177Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants.

OBJECTIVE: To retrospectively analyze toxicity, progression-free survival (PFS), overall survival (OS), and their determinants in patients with advanced pancreatic neuroendocrine tumors (PanNETs), previously pretreated with chemothe-r-apy, undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. METHODS: A total of 102 patients with advanced PanNETs, previously pretreated with one (67%) or several (33%) lines of chemotherapy, were included, of whom 90% had progressive disease and the majority (74.5%) had grade 2 tumors. 177Lu-DOTATATE, 7.4 GBq per cycle, was administered with 6- to 8-week intervals in 88% of patients utilizing a dosimetry-guided protocol until an absorbed dose of 23 Gy to the kidneys was reached. RESULTS: A mean dose of 32 ± 10.9 GBq per patient was administered in 1-10 cycles starting a median of 36 months after PanNET diagnosis. The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT. Independent risk factors for both progression and death were liver tumor burden >50%, more than one line of previous chemotherapy, and elevated alkaline phosphatase. Resection of the primary tumor was linked to longer survival. Bone marrow toxicity grade 3-4 occurred in 10.8%. One patient (1.0%) developed acute myeloid leukemia. Bone marrow toxicity was unrelated to type and length of previous chemotherapy, amount of administered activity, and absorbed dose to the bone marrow. CONCLUSION: 177Lu-DOTATATE therapy was feasible, highly effective, and safe in patients with advanced PanNETs heavily pretreated with chemotherapy. More than one line of chemotherapy was a therapy-related independent risk factor for shorter PFS and OS.

Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.

PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome. METHODS: The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%). RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity. CONCLUSIONS: Dosimetry-based therapy with 177Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Kidney dosimetry during 177Lu-DOTATATE therapy in patients with neuroendocrine tumors: aspects on calculation and tolerance.

BACKGROUND: Fractionated therapy with 177Lu-DOTATATE has been reported to be an effective treatment for patients with metastasized neuroendocrine tumors. To optimize the treatment, absorbed doses to risk organs are calculated for the individual patient. For each organ, absorbed dose due to activity in the organ itself (self-dose) and that originating from other organs (cross-dose) are calculated from serial measurements to obtain the activity distribution following treatment. The main aim of the present work were to calculate the cross-dose contribution to the total absorbed kidney dose. METHODS: Five hundred patients with neuroendocrine tumors undergoing therapy with 177Lu-DOTATATE were included. Scintigraphic planar whole body images and single photon emission computed tomography/computed tomography (SPECT/CT) over the abdomen were acquired at 1, 4 and 7 days after treatment. Kidney self-dose was calculated based on radioactivity distribution obtained from SPECT/CT. Cross-dose to kidneys was estimated using organ-based analysis of planar whole body images and cross-fire dose factors from Olinda/EXM 1.1. RESULTS: Cross-dose to kidneys in the majority of patients were less than 2% and almost all cross-doses were less than 10%. Cross-dose exceeded 10% only in rare cases of patients with high tumor burden and low absorbed doses to kidneys. CONCLUSIONS: The absorbed dose from 177Lu-octreotate to solid organs due to cross-fire is generally low and can usually be neglected.

Selective internal radiation therapy in patients with progressive neuroendocrine liver metastases.

