendocrine tumors. Here we present the effects of this therapy in a small number of patients with metastasized or inoperable paragangliomas, meningiomas, small cell lung carcinomas (SCLCs), and melanomas. METHODS: Twelve patients with paraganglioma, 5 with meningioma, 3 with SCLC, and 2 with eye melanoma were treated. Three meningiomas were very large and exophytic and all standard treatments had failed. Patients with melanoma had rapidly progressive disease (PD). The intended cumulative dose of 177Lu-octreotate was 22.2-29.6 GBq. Effects of the treatment on tumor size were evaluated using the Southwest Oncology Group criteria. RESULTS: Two of 4 patients with progressive paraganglioma had tumor regression and 1 had stable disease (SD). Of 5 patients with stable paraganglioma, 2 had SD, 2 had PD, and in 1 patient treatment outcome could not be determined. Paraganglioma was stable in 3 patients in whom the disease status at the beginning of therapy was unknown. One of 4 patients with progressive meningioma had SD and 3 patients had PD. One patient with stable meningioma at the beginning of therapy had SD. All patients with SCLC or melanoma died within 5 mo after starting therapy because of tumor progression. Although not statistically significant, a positive trend was found between high uptake on pretherapy somatostatin receptor scintigraphy and treatment outcome. CONCLUSION: 177Lu-octreotate can be effective in patients with paraganglioma and meningioma. Response rates are lower than those in patients with gastroenteropancreatic neuroendocrine tumors. Most meningiomas were very large. Further studies are needed to confirm the treatment outcome because of the limited number of patients. 177Lu-octreotate did not have antitumor effects in patients with small lung carcinoma and melanoma.     

Lutetium-labelled peptides for therapy of neuroendocrine tumours

Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours.     

Peptide receptor imaging and therapy.

This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be expressed, like sarcoidosis and autoimmune diseases. [(111)In-DTPA0]octreotide is a radiopharmaceutical that has great potential for helping visualize whether somatostatin receptor-positive tumors have recurred. The overall sensitivity of SRI to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of SRI in the localization or staging procedure may be very rewarding in terms of cost effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, such as breast cancer or malignant lymphomas, or in patients with granulomatous diseases has to be established. The application of radiolabeled peptides may be clinically useful in another way: after the injection of [(111)In-DTPA0]octreotide, surgeons can detect tumor localizations by a probe that is used during the operation. This may be of particular value if small tumors with a high receptor density are present (e.g., gastrinomas). As the success of peptide receptor scintigraphy for tumor visualization became clear, the next logical step was to try to label these peptides with radionuclides emitting alpha or beta particles, or Auger or conversion electrons, and to perform radiotherapy with these radiolabeled peptides. The results of the described studies with 90Y- and (111)In-labeled octreotide show that peptide receptor radionuclide therapy using radionuclides with appropriate particle ranges may become a new treatment modality. One might consider the use of radiolabeled somatostatin analogs first in an adjuvant setting after surgery of somatostatin receptor-positive tumors to eradicate occult metastases and second for cancer treatment at a later stage.     

New trends in peptide receptor radioligands.

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress the one or the other of five distinct hSSTR sub-type receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higher" high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including 99mTc-HYNIC-octreotide or 99mTc-depreotide (NEOSPECT; NEOTECT). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study "MAURITIUS" (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase IIa study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in >60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm "proof-of-principle" for their use in diagnosis as well as therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy.     

Therapy of neuroendocrine tumors with radiolabeled somatostatin-analogues.

Peptide receptor scintigraphy with the radioactive somatostatin-analogue [111In-DTPA0]octreotide (DTPA = diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of 111In- or 90Y-labeled octreotide-analogues. PRECLINICAL: We investigated the radiotherapeutic effect of 90Y- and 111In-labeled [DOTA0,Tyr3]octreotide (DOTA = tetraazacyclododecanetetraacetic acid) or [111In-DTPA0]octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in A) the flank or B) in the liver. PATIENTS: Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. PRECLINICAL RESULTS: A) Flank model: at least two 111MBq injections of [111In-DOTA0,Tyr3]octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of [90Y-DOTA0,Tyr3] octreotide yielded transient stable disease. B) Liver model: we found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq [111In-DTPA0]octreotide or 93 MBq [90Y-DOTA0,Tyr3]octreotide can inhibit the growth of somatostatin receptor-positive metastases. CLINICAL RESULTS: There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur. Promising beneficial effects on clinical symptoms, hormone production and tumor proliferation were found. Of the 21 patients with progressive disease at baseline and who received a cumulative dose of more than 20 GBq [111In-DTPA0]octreotide, 8 patients showed stabilisation of disease and 6 other patients a reduction in size of tumors. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand. CONCLUSION: Radionuclide therapy with octreotide-derivatives is feasible, both with 111In and 90Y as radionuclides.     

Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC.

The aim of this prospective phase II study was to evaluate the tumor response of neuroendocrine tumors to high-dose targeted irradiation with 7.4 GBq/m(2) of the radiolabeled somatostatin analog (90)Y-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe-Tyr(3)-octreotide (DOTATOC). In addition, we investigated the clinical benefit of (90)Y-DOTATOC regarding the malignant carcinoid syndrome and tumor-associated pain. METHODS: Thirty-nine patients (mean age, 55 y) with progressive neuroendocrine gastroenteropancreatic and bronchial tumors were included. The treatment consisted of 4 equal intravenous injections of a total of 7.4 GBq/m(2) (90)Y-DOTATOC, administered at intervals of 6 wk. After each treatment cycle, a standardized clinical benefit assessment using the National Cancer Institute grading criteria (NCI-CTC) was performed. RESULTS: The objective response rate according to World Health Organization (WHO) criteria was 23%. For endocrine pancreatic tumors (13 patients), the objective response rate was 38%. Complete remissions were found in 5% (2/39), partial remissions in 18% (7/39), stable disease in 69% (27/39), and progressive disease in 8% (3/39). A significant reduction of clinical symptoms could be found in 83% of patients with diarrhea, in 46% of patients with flush, in 63% of patients with wheezing, and in 75% of patients with pellagra. The overall clinical benefit was 63%. All responses (both clinical benefit and WHO response) were ongoing for the duration of follow-up (median, 6 mo; range, 2-12 mo). Side effects were grade 3 or 4 (NCI-CTC) lymphocytopenia in 23%, grade 3 anemia in 3%, and grade 2 renal insufficiency in 3%. CONCLUSION: High-dose targeted radiotherapy with 7.4 GBq/m(2) (90)Y-DOTATOC is a well-tolerated treatment for neuroendocrine tumors, with remarkable clinical benefit and objective response.