Evaluation of reconstruction methods and image noise levels concerning visual assessment of simulated liver lesions in 111In-octreotide SPECT imaging.

BACKGROUND: Early cancer detection is crucial for patients' survival. The image quality in 111In-octreotide SPECT imaging could be improved by using Monte Carlo (MC)-based reconstruction. The aim of this observational study was to determine the detection rate of simulated liver lesions for MC-based ordered subset expectation maximization (OSEM) reconstruction compared to conventional attenuation-corrected OSEM reconstruction. METHODS: Thirty-seven SPECT/CT examinations with 111In-octreotide were randomly selected. The inclusion criterion was no liver lesions at the time of examination and for the following 3 years. SPECT images of spheres representing lesions were simulated using MC. The raw data of the spheres were added to the raw data of the established healthy patients in 26 of the examinations, and the remaining 11 examinations were not modified. The images were reconstructed using conventional OSEM reconstruction with attenuation correction and post filtering (fAC OSEM) and MC-based OSEM reconstruction without and with post filtering (MC OSEM and fMC OSEM, respectively). The images were visually and blindly evaluated by a nuclear medicine specialist. The criteria evaluated were liver lesion yes or no, including coordinates if yes, with confidence level 1-3. The percentage of detected lesions and accuracy (percentage of correctly classified cases), as well as tumor-to-normal tissue concentration (TNC) ratios and signal-to-noise ratios (SNRs), were evaluated. RESULTS: The detection rates were 30.8% for fAC OSEM, 42.3% for fMC OSEM, and 50.0% for MC OSEM. The accuracies were 45.9% for fAC OSEM, 45.9% for fMC OSEM, and 54.1% for MC OSEM. The number of false positives was higher for fMC and MC OSEM. The observer's confidence level was higher in filtered images than in unfiltered images. TNC ratios were significantly higher, statistically, with MC OSEM and fMC OSEM than with AC OSEM, but SNRs were similar due to higher noise with MC OSEM. CONCLUSION: One in two lesions were found using MC OSEM versus one in three using conventional reconstruction. TNC ratios were significantly improved, statistically, using MC-based reconstruction, but the noise levels increased and consequently the confidence level of the observer decreased. For further improvements, image noise needs to be suppressed.

Incidental cardiac findings on somatostatin receptor PET/CT: What do they indicate and are they of clinical relevance?

We present the case of a 47-year-old man with a history of recurrent episodes of frontal headache, fever, and chest discomfort as well as longstanding, difficult to treat arterial hypertension. Clinical work-up revealed the unexpected finding of an underlying pheochromocytoma as well as recent "silent" myocardial infarction. Our case highlights the importance of paying attention to incidental cardiac findings on somatostatin receptor positron emission tomography/computed tomography, as routinely performed in patients with clinically suspected neuroendocrine tumors. These incidental cardiac findings cannot only indicate a primary or secondary (metastatic) neuroendocrine tumor, but also areas of myocardial inflammation, as somatostatin receptors cannot only be found on the majority of neuroendocrine tumors, but also among other tissues on the surface of activated macrophages and lymphocytes. The detection of myocardial inflammation is of clinical importance and its underlying etiology should be evaluated to prompt eventual necessary treatment, as it is a potential driving force for cardiac remodeling and poor prognosis.

ACTIVITY CONCENTRATION ESTIMATION IN AUTOMATED KIDNEY SEGMENTATION BASED ON CONVOLUTION NEURAL NETWORK METHOD FOR 177LU-SPECT/CT KIDNEY DOSIMETRY.

For 177Lu-DOTATATE treatments, dosimetry based on manual kidney segmentation from computed tomography (CT) is accurate but time consuming and might be affected by misregistration between CT and SPECT images. This study develops a convolution neural network (CNN) for automated kidney segmentation that accurately aligns CT segmented volume of interest (VOI) to the kidneys in SPECT images. The CNN was trained with SPECT/CT images performed over the abdominal area of 137 patients treated with 177Lu-DOTATATE. Activity concentrations in automated and manual segmentations were strongly correlated for both kidneys (r > 0.96, p < 0.01) in the testing cohort (n = 20). The Bland-Altman analyses demonstrated higher accuracy for the CNN segmentation compared to the manual segmented kidneys without VOI adjustment. The CNN demonstrated a potential for accurate kidney segmentation. The CNN was a fast and robust approach for assessment of activity concentrations in SPECT images, and performed equally well as the manual segmentation method.

EVALUATION OF THE SPATIAL RESOLUTION IN MONTE CARLO-BASED SPECT/CT RECONSTRUCTION OF 111IN-OCTREOTIDE IMAGES.