PURPOSE: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in patients with unresectable liver metastases from neuroendocrine tumours (NETLMs). METHODS: This retrospective study included 40 patients with progressive NETLMs (22 women, 18 men, mean age 61.6 years) who underwent SIRT with (90)Y-labelled resin microspheres. Tumour response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) on CT or MR images. Medical records were reviewed. RESULTS: In the 40 patients, 54 evaluable SIRT procedures were performed, 33 to the right liver lobe (mean activity 1.31 GBq), 13 to the left lobe (mean activity 0.85 GBq), and 8 to both lobes (mean activity 1.61 GBq). Late follow-up imaging (mean 20 months) was performed after 44 of the treatments. Objective tumour response and disease control rates were 54 % (29 of 54 treatments) and 94 % (51 treatments), respectively, at the early follow-up examination (mean 3 months) and 34 % (15 treatments) and 57 % (25 treatments), respectively at the late follow-up examination. Mean overall survival from the first SIRT was 34,8 months and survival rates at 1, 2, 3 and 5 years were 76 %, 59 %, 52 % and 35 % respectively. Adverse effects were generally mild and easily manageable, except in one patient who died from radiation-induced liver failure. Of the 45 patients, 18 (45 %) had received peptide receptor radionuclide therapy (PRRT) prior to SIRT. CONCLUSION: SIRT with (90)Y-labelled resin microspheres is a safe and effective treatment for patients with progressive NETLM, and also for those who have received prior PRRT.

Streptozocin and 5-Fluorouracil for the Treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity.

BACKGROUND: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumors (pNETs) over the past few decades. The objective of the current study was to assess the efficacy, prognostic factors and safety of the combination of STZ and 5-FU. PATIENTS AND METHODS: Medical records and radiological reports of 133 patients with pNETs who received the combination of STZ and 5-FU during the period 1981-2014 were retrospectively evaluated. RESULTS: The median survival from the start of treatment was 51.9 months in the whole group. In the radiologically evaluable patients (n = 100), progression-free survival was 23 months. Complete response was reached in 3 patients (3%), partial response in 25 patients (25%), 64 patients (64%) had stable disease, and 8 patients (8%) had progressive disease. In a multivariate analysis, surgery of the primary tumor and having a G3 tumor were significant positive and negative prognostic factors of survival from the start of treatment, respectively. Having either a G3 tumor or a stage IV tumor were significant prognostic factors for a shorter progression-free survival. Chemotherapy had to be discontinued in 29 patients due to side effects, of which kidney toxicity (mainly grades 1-2) was the most frequent. CONCLUSION: As shown in recent reports, the combination of STZ and 5-FU is effective in the treatment of pNETs in terms of survival and radiological response and has an acceptable toxicity profile.

Effect of temozolomide in patients with metastatic bronchial carcinoids.

INTRODUCTION: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. MATERIALS AND METHODS: All patients with progressive metastatic bronchial carcinoid treated with temozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. RESULTS: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11 (52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxicities grade 3-4 were noted in 4 patients, thrombocytopenia (n = 3) and leukopenia (n = 1). CONCLUSION: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining temozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients.

Metastases from neuroendocrine tumors to the breast are more common than previously thought. A diagnostic pitfall?

BACKGROUND: Metastases from neuroendocrine tumors (NETs) to the breast have been described as a rare phenomenon. Presentation, imaging results, and cytopathologic findings of these tumours may closely mimic those of a mammary carcinoma. METHODS: This study was a retrospective review of 661 patients with metastatic NETs, of whom 280 were females, treated at Uppsala University Hospital, Uppsala, Sweden. Patients with pathological breast lesions were identified. Histopathological slides from available NET breast lesions were analyzed for mammary carcinoma and neuroendocrine markers. RESULTS: We have identified 20 female patients with NET metastases to the breast, 11/235 with small intestinal NETs, 8/55 with lung NETs, and 1/6 with thymic NETs. There were no male patients with NET metastatic to the breast. Four patients had their breast lesion initially diagnosed as mammary carcinoma. Retrospectively, these lesions showed negative staining for mammary carcinoma markers. CONCLUSIONS: Metastases to the breast from neuroendocrine tumors may be more common than previously thought. Patients with a lesion to the breast and symptoms typical for NET may benefit from additional histopathological investigation, because NET metastases and mammary carcinoma have different immunohistochemical profiles.

Lung Carcinoids: A Comprehensive Review for Clinicians.

Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include cough, hemoptysis, wheezing, dyspnea, and recurrent pneumonia. Endocrine symptoms, such as carcinoid syndrome or ectopic Cushing's syndrome, are rare. Surgery is the primary treatment and should be considered in all patients with localized disease, even when thoracic lymph node metastases are present. Patients with distant metastases may be treated with somatostatin analogues, chemotherapy, preferably temozolomide-based, mTOR inhibitors, or peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Most patients have an excellent prognosis. Poor prognostic factors include atypical histology and lymph node metastases at diagnosis. Long-term follow-up is mandatory since metastases may occur late.

Improved health-related quality of life during peptide receptor radionuclide therapy in patients with neuroendocrine tumours.

Neuroendocrine tumours (NETs) can arise in different locations in the body, and may give rise to hormonal symptoms, which amongst other factors may affect patients' health-related quality of life (HRQoL). Up to four cycles of peptide receptor radionuclide therapy (PRRT) have been shown effective for symptom alleviation and prolonging progression-free survival. The aim of this study was to assess the patient's perspective regarding changes in their HRQoL during PRRT. HRQoL was assessed using the questionnaires for cancer in general, EORTC QLQ-C30, and the gastrointestinal NET-specifically EORTC QLQ-GINET21. Patients with NET (n = 204) rated their HRQoL before PRRT cycles one and four. The medical records of patients were reviewed and their HRQoL was compared to a matched reference population (n = 4910). HRQoL was found to improve during PRRT in aspects of global quality of life; role, social, and emotional functioning, and multiple symptom relief. Potential risk groups for worse HRQoL during PRRT were patients with overweight (BMI >25) who completed four cycles of PRRT and older patients (>65 years old). In conclusion, we found that PRRT improves HRQoL in patients with NETs. The results of this study may be used to improve person-centred care.

Minor changes in effective half-life during fractionated 177Lu-octreotate therapy.

AIMS: Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. PATIENTS: Thirty patients, 13 women and 17 men, were included in the study. METHODS: During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. RESULTS: The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively. DISCUSSION: The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). CONCLUSION: With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N.

Background: Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. "A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N" (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule. Methods: The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022. Results: The pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3-5 years. Discussion: In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.

Metastatic Pheochromocytomas and Abdominal Paragangliomas.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas will exhibit metastatic behavior. EVIDENCE ACQUISITION: Extensive searches in the PubMed database with various combinations of the key words pheochromocytoma, paraganglioma, metastatic, malignant, diagnosis, pathology, genetic, and treatment were the basis for the present review. DATA SYNTHESIS: To pinpoint metastatic potential in PPGLs is difficult, but nevertheless crucial for the individual patient to receive tailor-made follow-up and adjuvant treatment following primary surgery. A combination of histological workup and molecular predictive markers can possibly aid the clinicians in this aspect. Most patients with PPGLs have localized disease and may be cured by surgery. Plasma metanephrines are the main biochemical tests. Genetic testing is important, both for counseling and prognostic estimation. Apart from computed tomography and magnetic resonance imaging, molecular imaging using 68Ga-DOTATOC/DOTATATE should be performed. 123I-MIBG scintigraphy may be performed to determine whether 131I-MIBG therapy is a possible option. As first-line treatment in patients with metastatic disease, 177Lu-DOTATATE or 131I-MIBG is recommended, depending on which shows best expression. In patients with very low proliferative activity, watch-and-wait or primary treatment with long-acting somatostatin analogues may be considered. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect. CONCLUSIONS: Metastatic PPGLs need individualized management and should always be discussed in specialized and interdisciplinary tumor boards. Further studies and newer treatment modalities are urgently needed.

Individualized dosimetry in patients undergoing therapy with (177)Lu-DOTA-D-Phe (1)-Tyr (3)-octreotate.

