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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.

Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, Murphy K, Haberkorn U, Morgenstern A - Eur. J. Nucl. Med. Mol. Imaging (2014)

Bottom Line: Chronic kidney toxicity was moderate.Acute haematotoxicity was even less pronounced than with the preceding beta therapies.TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses.

View Article: PubMed Central - PubMed

Affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany, clemens.kratochwil@t-online.de.

ABSTRACT

Purpose: Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as (90)Y/(177)Lu-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 (213)Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters.

Methods: Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with (90)Y/(177)Lu-DOTATOC were treated with an intraarterial infusion of (213)Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of (213)Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and (68)Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients.

Results: The biodistribution of (213)Bi-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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Related in: MedlinePlus

Comparison of alpha and beta emitters. a, c After binding of the radionuclide-labelled octreotide analogue DOTATOC to the somatostatin receptor subtype-2 (SSR2), which is overexpressed in NETs, the emitted alpha particle causes high-density ionization effects, resulting mainly in double-strand DNA breaks. In contrast, the beta particles emitted by established radiopharmaceuticals mainly cause repairable single-strand DNA damage. b, d The tissue range of alpha emitters (about 80 μm) is approximately two cell diameters. The mean tissue range of the beta emitter 90Y (3 mm) is approximately 75 cell diameters. Thus, alpha emitters result in less “cross-fire” radiation to surrounding normal tissue
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Fig1: Comparison of alpha and beta emitters. a, c After binding of the radionuclide-labelled octreotide analogue DOTATOC to the somatostatin receptor subtype-2 (SSR2), which is overexpressed in NETs, the emitted alpha particle causes high-density ionization effects, resulting mainly in double-strand DNA breaks. In contrast, the beta particles emitted by established radiopharmaceuticals mainly cause repairable single-strand DNA damage. b, d The tissue range of alpha emitters (about 80 μm) is approximately two cell diameters. The mean tissue range of the beta emitter 90Y (3 mm) is approximately 75 cell diameters. Thus, alpha emitters result in less “cross-fire” radiation to surrounding normal tissue

Mentions: 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.Fig. 1


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

Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, Murphy K, Haberkorn U, Morgenstern A - Eur. J. Nucl. Med. Mol. Imaging (2014)

Comparison of alpha and beta emitters. a, c After binding of the radionuclide-labelled octreotide analogue DOTATOC to the somatostatin receptor subtype-2 (SSR2), which is overexpressed in NETs, the emitted alpha particle causes high-density ionization effects, resulting mainly in double-strand DNA breaks. In contrast, the beta particles emitted by established radiopharmaceuticals mainly cause repairable single-strand DNA damage. b, d The tissue range of alpha emitters (about 80 μm) is approximately two cell diameters. The mean tissue range of the beta emitter 90Y (3 mm) is approximately 75 cell diameters. Thus, alpha emitters result in less “cross-fire” radiation to surrounding normal tissue
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4525192&req=5

Fig1: Comparison of alpha and beta emitters. a, c After binding of the radionuclide-labelled octreotide analogue DOTATOC to the somatostatin receptor subtype-2 (SSR2), which is overexpressed in NETs, the emitted alpha particle causes high-density ionization effects, resulting mainly in double-strand DNA breaks. In contrast, the beta particles emitted by established radiopharmaceuticals mainly cause repairable single-strand DNA damage. b, d The tissue range of alpha emitters (about 80 μm) is approximately two cell diameters. The mean tissue range of the beta emitter 90Y (3 mm) is approximately 75 cell diameters. Thus, alpha emitters result in less “cross-fire” radiation to surrounding normal tissue
Mentions: 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.Fig. 1

Bottom Line: Chronic kidney toxicity was moderate.Acute haematotoxicity was even less pronounced than with the preceding beta therapies.TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses.

View Article: PubMed Central - PubMed

Affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany, clemens.kratochwil@t-online.de.

ABSTRACT

Purpose: Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as (90)Y/(177)Lu-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 (213)Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters.

Methods: Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with (90)Y/(177)Lu-DOTATOC were treated with an intraarterial infusion of (213)Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of (213)Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and (68)Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients.

Results: The biodistribution of (213)Bi-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.

Show MeSH
Related in: MedlinePlus