Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors

Bodei, Lisa; Kidd, Mark; Prasad, Vikas; Modlin, Irvin M.

doi:10.1159/000402936

Cited by 14 publications

(11 citation statements)

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“…The clinical responses for diarrhoea and flushing continued to improve during treatment with LAN and during the follow-up period supporting the notion of maintenance therapy with LAN following PRRT. The adverse events reported were also consistent with published data on the use of PRRT [ 8 , 27 – 29 ]. Most patients (52.2%) in the GEP-NET FAS group received a LAN dosage of 120 mg every 28 days.…”

Section: Discussionsupporting

confidence: 88%

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice

Prasad

Srirajaskanthan

Toumpanakis

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177 Lu-DOTATOC or 177 Lu-DOTATATE (LAN–peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). Methods International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN–PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. Results Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN–PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs ( n = 23) was stable disease ( n = 14, 60.9%), partial response ( n = 8, 34.8%) and progressive disease ( n = 1, 4.3%). The ORR was 27.3% at end of last LAN–PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. Conclusion Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. Trial registration Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578

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Section: Discussionsupporting

confidence: 88%

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice

Prasad

Srirajaskanthan

Toumpanakis

et al. 2020

Eur J Nucl Med Mol Imaging

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“…Mild adverse events resulting from this type of therapy include nausea, vomiting, fatigue, fever, and diarrhea [6]. Greater hematological and renal toxicities have been also reported, particularly with 90 Y-DOTATOC versus 177 Lu-DOTATATE [16]. While most symptoms are described as manageable, several studies have shown resultant myelodysplastic syndrome, acute leukemia, or other cancers, which have also been reported in other standard of care radiotherapies, such as with 131 I-MIBG [13,[16][17][18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Greater hematological and renal toxicities have been also reported, particularly with 90 Y-DOTATOC versus 177 Lu-DOTATATE [16]. While most symptoms are described as manageable, several studies have shown resultant myelodysplastic syndrome, acute leukemia, or other cancers, which have also been reported in other standard of care radiotherapies, such as with 131 I-MIBG [13,[16][17][18][19][20][21]. Here, we show two cases where the patients received either 177 Lu/ 90 Y-DOTATOC or 177 Lu-DOTATATE and demonstrated remarkable response rates with almost complete resolution of several foci.…”

Section: Discussionmentioning

confidence: 99%

“…The risk factors of poor response to PRRT apart from higher Ki-67 index and high uptake on 18 F-FDG have been found to be higher tumor burden, involvement of more than two organ systems, poor performance status (Karnofsky performance scale score), and identified progressive disease after first PRRT [35,36]. Furthermore, several results have also shown that when PRRT is delivered as salvage therapy after chemotherapy in particular, there was a tendency for progression free survival to decline and a greater tendency for long-term hematologic consequences [6,16,21]. Therefore, following relapse, the tumor could become increasingly aggressive or its sensitivity to radiation could have diminished, which may warrant a repeat tumor biopsy to reassess Ki-67 levels after recurrence of the disease [34].…”

Section: Discussionmentioning

confidence: 99%

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Eruption of Metastatic Paraganglioma After Successful Therapy with 177Lu/90Y-DOTATOC and 177Lu-DOTATATE

Wolf

Jha

Berkel

et al. 2019

Nucl Med Mol Imaging

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Metastatic paraganglioma treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been introduced as a novel management option for metastatic neuroendocrine tumors demonstrating safety, efficacy, and increased quality of life. We present two cases of marked progression of metastatic paraganglioma following initial partial response to PRRT. Given their positivity on 68 Ga-DOTATATE PET/CT and 111 In-octreotide SPECT, they underwent PRRT. Imaging following treatment revealed significant improvement in size and intensity, with some foci nearly completely resolved in one patient, and disease regression with a decrease in the number and size of bone and liver lesions in the second patient. Within months, repeat imaging in both patients revealed extensive metastatic disease with new lesions, which eventually lead to their deaths. The mechanism for rapid disease progression after partial response is not well understood, although it could be related to initially high Ki-67 levels or 18 F-FDG PET/CT SUV max values. However, naturally rapid disease progression despite PRRT response cannot be excluded. This finding warrants the importance of proper patient counseling along with early and accurate pre-PRRT assessment, taking into consideration the above potential risk factors for therapy response in order to personalize treatment regimens and achieve maximum patient benefit.

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“…Lutetium-177 therefore provides excellent properties both for RIT and immuno-SPECT-imaging of small solid tumors or metastatic lesions even at an early stage of the disease. A number of 177 Lu-labeled radiopharmaceuticals such as the somatostatin analogues 177 Lu-DOTATOC/DOTATATE have already demonstrated the great potential of 177 Lu-based endoradiotherapy (Bodei et al 2015;Demirci et al 2018;Forrer et al 2005;Kasi et al 2019). Nevertheless, both radiometals 90 Y and 177 Lu are typical candidates for mAb-based applications.…”

Section: Introductionmentioning

confidence: 99%

AAZTA5-squaramide ester: promising tool for 177Lu-labeling of monoclonal antibodies under mild conditions

Klasen¹,

Moon²,

Rösch³

2020

Preprint

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Background Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)‐6‐[bis(carboxymethyl)]amino‐6‐methylperhydro‐1,4‐diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA5-SA being coupled to a model antibody (bevacizumab) in comparison to DOTA-SA using the therapeutic nuclide lutetium-177. Results As proof-of-concept, bevacizumab was first functionalized with either AAZTA5-SA or DOTA-SA. After purification via fractionated size exclusion chromatography (SEC), the corresponding immunoconjugates were subsequently radiolabeled with lutetium-177 at pH 7 and room temperature (RT) as well as 37 °C. After 90 min, labeling of AAZTA5-SA-mAb resulted in almost quantitative radiochemical yields (RCY) of > 98% and > 99%, respectively. After purification via SEC, the radioconjugate [177Lu]Lu-AAZTA5-SA-mAb could be obtained with a purity of > 99% and an apparent specific activity of 4.5 GBq/µmol. In contrast, 177Lu-labeling of DOTA-SA-mAb showed negligible radiochemical yields of < 2% both at room temperature and 37 °C. In vitro complex stability measurements of [177Lu]Lu-AAZTA5-SA-mAb in human serum at 37 °C indicated > 99% protein bound activity within 15 days. In phosphate buffered saline (PBS), a slightly decreased stability of > 93% intact conjugate was observed over the same period. Conclusion Coupling of AAZTA5-SA to the monoclonal antibody bevacizumab allowed for 177Lu-labeling with almost quantitative radiochemical yields both at room temperature and 37 °C. Within 15 days, the resulting radioconjugate indicated very high in vitro complex stability both in human serum and PBS. Therefore, AAZTA5-SA is a promising tool for 177Lu-labeling of sensitive biomolecules such as antibodies for theranostic applications.

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Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors

Cited by 14 publications

References 0 publications

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice

Eruption of Metastatic Paraganglioma After Successful Therapy with 177Lu/90Y-DOTATOC and 177Lu-DOTATATE

AAZTA5-squaramide ester: promising tool for 177Lu-labeling of monoclonal antibodies under mild conditions

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