Roelf Valkema

Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours

Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various 111In, 90Y, or 177Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with 111Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like 90Y and 177Lu were developed. Reported anti-tumour effects of [90Y-DOTA0,Tyr3]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [177Lu-DOTA0,Tyr3]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non-radioiodine-avid differentiated thyroid carcinoma might become more important.

Peptide-receptor radionuclide therapy for endocrine tumors

Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a promising option for the treatment of somatostatin-receptor-positive endocrine tumors. Treatment with somatostatin analogs labeled with 111In, 90Y or 177Lu can result in symptomatic improvement, although tumor remission is seldom achieved with 111In-labeled analogs. In this Review, the findings of several studies on the use of PRRT for endocrine tumors are evaluated. Large variation in the antitumor effects of 90Y-octreotide was reported between studies: an objective response (≥50% tumor regression) was achieved in 9–33% of patients. After treatment with 177Lu-octreotate, an objective response was achieved in 29% of patients and a minor response (25–50% tumor regression) was achieved in 16% of patients; stable disease was present in 35% of patients. Treatment with 177Lu-octreotate resulted in a survival benefit of several years and markedly improved quality of life. Serious, delayed adverse effects were rare after PRRT. Although randomized, clinical trials have not yet been performed, data on the use of PRRT compare favorably with those from other treatment approaches, such as chemotherapy. If these results can be replicated in large, controlled trials, PRRT might become the preferred option in patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors.

Radiolabelled peptides for tumour therapy: current status and future directions. Plenary lecture at the EANM 2002.

On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, e.g. overexpression in many tumours, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualisation of receptor-positive tumours were radiolabelled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicentre studies have already shown an effective therapeutic response when using radiolabelled somatostatin analogues to treat receptor-positive tumours. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumours, such as medullary thyroid carcinoma, radiolabelled minigastrin analogues are currently being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabelled peptides. The combination of different radionuclides, such as 177Lu- and 90Y-labelled somatostatin analogues, to reach a wider tumour region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y1) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multi-receptor tumour targeting using the combination of bombesin and NPY(Y1) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.

Somatostatin receptor: Scintigraphy and radionuclide therapy

Peptide receptor scintigraphy is more sensitive at the biological than anatomical level, in contrast to conventional imaging, which it complements. Neuroendocrine tumours have the most somatostatin receptors in vitro and their metastases are somatostatin receptor positive in vitro, so that [111In-DTPA-D-Phe1]octreotide (OCT) can be used to image them. OCT was compared with conventional imaging techniques (CON) in a European Multicentre Trial. In 350 evaluable patients, CON detected 88%, and OCT 80% (glucagonomas 100%, VIPomas 88%, carcinoids 87%, non-functioning islet cell tumours 82%, insulinomas 46%) of tumour sites but there was no systematic use of abdominal single-photon-emission computerised tomography. OCT demonstrated multiple tumour sites in 62 of 178 patients in whom CON had found only 1 lesion, with 60% confirmed. 12/16 lesions detected by OCT in 11 patients with no lesions according to CON were also confirmed. The impact of OCT on management was evaluated in 235 patients and affected 40%: it determined 29 surgical decisions, led to octreotide therapy in 47, and modified octreotide dose in 18. Six end-stage patients with neuroendocrine tumours were treated with OCT radionuclide therapy (up to a cumulative dose of 53 GBq per patient) in a phase I trial. There were no major side-effects after up to 2 years treatment, with impressive effects on hormone production and a likely anti-proliferative effect.

Peptide Receptor Radionuclide Therapy

Abstract: On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, for example, overexpression in many tumors, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualization of receptor‐positive tumors were radiolabeled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicenter studies already have shown an effective therapeutic response when using radiolabeled somatostatin analogues to treat receptor‐positive tumors. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK‐B receptor‐positive tumors, such as medullary thyroid carcinoma, radiolabeled minigastrin analogues currently are being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabeled peptides. The combination of different radionuclides, such as 177Lu‐ and 90Y‐labeled somatostatin analogues, to reach a wider tumor region of high curability, has been described. A variety of other peptide‐based radioligands, such as bombesin and NPY(Y1) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multireceptor tumor targeting using the combination of bombesin and NPY(Y1) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.

Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [(111)In-DTPA(0)]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate, a survival benefit of several years compared with historical controls has been reported.

OctreoTherTM: Ongoing Early Clinical Development of a Somatostatin-Receptor-Targeted Radionuclide Antineoplastic Therapy

OctreoTherTM (90Y-DOTA-D-Phe1-Tyr3-octreotide, a.k.a. 90Y-SMT 487) consists of a somatostatin peptide analogue (Tyr3-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan®) it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle × 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.

Preclinical and Clinical Studies of Peptide Receptor Radionuclide Therapy

In the 1980s, the (111)In-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst(2)) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PRRT) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr(3)-octreotate (DOTATATE) and DOTA, Tyr(3)-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst(2), have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PRRT. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PRRT with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PRRT could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PRRT. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PRRT and describes clinical and preclinical studies regarding PRRT optimizing strategies.

Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging?

This paper reviews issues concerning 86Y positron emission tomography (PET), 90Y PET and 90Y bremsstrahlung imaging. Specific methods and corrections developed for quantitative imaging, for application in preclinical and clinical studies, and to assess 90Y dosimetry are discussed. The potential imaging capabilities with the radioisotopes 87Y and 88Y are also considered. Additional studies required to assess specific unaddressed issues are also identified.

Evaluation of left ventricular function and volumes in patients with ischaemic cardiomyopathy: gated single-photon emission computed tomography versus two-dimensional echocardiography

Abstract. The objective of this study was to perform a head-to-head comparison between two-dimensional (2D) echocardiography and gated single-photon emission computed tomography (SPET) for the evaluation of left ventricular (LV) function and volumes in patients with severe ischaemic LV dysfunction. Thirty-two patients with chronic ischaemic LV dysfunction [mean LV ejection fraction (EF) 25%±6%] were studied with gated SPET and 2D echocardiography. Regional wall motion was evaluated by both modalities and scored by two independent observers using a 16-segment model with a 5-point scoring system (1= normokinesia, 2= mild hypokinesia, 3= severe hypokinesia, 4= akinesia and 5= dyskinesia). LVEF and LV end-diastolic and end-systolic volumes were evaluated by 2D echocardiography using the Simpsons biplane discs method. The same parameters were calculated using quantitative gated SPET software (QGS, Cedars-Sinai Medical Center). The overall agreement between the two imaging modalities for assessment of regional wall motion was 69%. The correlations between gated SPET and 2D echocardiography for the assessment of end-diastolic and end-systolic volumes were excellent (r=0.94, P<0.01, and r=0.96, P<0.01, respectively). The correlation for LVEF was also good (r=0.83, P<0.01). In conclusion: in patients with ischaemic cardiomyopathy, close and significant relations between gated SPET and 2D echocardiography were observed for the assessment of regional and global LV function and LV volumes; gated SPET has the advantage that it provides information on both LV function/dimensions and perfusion.