Dik J. Kwekkeboom

Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

Treatment With the Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate: Toxicity, Efficacy, and Survival

PURPOSE Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [(177)Lu-DOTA(0),Tyr(3)]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. PATIENTS AND METHODS Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. RESULTS Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. CONCLUSION Treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first‐line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium‐177 (177Lu)–Dotatate in patients with advanced, progressive, somatostatin‐receptor–positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well‐differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu‐Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long‐acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu‐Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression‐free survival. Secondary end points included the objective response rate, overall survival, safety, and the side‐effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data‐cutoff date for the primary analysis, the estimated rate of progression‐free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu‐Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu‐Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu‐Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu‐Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu‐Dotatate resulted in markedly longer progression‐free survival and a significantly higher response rate than high‐dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu‐Dotatate group. (Funded by Advanced Accelerator Applications; NETTER‐1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011‐005049‐11.)

Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: Foregut, midgut, hindgut, and unknown primary

a DRK Kliniken Westend, Berlin , Germany; b UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hopital Louis Mourier, Colombes , France; c Medicine and Surgery, General Surgery Section, MED/18 – General Surgery and d Department of Pathology, University of Verona, Verona , Italy; e Netherlands Cancer Centre, Amsterdam , and f Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands;

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification

Well-Differentiated Pancreatic Nonfunctioning Tumors/Carcinoma

Departments of a Surgery and b Radiology, University of Verona, Verona , Italy; c Department of Internal Medicine, Charite, University of Berlin, Berlin , Germany; d Department of Nuclear Medicine, University of Rotterdam, Rotterdam , The Netherlands; e M. Korner, University of Bern, Institut fur Pathologie, Bern , Switzerland; f Department of Oncology, South Florida University, Tampa, Fla. , USA; g Department of Internal Medicine, Charite, University of Berlin, Berlin , Germany; h Department of Radiology, Charite Universitatsmedizin, Berlin , Germany; i Department of Surgery, Stadtisches Klinikum Neuss, Lukas Hospital, Neuss , Germany; j Department of Surgery, Zurich Hospital, Zurich , Switzerland; k Department of Surgery, Vivantes Humboldt Hospital, Berlin , Germany; l Department of Endocrine Oncology, University of Uppsala, Uppsala , Sweden; m Department of Pathology, University of Lyon, Lyon , France

Well-differentiated pancreatic tumor/carcinoma: Insulinoma

a Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam, The Netherlands; b Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna , Austria; c Hospices Civils de Lyon, Hopital Edouard-Herriot Service Central d‘Anatomie et Cytologie Pathologiques, Lyon , France; d Centre de Medecine Nucleaire, Universite Catholique de Louvain, Brussels , Belgium; e Department of Pathology, University of Kiel, Kiel , Germany; f B Unit of Surgery, Department of Surgery, University of Verona, Verona , Italy; g Department of Nuclear Medicine, Erasmus MC, Rotterdam , The Netherlands; h Department of Endocrine Oncology, University Hospital, Uppsala , Sweden; i Department of Internal Medicine, Division of Hepatology and Gastroenterology, Interdisciplinary Center of Metabolism and Endocrinology, Charite, Campus Virchow Hospital, University for Medicine Berlin, Berlin , Germany; j Service de Gastroenterologie-Pancreatologie, Pole des Maladies de l‘Appareil Digestif, Hopital Beaujon, Clichy , France; k Department of Pathology and Laboratory Medicine, Universita degli Studi, Parma, Italy; l Department of Endocrinology, Genoa University, Genoa , Italy

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.

ENETS Consensus Guidelines for the Management of Patients with Gastroduodenal Neoplasms

a Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , Italy; b Department of Oncology, Royal Free University UFR Bichat-Beaujon-Louis Mourier, Colombes , France; c Digestive Oncology, University Hospital Gasthuisberg/Leuven, Leuven , Belgium; d Institute of Pathology, Catholic University – Policlinic A. Gemelli, Rome , Italy; e Department of Endocrinology, Medical University of Silesia, Katowice , Poland; f Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark; g Department of Pathology, Tohoku University Graduate School of Medicine, Sendai , Japan; h Department of Internal Medicine and Gastroenterology, St. Orsola Hospital, University of Bologna, Bologna , Italy; i Institut Catala d’Oncologia (IDIBELL), Barcelona , Spain; j Department of Gastroenterology, Beaujon Hospital, Clichy , France

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.