Teunissen, J.J.M.

Peptide receptor radionuclide therapy (PRRT) for GEP-NETs (Article)

2012-12-01T00:00:00Z

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs).90Y-DOTATOC and177Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15-35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of90Y-DOTATOC. Options to improve PRRT may include combinations of radioactive labelled somatostatin analogues and the use of radiosensitising drugs combined with PRRT. Other therapeutic applications of PRRT may include intra-arterial administration, neo-adjuvant treatment and additional PRRT cycles in patients with progressive disease, who have benefited from initial therapy. Considering the mild side-effects, PRRT may well become the first-line therapy in patients with metastasised or inoperable GEP-NETs if more widespread use of PRRT can be accomplished.

Tumor response assessment to treatment with [ 177Lu-DOTA 0,Tyr 3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors: Differential response of bone versus soft-tissue lesions (Article)

2012-09-01T00:00:00Z

We have noted that bone lesions on CT respond differently from soft-tissue lesions to treatment with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). We therefore compared the response of bone lesions with that of soft-tissue lesions to treatment with177Luoctreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors (NETs). Methods: Forty-two patients with well-differentiated NETs who had bone metastases that were positive on [111In-DTPA0]octreotide somatostatin receptor scintigraphy (SRS) before treatment, and who had soft-tissue lesions, were studied. All patients had had a minimum of 1 follow-up CT scan. Lesions were scored on CT and bone lesions also on SRS before and after treatment. Tumor markers (chromogranin A and 5-hydroxyindoleacetic acid) before and after treatment were compared. Results: Because bone lesions were not visible on CT before treatment in 11 of 42 patients (26%), bone and softtissue lesions were evaluated in 31 patients. Whereas bone lesions increased in size, soft-tissue lesions decreased in size. The percentage change in bone and soft-tissue lesions was significantly different at all time points up to 12 mo of follow-up (P < 0.001). The intensity or number of bone lesions on SRS decreased after treatment in 19 of 23 patients (83%) in whom SRS after treatment was available. The tumor markers also decreased significantly after treatment. In 1 patient, bone lesions became visible on CT after treatment, mimicking progressive disease with "new" bone lesions, although there was an overall treatment response. Conclusion: In patients with NETs, the apparent increase in size of bone lesions or the appearance of new bone lesions on CT after treatment with177Lu-octreotate should be interpreted cautiously, as this finding may be therapy-related rather than indicative of tumor progression. Copyright

Treatment of Gastroenteropancreatic Neuroendocrine Tumors with Peptide Receptor Radionuclide Therapy (Article)

2012-01-10T00:00:00Z

The primary treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs) is surgery with curative intent or debulking of the tumor mass. In case of metastatic disease, cytoreductive options are limited. A relatively new therapeutic modality, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, is currently available in a number of mostly European centers. Complete and partial responses obtained after treatment with [90Y-DOTA0,Tyr3]octreotide are in the same range as after treatment with [177Lu-DOTA0,Tyr3]octreotate (i.e. 10-30%). However, significant nephrotoxicity has been observed after treatment with [90Y-DOTA0,Tyr3]octreotide. Options to improve PRRT may include combinations of radioactive labeled somatostatin analogs, intra-arterial administration, and the use of radiosensitizing drugs combined with PRRT. Other therapeutic applications of PRRT may include additional therapy cycles in patients with progressive disease after benefit from initial therapy, PRRT in adjuvant or neoadjuvant setting, or PRRT combined with new targeted therapies, such as sunitinib or everolimus. Randomized clinical trials comparing PRRT with other treatment modalities, or comparing various radioactive labeled somatostatin analogs should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs. Copyright

Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy (Article)

2011-11-01T00:00:00Z

Context: Insulinomas are relatively rare neuroendocrine tumors of the pancreas. Only 10% are considered malignant. Control of insulin hypersecretion and hypoglycemia in patients with malignant insulinomas may be extremely difficult. Different medications and chemotherapy schedules have been used. Patients: Five patients with metastatic insulinomas and severe, poorly controllable, hypoglycemia are described. These patients required continuous glucose infusion to control severe hypoglycemia, which were induced by the high levels of insulin secretion. Conventional medications, such as diazoxide, or streptozotocin-based chemotherapies had been used to control hypoglycemia but were ineffective and/or produced adverse effects. All patients were treated with sc octreotide. Intervention: Peptide receptor radionuclide therapy with radiolabeled-somatostatin analogs was used. Results: After the start of radiolabeled somatostatin analog therapy, the five patients with metastatic insulinomas had stable disease for a mean period of 27 months. During these months, the patients were without any hypoglycemic episodes. Finally, three of five patients died because of progressive disease. Conclusions: Radiolabeled somatostatin analog therapy can stabilize tumor growth and can be very successful in further controlling severe hypoglycemia in malignant insulinomas. In our series, this eventually resulted in improved survival outside the hospital setting. Copyright

Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours (Article)

2011-10-01T00:00:00Z

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [111In-DTPA0]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 [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3] 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 [177Lu-DOTA0,Tyr3]octreotate, a survival benefit of several years compared with historical controls has been reported.

Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [ 177Lu-DOTA 0,Tyr 3]octreotate (Article)

2011-09-01T00:00:00Z

Quality of life (QOL) is an important outcome in cancer therapy. In this study, we investigated the QOL and symptoms after [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy in patients with inoperable or metastasized gastroenteropancreatic or bronchial neuroendocrine tumors (NETs). Methods: Two hundred sixty-five Dutch patients completed the QOL questionnaire of the European Organization for the Research and Treatment of Cancer after being treated for NETs. ANOVA was used for statistical analyses, with a P value of 0.05 or less being considered significant. Differences of at least 10 points in global health status (GHS)/QOL scores, symptom scores, and Karnofsky performance scores (KPS) before and after therapy were regarded as indicating an improvement. Results: Regardless of the treatment outcome, GHS/QOL, insomnia, appetite loss, and diarrhea improved significantly in the total group. These improvements were also seen in patients with bone metastases or a decrease of 50% or more in chromogranin A. Improvement in the scores by at least 10 points was also analyzed in a subgroup of patients with decreased GHS/QOL or symptoms at the start of therapy: in 36% of these patients, GHS/QOL improved after therapy; in 49%, fatigue; in 70%, nausea plus vomiting; in 53%, pain; in 44%, dyspnea; in 59%, insomnia; in 63%, appetite loss; in 60%, constipation; and in 67%, diarrhea. Additionally, we did not see a statistically significant deterioration in patients who had GHS/QOL 100, KPS 100, or no symptoms at the start. In patients with initial stable disease or remission after treatment, GHS/QOL and KPS decreased significantly when re-growth of the tumors occurred. Conclusion: GHS/QOL, KPS, and symptoms improved significantly after177Lu-octreotate therapy, and there was no significant decrease in QOL in patients who had no symptoms before therapy. In patients who had suboptimal scores for GHS/QOL or symptoms before therapy, a clinically significant improvement was demonstrated. Our results indicate that177Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients' self-assessed QOL. Copyright

Preclinical and Clinical Studies of Peptide Receptor Radionuclide Therapy (Article)

2010-05-01T00:00:00Z

In the 1980s, the111In-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst2) 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), Tyr3-octreotate (DOTATATE) and DOTA, Tyr3-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst2, 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.

Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors (Article)

2010-03-01T00:00:00Z

Somatostatin receptor imaging (SRI) with [111In-DTPA 0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Newer radiolabeled somatostatin analogs which can be used in positron emission tomography (PET) imaging, and which have a higher affinity for the somatostatin receptor, especially receptor subtype-2, have been developed. It would be desirable, however, if one radiolabeled analog became the new standard for PET imaging, because the current application of a multitude of analogs implies a fragmented knowledge on the interpretation of the images that are obtained in clinical practice. In our view, the most likely candidates for such a universal PET tracer for SRI are [68Ga-DOTA0,Tyr3]octreotate or [68Ga-DOTA0,Tyr3]octreotide. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [ 90Y-DOTA0,Tyr3]octreotide and [ 177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr 3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]- octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.

Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors (Article)

2010-03-01T00:00:00Z

Somatostatin receptor imaging with [111In-DTPA0)octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors. Treatment with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized, well-differentiated neuroendocrine tumors. Symptomatic improvement may occur with all111In,90Y, or177Lu-labeled somatostatin analogues that have been used for peptide receptor radionuclide therapy. The results that were obtained with [90Y-DOTA0, Tyr3]octreotide and [177Lu-DOTA0, Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months, respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0, Tyr3]octreotate. Finally, compared with historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [177Lu-DOTA0, Tyr3]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of peptide receptor radionuclide therapy can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable gastroenteropancreatic neuroendocrine tumors.

Bone marrow dosimetry in peptide receptor radionuclide therapy with [ 177Lu-DOTA0,Tyr3]octreotate (Article)

2009-07-01T00:00:00Z

Purpose: Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called "remainder of the body" to the bone marrow. Methods: Bone marrow aspirates were drawn in 15 patients after treatment with [177Lu-DOTA0,Tyr3]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. Results: A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found (r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose. Conclusion: (1) After PRRT with [177Lu-DOTA0,Tyr3]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary.

