Jaap J.M. Teunissen

Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate in Patients With Endocrine Gastroenteropancreatic Tumors

PURPOSE There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 year. Here, we present the results of treatment with a radiolabeled somatostatin analog, [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). PATIENTS AND METHODS One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate. RESULTS One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and progressive disease (PD) in 22 patients (18%). Higher remission rates were positively correlated with high uptake on pretherapy somatostatin receptor imaging and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low performance score and extensive disease. Median time to progression in 103 patients who either had SD or tumor regression was more than 36 months. CONCLUSION Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors. Serious side effects are rare. The median time to progression compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.

Quality of Life in Patients With Gastroenteropancreatic Tumors Treated With [177Lu-DOTA0,Tyr3]octreotate

PURPOSE To evaluate the quality of life (QoL) in patients with metastatic somatostatin receptor positive gastroenteropancreatic tumors treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) therapy. PATIENTS AND METHODS Fifty patients who had been treated with 600 to 800 mCi of (177)Lu-octreotate and had a follow-up of at least 3 months were studied. The patients completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 before therapy and at follow-up visit 6 weeks after the last cycle. Overall QoL and specific QoL domains of both the total group of patients and subgroups according to treatment outcome were analyzed. Twenty-four patients had regression, 19 had stable disease, six had progressive disease, and one had nonassessable disease status. Analysis of variance was used for statistical comparison. RESULTS A significant improvement in the global health status/QoL scale was observed after therapy with (177)Lu-octreotate (P <.01). The score increased significantly six weeks after therapy to a mean of 78.2, up from 69.0 (scale range, 0 to 100). Furthermore, significant improvement was observed in the role, emotional, and social function scales. The symptom scores for fatigue, insomnia, and pain were significantly decreased. Patients with proven tumor regression most frequently had an improvement of QoL domains. Unexpectedly, patients with progressive disease also indicated an improvement in their global health/QoL score. CONCLUSION (177)Lu-octreotate therapy significantly improved the global health/QoL and several function and symptom scales in patients with metastasized gastroenteropancreatic tumors, but especially in those patients with proven tumor regression.

Quality of Life in 265 Patients with Gastroenteropancreatic or Bronchial Neuroendocrine Tumors Treated with [177Lu-DOTA0,Tyr3]Octreotate

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 regrowth of the tumors occurred. Conclusion: GHS/QOL, KPS, and symptoms improved significantly after 177Lu-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 that 177Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients’ self-assessed QOL.

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.

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.

Treatment of Gastroenteropancreatic Neuroendocrine Tumors with Peptide Receptor Radionuclide Therapy

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.

Peptide receptor radionuclide therapy (PRRT) for GEP-NETs

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). (90)Y-DOTATOC and (177)Lu-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 of (90)Y-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.

Improved Control of Severe Hypoglycemia in Patients with Malignant Insulinomas by Peptide Receptor Radionuclide Therapy

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.

Peptide receptor radionuclide therapy using radiolabeled somatostatin analogs: focus on future developments

Peptide receptor radionuclide therapy (PRRT) has been shown to be an effective treatment for neuroendocrine tumors (NETs) if curative surgery is not an option. A majority of NETs abundantly express somatostatin receptors. Consequently, following administration of somatostatin (SST) analogs labeled with γ-emitting radionuclides, these tumors can be imaged for diagnosis, staging or follow-up purposes. Furthermore, when β-emitting radionuclides are used, radiolabeled peptides (radiopeptides) can also be used for the treatment for NET patients. Even though excellent results have been achieved with PRRT, complete responses are still rare, which means that there is room for improvement. In this review, we highlight some of the directions currently under investigation in pilot clinical studies or in preclinical development to achieve this goal. Although randomized clinical trials are still lacking, early studies have shown that tumor response might be improved by application of other radionuclides, such as α-emitters or radionuclide combinations, or by adjustment of radiopeptide administration routes. Individualized dosimetry and better insight into tumor and normal organ radiation doses may allow adjustment of the amount of administered activity per cycle or the number of treatment cycles, resulting in more personalized treatment schedules. Other options include the application of novel (radiolabeled) SST analogs with improved tumor uptake and radionuclide retention time, or a combination of PRRT with other systemic therapies, such as chemotherapy or treatment with radio sensitizers. Though promising directions appear to bring improvements of PRRT within reach, additional research (including randomized clinical trials) is needed to achieve such improvements.

Neoadjuvant Treatment of Nonfunctioning Pancreatic Neuroendocrine Tumors with [177Lu-DOTA0,Tyr3]Octreotate

Pancreatic neuroendocrine tumors (NETs) are rare neoplasms for which surgery has almost the only potential for cure. When surgery is not possible because of tumor size and vascular involvement, neoadjuvant treatment with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) may be an option. Methods: We studied 29 Dutch patients with a pathology-proven nonfunctioning pancreatic NET treated with 177Lu-octreotate. All patients had a borderline or unresectable pancreatic tumor (group 1) or oligometastatic disease (defined as ≤3 liver metastases) (group 2). Progression-free survival (PFS) was analyzed using the Kaplan–Meier method and Cox proportional hazards modeling. Results: After the treatment with 177Lu-octreotate, successful surgery was performed in 9 of 29 patients (31%). Six patients had a Whipple procedure, 2 patients had a pylorus-preserving pancreaticoduodenectomy, and 1 patient had a distal pancreatectomy and splenectomy. The median PFS was 69 mo for patients with successful surgery and 49 mo for the other patients. For comparison, the median PFS in 90 other patients with a nonfunctioning pancreatic NET with more than 3 liver metastases or other metastases was 25 mo. Conclusion: Neoadjuvant treatment with 177Lu-octreotate is a valuable option for patients with initially unresectable pancreatic NETs.