PURPOSE: In recent years, targeted radionuclide therapy with [(177)Lu-DOTA(0), Tyr(3)]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging. METHODS: Attenuation-corrected SPECT data were analysed both by using organ-based volumes of interest (VOIs) to obtain the total radioactivity in the organ, and by using small VOIs to measure the tissue radioactivity concentration. During the first treatment session in 24 patients, imaging was performed 1, 24, 96 and 168 h after [(177)Lu-DOTA(0), Tyr(3)]octreotate infusion. Absorbed doses in non tumour-affected kidney, liver and spleen were calculated and compared for all three methods (planar imaging, SPECT organ VOIs, SPECT small VOIs). RESULTS: Planar and SPECT dosimetry were comparable in areas free of tumours, but due to overlap the planar dosimetry highly overestimated the absorbed dose in organs with tumours. Furthermore, SPECT dosimetry based on small VOIs proved to be more reliable than whole-organ dosimetry. CONCLUSION: We conclude that SPECT dosimetry based on small VOIs is feasible and more accurate than conventional planar dosimetry, and thus may contribute towards optimising targeted radionuclide therapy.

Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut carcinoid tumors.

BACKGROUND: Patients with malignant midgut carcinoids are occasionally diagnosed with limited tumor spread, and surgery with radical intention is performed. Despite curative intent, recurrences occur frequently, motivating long-term biochemical and radiological follow-up. This study aimed to compare the usefulness of various methods in detecting such recurrences. METHODS: This retrospective study included 56 patients with radically operated midgut carcinoids referred to our University Hospital for evaluation and follow-up between 1985 and 2004. Patients were monitored 1-3 times per year using plasma-chromogranin A (P-CgA), urinary 5-hydroxyindoleacetic acid (U-5HIAA) concentrations as well as radiological examinations, including ultrasonography, computerized tomography or magnetic resonance investigation. In a subset of cases, somatostatin receptor scintigraphy and/or positron emission tomography with 5-hydroxytryptophan was performed. Time from operation until established recurrence was recorded. RESULTS: Tumor recurrence was established in 33 of 56 patients after a median of 32 months (range 6-217). Elevated P-CgA was the first marker to become pathologically elevated in 28 of these 33 patients (85%). In 3 of these 28 patients, radiology was simultaneously positive for a recurrence. CONCLUSION: P-CgA was the first marker to indicate tumor recurrence in the majority of radically operated midgut carcinoid patients. To avoid unnecessary and costly examinations in asymptomatic patients, we suggest that follow-up should comprise measurements of P-CgA twice a year and annual ultrasonography until P-CgA is elevated or clinical symptoms occur, at which time all efforts should be made to identify recurrent tumor lesions in order to give the patient the best possible treatment which, if possible, should be surgical removal of the recurrence.

Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.

Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study.

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors.

PURPOSE: A retrospective analysis of the toxicity and efficacy of temozolomide in advanced neuroendocrine tumors. EXPERIMENTAL DESIGN: Thirty-six patients with advanced stages of neuroendocrine tumor (1 gastric, 7 thymic and 13 bronchial carcinoids, 12 pancreatic endocrine tumors, 1 paraganglioma, 1 neuroendocrine foregut, and 1 neuroendocrine cecal cancer) were treated with temozolomide (200 mg/m(2)) for 5 days every 4 weeks. Patients had previously received a mean of 2.4 antitumoral medical regimens. Tumor response was evaluated radiologically according to the Response Evaluation Criteria in Solid Tumors every 3 months on an intent-to-treat basis. The circulating tumor marker plasma chromogranin A was also assessed. The expression of O(6)-methylguanine DNA methyltransferase, an enzyme implicated in chemotherapy resistance, was studied by immunohistochemistry (n=23) and compared with response to temozolomide. RESULTS: Median overall time to progression was 7 months (95% confidence interval, 3-10). Radiologic response was seen in 14% of patients and stable disease in 53%. Side effects were mainly hematologic; 14% experienced grade 3 or 4 thrombocytopenia (National Cancer Institute toxicity criteria). Ten patients had tumors with O(6)-methylguanine DNA methyltransferase immunoreactivity in <10% of nuclei, whereas four patients showed radiologic responses. CONCLUSIONS: Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses.

Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report.

Gastrinomas may occur in the pancreas, duodenum or peripancreatic lymph nodes. The gastrin overproduction leads to the Zollinger-Ellison syndrome with multiple gastric and duodenal ulcers and diarrhea. About two thirds of gastrinomas are malignant. Diagnosis is made by clinical history, gastroscopy, and measurement of serum gastrin, gastric juice pH, CT scan, endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery should always be considered if the liver is not involved. Proton pump inhibitors offer symptomatic relief. Medical therapy for tumor control includes biotherapy with alpha-interferon and somatostatin analogs yielding a response rate of about 10-15%, chemotherapy or targeted radiotherapy. We describe a patient with almost complete response on treatment with Sandostatin LAR, a long-acting somatostatin analog. In patients with metastatic gastrinomas not suitable for chemotherapy, interferon or targeted radiotherapy, single therapy with somatostatin analogs may be an alternative.

Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years.

BACKGROUND: Glucagon-secreting endocrine pancreatic tumor is a rare disease, hence controlled studies on clinical management are lacking. In an attempt to assess the efficacy of diagnostic and therapeutic measures in patients with glucagonoma, a retrospective study was performed using the archives of a tertiary care center. PATIENTS AND METHODS: Records from 340 patients with endocrine pancreatic tumors were reassessed and 23 patients with malignant endocrine pancreatic tumor and elevated plasma glucagon levels were identified. RESULTS: About 7% of patients with histologically verified tumors fullfilled our criteria for glucagonoma. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma. Seventy eight percent had metastatic disease to the liver at diagnosis. Necrolytic migratory erythema was diagnosed or clinically suspected in 52%. Somatostatin receptor scintigraphy was positive in 95%. Nineteen patients received chemotherapy at some point, in 18 cases streptozotocin and 5 FU. With this treatment, objective radiological responses were seen in 50% of evaluable patients. Other treatment modalities used were interferon, somatostatin analogs, hepatic artery embolization, radio-frequency ablation of liver metastases, and radiolabeled somatostatin analogs. During the study period, 11 patients died at a median of 80 months from diagnosis whereas 11 patients are still alive after a median follow up of 52 months. One patient was lost to follow-up. CONCLUSIONS: Glucagonomas represent 7% of our comprehensive referral material of endocrine pancreatic tumors. Necrolytic migratory erythema was a common finding (52%) and diabetes less frequent at presentation than previously reported. Tumors were positive on somatostatin receptor scintigraphy and objective responses were seen to chemotherapy.

Whole-body MRI including diffusion-weighted MRI compared with 5-HTP PET/CT in the detection of neuroendocrine tumors.

AIM: We wanted to explore if whole-body magnetic resonance imaging (MRI) including diffusion-weighted (DW) and liver-specific contrast agent-enhanced imaging could be valuable in lesion detection of neuroendocrine tumors (NET). [11C]-5-Hydroxytryptophan positron emission tomography/computed tomography (5-HTP PET/CT) was used for comparison. MATERIALS AND METHODS: Twenty-one patients with NET were investigated with whole-body MRI, including DW imaging (DWI) and contrast-enhanced imaging of the liver, and whole-body 5-HTP PET/CT. Seven additional patients underwent upper abdomen MRI including DWI, liver-specific contrast agent-enhanced imaging, and 5-HTP PET/CT. RESULTS: There was a patient-based concordance of 61% and a lesion-based concordance of 53% between the modalities. MRI showed good concordance with PET in detecting bone metastases but was less sensitive in detecting metastases in mediastinal lymph nodes. MRI detected more liver metastases than 5-HTP PET/CT. CONCLUSION: Whole-body MRI with DWI did not detect all NET lesions found with whole-body 5-HTP PET/CT. Our findings indicate that MRI of the liver including liver-specific contrast agent-enhanced imaging and DWI could be a useful complement to whole-body 5-HTP PET/CT.