The purpose was to evaluate the spatial resolution in 111In-octreotide single-photom emission computed tomography (SPECT)/computed tomography (CT) imaging following reconstructions with three different ordered subset expectation maximizations (OSEM) reconstruction algorithms; attenuation corrected (AC) OSEM, AC OSEM with resolution recovery (ACRR OSEM) and Monte Carlo-based OSEM reconstruction (MC OSEM). SPECT/CT imaging of a triple line phantom containing 111In in air and water was performed. The spatial resolution, represented by the full width at half maximum (FWHM) of a line profile, was determined for each line, for X and Y direction and for all reconstructions. The mean FWHM was 12.2 mm (±standard deviation [SD] 3.7 mm) for AC OSEM, 9.3 mm (±SD 2.5 mm) for ACRR OSEM and 8.2 mm (±SD 2.0 mm) for MC OSEM. MC-based SPECT/CT reconstruction clearly improves the spatial resolution in 111In-octreotide imaging and since MC simulations can be performed for all photon energies MC OSEM has the potential to improve SPECT/CT imaging overall.

Deep-Learning Generation of Synthetic Intermediate Projections Improves 177Lu SPECT Images Reconstructed with Sparsely Acquired Projections.

The aims of this study were to decrease the 177Lu-SPECT acquisition time by reducing the number of projections and to circumvent image degradation by adding deep-learning-generated synthesized projections. Methods: We constructed a deep convolutional U-net-shaped neural network for generation of synthetic intermediate projections (CUSIPs). The number of SPECT investigations was 352 for training, 37 for validation, and 15 for testing. The input was every fourth projection of 120 acquired SPECT projections, that is, 30 projections. The output was 30 synthetic intermediate projections (SIPs) per CUSIP. SPECT images were reconstructed with 120 or 30 projections, or with 120 projections when 90 SIPs were generated from 30 projections (30-120SIPs), using 3 CUSIPs. The reconstructions were performed with 2 ordered-subset expectation maximization (OSEM) algorithms: attenuation-corrected (AC) OSEM, and attenuation, scatter, and collimator response-corrected (ASCC) OSEM. The quality of the SIPs and SPECT images was quantitatively evaluated with root-mean-square error, peak signal-to-noise ratio (PSNR), and structural similarity (SSIM) index metrics. From a Jaszczak SPECT phantom, the recovery and signal-to-noise ratio (SNR) were determined. In addition, an experienced observer qualitatively assessed the SPECT image quality of the test set. Kidney activity concentrations, as determined from the different SPECT images, were compared. Results: The generated SIPs had a mean SSIM value of 0.926 (SD, 0.061). For AC-OSEM, the reconstruction with 30-120SIPs had higher SSIM (0.993 vs. 0.989, P < 0.001) and PSNR (49.5 vs. 47.2, P < 0.001) values than the reconstruction with 30 projections. ASCC-OSEM had higher SSIM and PSNR values than AC-OSEM (P < 0.001). There was a minor loss in recovery for 30-120SIPs, but SNR was clearly improved compared with 30 projections. The observer assessed 27 of 30 images reconstructed with 30 projections as having unacceptable noise levels, whereas the corresponding values were 2 of 60 for 30-120SIPs and 120 projections. Image quality did not differ significantly between 30-120SIPs and 120 projections. The kidney activity concentration was similar between the different projection sets, excepting a minor reduction of 2.5% for ASCC-OSEM 30-120SIPs. Conclusion: Adopting SIPs for sparsely acquired projections considerably recovers image quality and could allow a reduced SPECT acquisition time in clinical dosimetry protocols.

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During 177Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases.

This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose-response relationship during treatment with 177Lu-DOTATATE in patients with and without skeletal metastases. Methods: This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of 177Lu-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection. The bone marrow absorbed doses were calculated from the cross doses of the high- and low-uptake compartments and the self-dose, using the time-activity concentration curve for the low-uptake compartment. This time-activity concentration curve was adjusted using a fixed constant of 1.8 for the planar dosimetry method and using the activity concentrations in vertebral bodies in SPECT images at 24 h after injection of 177Lu-DOTATATE in 4 hybrid methods: L4-SPECT used the activity concentration in the L4 vertebra, whereas V-SPECT, L-SPECT, and T-SPECT used the median activity concentration in all visible vertebrae, lumbar vertebrae, and thoracic vertebrae, respectively. Results: Using the planar method, L4-SPECT, V-SPECT, L-SPECT, and T-SPECT, the estimated median bone marrow absorbed doses were 0.19, 0.36, 0.40, 0.39, and 0.46 Gy/7.4 GBq, respectively, with respective ranges of 0.12-0.33, 0.15-1.44, 0.19-1.71, 0.21-1.60, and 0.18-2.12 Gy/7.4 GBq. For all methods, the bone marrow absorbed dose significantly correlated with decreased platelet counts. This correlation increased after treatment fraction 2: the Spearman correlation (rs) were -0.49 for the planar method, -0.61 for L4-SPECT, -0.63 for V-SPECT, -0.63 for L-SPECT, and -0.57 for T-SPECT. A separate analysis revealed an increased correlation for patients without skeletal metastases using the planar method (rs = -0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (rs = -0.61 to -0.74). The mean bone marrow absorbed doses were 3%-69% higher for patients with skeletal metastases than for patients without. Conclusion: The estimated bone marrow absorbed doses by image-based techniques and the correlation with platelets are influenced by the choice of measured vertebrae and the presence of skeletal metastases.

