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

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.

Fig. 1

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

Fig. 2

Diagnostic ⁶⁸Ga-DOTATOC PET scans in NET patients 1, 2 and 6 (a, b, c). d In patient 1 the largest lesion was highly selectively cannulated for intraarterial administration of ²¹³Bi-DOTATOC (top left); 440 keV SPECT scan (bottom left) and whole-body planar (right) scans 45 min after injection demonstrate peak uptake in the target lesion in liver segment 6. e Patient 2 received two therapeutic injections, one into liver segments 5 – 8 (top left) and one into segment 4a/b (top right); 440 keV emission scans (bottom left and right) 045 min after injection show the impact of intraarterial administration for fast tumour targeting and regionally intensified peptide accumulation. f In whole-liver treatment (patient 6) the hepatic biodistribution of ²¹³Bi-DOTATOC is the same as the distribution of ⁶⁸Ga-DOTATOC, but in comparison to systemic treatment spares the spleen

Fig. 3

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)

Fig. 4

Patient 3 with the acute danger of occlusion of both the liver veins and the lower caval vein due to a large lesion in the upper central liver (a, MR image) which was addressed by locoregional DOTATOC therapy administered into the proper hepatic artery (b, digital subtraction angiogram). Intense ⁶⁸Ga-DOTATOC uptake and uptake of contrast medium for CT was present in the initial staging (c, fused PET/CT image). Only PET-negative, morphologically cystic residuals were found 6 months after therapy (d, fused PET/CT image)

Fig. 5

Patient 5 before therapy (a–c) and after three cycles of ²¹³Bi-DOTATOC (d–f) to a dose of 4 GBq. a Beta-resistant residuals in the liver (long arrows) and primary tumour (short arrow) are present in the DOTATOC PET maximum intensity projection image. b CE-CT image with the primary tumour outlined in red. c In the MR image with hepatocyte-specific contrast medium, the liver metastases appear as black cavities against the enhancing normal liver parenchyma. d–f After three cycles of ²¹³Bi-DOTATOC to a dose of 4 GBq, the lesions have diminished on the PET image (d) and CT image (e). Also on the MR image (f), the residual lesion has almost disappeared as shown by the growth of normal hepatocytes demonstrated by the uptake of the hepatocyte-specific contrast medium

Fig. 6

Patient 7 with an extensive tumour burden in the left liver lobe and multiple lesions in the right lobe, as well as disseminated bone marrow metastases predominantly in the spine and pelvis. These are demonstrated in coronal and sagittal ⁶⁸Ga-DOTATOC-PET maximum intensity projections (a). As expected, liver metastases showed significant shrinkage after administration of 10.5 GBq of ²¹³Bi-DOTATOC into the common hepatic artery. Additional systemic efficiency resulting from the ²¹³Bi-DOTATOC reaching the systemic circulation after the first pass of the liver was noted after 6 months in that most of the bone marrow metastases had also diminished (b)

Fig. 7

Patient with bone marrow carcinosis arising from neuroendocrine prostate cancer. After systemic therapy with 3.3 GBq ²¹³Bi-DOTATOC only grade I thrombopenia (>100.000/μl), grade I neutropenia (neutrophils >2,000/mm³) and grade I total WBC (>3,000/mm³) were observed 2 weeks after therapy and recovered until week 4. Red blood cells, haemoglobin gammaGT and creatinine showed no relevant change within 5 months (circles platelets, triangles haemoglobin, inverted triangles red blood cell count, black squares total white blood cell count, white squares absolute neutrophil count, grey squares absolute lymphocyte count, hexagons creatinine, diamonds gammaGT)