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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

Patient 2 with disseminated liver metastases. a–c Initial findings. Coronal (a) and transaxial (b) slices through the liver performed with a hepatocyte-specific contrast medium. Metastases appear as “black holes” against the enhanced normal liver parenchyma. In the diffusion-weighted image (c), metastases show high signal intensities, while normal liver appears dark. d–f After three cycles of 213Bi-DOTATOC to a cumulative dose of 12 GBq, most of the liver parenchyma has recovered to a normal appearance. The images with hepatocyte-specific contrast medium appear homogeneous (d, e), and most of the disseminated diffusion restrictions have diminished (f)
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Fig3: Patient 2 with disseminated liver metastases. a–c Initial findings. Coronal (a) and transaxial (b) slices through the liver performed with a hepatocyte-specific contrast medium. Metastases appear as “black holes” against the enhanced normal liver parenchyma. In the diffusion-weighted image (c), metastases show high signal intensities, while normal liver appears dark. d–f After three cycles of 213Bi-DOTATOC to a cumulative dose of 12 GBq, most of the liver parenchyma has recovered to a normal appearance. The images with hepatocyte-specific contrast medium appear homogeneous (d, e), and most of the disseminated diffusion restrictions have diminished (f)

Mentions: All patients had presented with a specific clinical challenge when 213Bi-DOTATOC treatment was offered. Patient 1 with multiple liver metastases received intraarterial therapy with 177Lu-DOTATOC. During follow-up, all except one metastasis showed a response. However, the nonresponding lesion showed rapid progression. The segmental branch of the feeding liver artery was catheterized highly selectively to administer 1 GBq of 213Bi-DOTATOC. Subsiding restaging presented partial remission including the previously nonresponding lesion. The staging examination, angiography and restaging are shown in Fig. 2a, d and Supplementary Fig. 4. Subsequently the patient received four additional cycles of 213Bi-DOTATOC to a cumulative administered activity of 16 GBq. Patient 2 presented with highly disseminated metastatic NET in the liver embedded in only small bridges of healthy tissue. With their tissue range of several millimetres, we hypothesized that beta emitters would probably have caused radiation-induced failure of the remaining normal liver parenchyma. 213Bi-DOTATOC was administered in five cycles (19.5 GBq) by intraarterial injection. Liver enzymes returned to normal within 6 weeks and a substantial radiological response was seen (Fig. 3). No acute liver toxicity was observed. At the time of this report, this response had been maintained for 30 months. Myelodysplastic syndrome (MDS) was diagnosed 24 months after TAT, i.e. 5 years after the first PRRT with 90Y-DOTATOC. Six months later, MDS progressed into acute myeloid leukaemia (AML) and the patient died.Fig. 3


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)

Patient 2 with disseminated liver metastases. a–c Initial findings. Coronal (a) and transaxial (b) slices through the liver performed with a hepatocyte-specific contrast medium. Metastases appear as “black holes” against the enhanced normal liver parenchyma. In the diffusion-weighted image (c), metastases show high signal intensities, while normal liver appears dark. d–f After three cycles of 213Bi-DOTATOC to a cumulative dose of 12 GBq, most of the liver parenchyma has recovered to a normal appearance. The images with hepatocyte-specific contrast medium appear homogeneous (d, e), and most of the disseminated diffusion restrictions have diminished (f)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4525192&req=5

Fig3: Patient 2 with disseminated liver metastases. a–c Initial findings. Coronal (a) and transaxial (b) slices through the liver performed with a hepatocyte-specific contrast medium. Metastases appear as “black holes” against the enhanced normal liver parenchyma. In the diffusion-weighted image (c), metastases show high signal intensities, while normal liver appears dark. d–f After three cycles of 213Bi-DOTATOC to a cumulative dose of 12 GBq, most of the liver parenchyma has recovered to a normal appearance. The images with hepatocyte-specific contrast medium appear homogeneous (d, e), and most of the disseminated diffusion restrictions have diminished (f)
Mentions: All patients had presented with a specific clinical challenge when 213Bi-DOTATOC treatment was offered. Patient 1 with multiple liver metastases received intraarterial therapy with 177Lu-DOTATOC. During follow-up, all except one metastasis showed a response. However, the nonresponding lesion showed rapid progression. The segmental branch of the feeding liver artery was catheterized highly selectively to administer 1 GBq of 213Bi-DOTATOC. Subsiding restaging presented partial remission including the previously nonresponding lesion. The staging examination, angiography and restaging are shown in Fig. 2a, d and Supplementary Fig. 4. Subsequently the patient received four additional cycles of 213Bi-DOTATOC to a cumulative administered activity of 16 GBq. Patient 2 presented with highly disseminated metastatic NET in the liver embedded in only small bridges of healthy tissue. With their tissue range of several millimetres, we hypothesized that beta emitters would probably have caused radiation-induced failure of the remaining normal liver parenchyma. 213Bi-DOTATOC was administered in five cycles (19.5 GBq) by intraarterial injection. Liver enzymes returned to normal within 6 weeks and a substantial radiological response was seen (Fig. 3). No acute liver toxicity was observed. At the time of this report, this response had been maintained for 30 months. Myelodysplastic syndrome (MDS) was diagnosed 24 months after TAT, i.e. 5 years after the first PRRT with 90Y-DOTATOC. Six months later, MDS progressed into acute myeloid leukaemia (AML) and the patient died.Fig. 3

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