213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

European Journal of Nuclear Medicine and Molecular Imaging, Sep 2014

Purpose Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as 90Y/177Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with 213Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Methods Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC were treated with an intraarterial infusion of 213Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of 213Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and 68Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. Results The biodistribution of 213Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. Conclusion TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses.

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213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

Eur J Nucl Med Mol Imaging 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience C. Kratochwil 0 1 F. L. Giesel 0 1 F. Bruchertseifer 0 1 W. Mier 0 1 C. Apostolidis 0 1 R. Boll 0 1 K. Murphy 0 1 U. Haberkorn 0 1 A. Morgenstern 0 1 0 F. Bruchertseifer 1 C. Kratochwil ( Purpose Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as 90Y/177Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with 213Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Methods Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC were treated with an intraarterial infusion of 213Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of 213BiDOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and 68Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. Results The biodistribution of 213Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. Conclusion TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. Targeted alpha therapy (TAT); 213Bi; 225Ac; DOTATOC - The first two authors C. Kratochwil and F.L. Giesel contributed equally to this work. Introduction Well-differentiated neuroendocrine tumours (NETs) demonstrate modest responses to conventional chemotherapy due to their slow proliferation rate [ 1 ]. However, the expression of somatostatin receptors by NET enables targeting with highaffinity peptides. When these octreotide analogue peptides are labelled with beta emitters such as 90Y [ 2 ] or 177Lu [ 3 ] promising anti-tumour effects have been observed. Recently, it has also been demonstrated that an improved tumour to nontumour uptake of radiolabelled DOTATOC is achieved after intraarterial administration in liver metastatic NET patients [ 4, 5 ]. However, patients with recurrences are usually refractory to further treatment with beta radiation therapy. Alpha radiation is characterized by high linear energy transfer causing production of 2,000 – 7,000 ion pairs per micrometre, leading to clustered double-strand DNA breaks resulting in rapid cell death from even a single exposure to a few alpha particles. The short range of alpha particles (50 – 100 μm, i.e. about two or three cell diameters) limits the effective range of treatment but also limits damage to untargeted tissue. In contrast, beta-emitting radionuclides result in fewer than 20 ion pairs per micrometre and commonly cause only single-strand DNA breaks with less lethality and more spillover effects caused by “crossfire” (Fig. 1). It has already been demonstrated that the alpha emitter 213Bi is able to overcome radioresistance to beta emitters in vitro [ 6 ]. The alpha emitters 225Ac and 213Bi used to label the somatostatin analogue DOTATOC have demonstrated already promising antitumour effects with a favourable therapeutic range in animal studies [ 7, 8 ]. Therefore, it seemed reasonable that peptide targeted alpha therapy (TAT) with 213Bi-DOTATOC delivered directly to metastases via intraarterial administration might offer effective therapy to NET patients who have acquired resistance to other therapies. Here we report the first-in-human experience with 213BiDOTATOC TAT in patients refractory to nonradioactive octreotide and tandem therapy [ 9 ] with 90Y/177Lu-DOTATOC. Materials and methods Patients This was a retrospective study of patients with differentiated neuroendocrine tumours. The diagnosis was confirmed histologically. These patients were not surgical candidates. Systemic standard therapies such as chemotherapy in highgrade or nonradioactive octreotide in low-grade tumours had previously failed to stop tumour growth. Pretreatment also included innovative peptide receptor radiation therapy (PRRT) with octreotide analogues tagged with a beta emitter. When patients showed progression with that treatment (new lesions on PET or progression on CT >30 % within the previous 2 – 6 months) TAT was offered as an alternative therapy. Seven consecutive patients with prognosis-affecting liver metastases arising from a pulmonary (one patient), pancreatic (four patients), enteric (one patient) or unknown primary (one patient) received intraarterial administration into the common hepatic artery between Nove (...truncated)


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C. Kratochwil, F. L. Giesel, F. Bruchertseifer, W. Mier, C. Apostolidis, R. Boll, K. Murphy, U. Haberkorn, A. Morgenstern. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience, European Journal of Nuclear Medicine and Molecular Imaging, 2014, pp. 2106-2119, Volume 41, Issue 11, DOI: 10.1007/s00259-014-2857-9