Effects of therapy with [177Lu-DOTA0,Tyr 3]octreotate on endocrine function (Article)

2009-06-03T00:00:00Z

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. Methods: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. Results: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 ± 16 to 25 ± 4 ng/l, p < 0.05) and follicle-stimulating hormone (FSH) levels increased (5.9 ± 0.5 to 22.7 ± 1.4 IU/l, p < 0.05). These levels returned to near baseline levels. Total testosterone and sex hormone binding globulin (SHBG) levels decreased (15.0 ± 0.9 to 10.6 ± 1.0 nmol/l, p < 0.05 and 61.8 ± 8.7 to 33.2 ± 3.7 nmol, p < 0.05), respectively, whereas non-SHBG-bound T did not change. An increase (5.2 ± 0.6 to 7.7 ± 0.7 IU/l, p < 0.05) of luteinizing hormone (LH) levels was found at 3 months of follow-up returning to baseline levels thereafter. In 21 postmenopausal women, a decrease in levels of FSH (74.4 ± 5.6 to 62.4 ± 7.7 IU/l, p < 0.05) and LH (26.8 ± 2.1 to 21.1 ± 3.0 IU/l, p < 0.05) was found. Of 66 patients, 2 developed persistent primary hypothyroidism. Free thyroxine (FT4) levels decreased (17.7 ± 0.4 to 15.6 ± 0.6 pmol/l, p < 0.05), whereas thyroid-stimulating hormone (TSH) and triiodothyronine (T3) levels did not change. Reverse triiodothyronine (rT3) levels decreased (0.38 ± 0.03 to 0.30 ± 0.01 nmol/l, p < 0.05). Before and after therapy adrenocorticotropic hormone (ACTH) stimulation tests showed an adequate response of serum cortisol (> 550 nmol/l, n = 18). Five patients developed elevated HbA1clevels (> 6.5%). Conclusion: In men177Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA1c. Therefore, PRRT with177Lu-octreotate can be regarded as a safe treatment modality with respect to short-and long-term endocrine function.

Endocrine Tumours - Molecular Radiation on Target Peptide Receptor Radionuclide Therapy with Lutetium-octreotate (Doctoral Thesis)

2008-12-10T00:00:00Z

The concept of radiolabelled peptide analogues to target cell membrane-bound receptors is subject of an increasing number of research projects and source of inspiration for many researchers throughout the world. The first application of radiolabelled peptides in the human was introduced by Krenning et al. in 1989. The somatostatin analogue Tyr3-octreotide was labelled with 123I and scintigraphy to localise somatostatin receptor positive tumours was established. However, the use of 123I-Tyr3-octreotide for scintigraphy had several major drawbacks regarding its metabolic behaviour, preparation difficulties and the relatively short physical half-life of the radionuclide. Therefore, another radiolabelled analogue of somatostatin, 111In-DTPA-D-Phe1-octreotide was introduced which had several advantages such as easy preparation, general availability, appropriate half-life and absence of major interference in the upper abdominal region. In 1994, 111In-DTPA-D-Phe1-octreotide (OctreoScan(R)) was approved by the U.S. Food and Drug Administration (FDA) and since then OctreoScan(R) has become a commonly used imaging technique to diagnose neuroendocrine tumours, such as carcinoids and neuroendocrine tumours of the pancreas. These tumours have a high expression of somatostatin receptors, especially the receptor subtype in common.

Multimodality management of a polyfunctional pancreatic endocrine carcinoma with markedly elevated serum vasoactive intestinal polypeptide and calcitonin levels (Article)

2008-04-01T00:00:00Z

We present an unusual case of a 52-year-old woman with severe, uncontrollable, refractory diarrhea attributable to pancreatic endocrine carcinoma (ECA) with markedly elevated serum vasoactive intestinal polypeptide (VIP) and calcitonin levels. After initial correction of fluid and electrolyte abnormalities, the patient was treated with high-dose octreotide. Shortly thereafter, due to the intractable nature of her diarrhea, she underwent cytoreductive hepatic surgery. The pancreatosplenectomy specimen showed a poorly differentiated ECA of the distal pancreas, immunoreactive for synaptophysin, CD56, and S100 protein, with morphologically similar hepatic and lymph node metastases. Postoperatively, her diarrhea improved, along with decline in serum VIP and calcitonin levels. Systemic chemotherapy with etoposide and cisplatin did not result in any radiographic and biochemical improvement. Having radiologically stable disease with depot-octreotide and short-acting octreotide (Sandostatin), she was subjected to peptide receptor radiotherapy with [Lu-DOTA,Tyr]octreotate (LuTate) that resulted in marked clinical and biochemical improvement, along with dramatic reduction in the number and size of hepatic metastases. In summary, this is a unique case of metastatic VIP- and calcitonin-secreting pancreatic ECA with dramatic sustained clinical, biochemical, and objective tumor response to peptide receptor radionuclide therapy.

Treatment of Patients Who Have Endocrine Gastroenteropancreatic Tumors with Radiolabeled Somatostatin Analogues (Article)

2007-06-01T00:00:00Z

Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients who have inoperable or metastasized endocrine tumors. Symptomatic improvement may occur with all111In-,90Y-, or177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy. The results that were obtained with [90Y-DOTA°,Tyr3]octreotide and [177Lu-DOTA°,Tyr3]octreotate are encouraging in tumor regression. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild. These data compare favorably with the limited number of alternative treatment approaches.