18F-FDG PET/CT in the diagnosis of prosthetic valve endocarditis.

Recent studies have shown promising results using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the diagnosis of prosthetic valve endocarditis (PVE). However, previous studies did not include negative controls. The aim of this study was to compare (18)F-FDG-uptake around prosthetic aortic valves in patients with and without PVE and to determine the diagnostic performance of (18)F-FDG PET/CT in the diagnosis of PVE. (18)F-FDG PET/CT examinations in patients with a prosthetic aortic valve performed 2008-2014 were retrieved. Eight patients with a final diagnosis of definite PVE were included in the analysis of the diagnostic performance of (18)F-FDG PET/CT. Examinations performed on suspicion of malignancy in patients without PVE (n = 19) were used as negative controls. Visual and semi-quantitative analysis was performed. Maximal standardized uptake value (SUVmax) in the valve area was measured and SUVratio was calculated by dividing valve SUVmax by SUVmax in the descending aorta. The sensitivity was 75 %, specificity 84 %, positive likelihood ratio [LR(+)] 4.8 and negative likelihood ratio [LR(-)] 0.3 on visual analysis. Both SUVmax and SUVratio were significantly higher in PVE patients [5.8 (IQR 3.5-6.5) and 2.4 (IQR 1.7-3.0)] compared to non-PVE patients [3.2 (IQR 2.8-3.8) and 1.5 (IQR 1.3-1.6)] (p < 0.001). ROC-curve analysis of SUVratio yielded an area under the curve of 0.90 (95 % CI 0.74-1.0). (18)F-FDG-uptake around non-infected aortic prosthetic valves was low. The level of (18)F-FDG-uptake in the prosthetic valve area showed a good diagnostic performance in the diagnosis of PVE.

Neuroendocrine tumours: the role of imaging for diagnosis and therapy.

In patients with neuroendocrine tumours (NETs), a combination of morphological imaging and nuclear medicine techniques is mandatory for primary tumour visualization, staging and evaluation of somatostatin receptor status. CT and MRI are well-suited for discerning small lesions that might escape detection by single photon emission tomography (SPECT) or PET, as well as for assessing the local invasiveness of the tumour or the response to therapy. Somatostatin receptor imaging, by (111)In-pentetreotide scintigraphy or PET with (68)Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with (111)In-pentetreotide is the more frequently available of the two techniques to determine somatostatin receptor expression and is needed to select patients for peptide receptor radionuclide therapy. In the future, because of its higher sensitivity, PET with (68)Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas (18)F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with (18)F-dihydroxy-L-phenylalanine or (11)C-5-hydroxy-L-tryptophan is a useful problem-solving tool and could be considered for the evaluation of therapy response in the future. This article reviews the role of imaging for the diagnosis and management of intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed.

Unnecessary surgery for acute abdomen secondary to angiotensin-converting enzyme inhibitor use.

Acute abdominal pain is the reason for 5% to 10% of all emergency department visits. In 1 in every 9 patients, operated on for an acute abdomen, laparotomy is negative. In a minority of patients, the acute abdomen is caused by side effects of medication. We present a case of unnecessary abdominal surgery in a patient with acute abdominal pain caused by intestinal angioedema (AE), which was eventually due to angiotensin-converting enzyme inhibitor (ACE-i) use. We hope that this case report increases awareness of this underdiagnosed side effect. Emergency department physicians, surgeons, internists, and family physicians should always consider ACE-i in the differential diagnosis of unexplained abdominal pain. Since early withdrawal of the medication causing intestinal AE can prevent further complications and, in some cases, needless surgery, we propose an altered version of the known diagnostic algorithm, in which ACE-i and nonsteroidal anti-inflammatory drugs-induced AE is excluded at an early stage.

Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate.

UNLABELLED: Quality of life (QOL) is an important outcome in cancer therapy. In this study, we investigated the QOL and symptoms after [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-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 (177)Lu-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 (177)Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients' self-assessed QOL.

Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors.

Somatostatin receptor imaging with [(111)In-DTPA(0))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 all (111)In, (90)Y, or (177)Lu-labeled somatostatin analogues that have been used for peptide receptor radionuclide therapy. The results that were obtained with [(90)Y-DOTA(0), Tyr(3)]octreotide and [(177)Lu-DOTA(0), Tyr(3)]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 [(177)Lu-DOTA(0), Tyr(3)]octreotate. Finally, compared with historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [(177)Lu-DOTA(0), Tyr(3)]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.

Salvage therapy with (177)Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors.

UNLABELLED: Regular therapy with the radiolabeled somatostatin analog (177)Lu-octreotate (22.2-29.6 GBq) in patients with gastroenteropancreatic or bronchial neuroendocrine tumors results in tumor remission in 46% of patients, including minor response. We present the effects of additional therapy with (177)Lu-octreotate in patients in whom progressive disease developed after an initial benefit from regular therapy. METHODS: Thirty-three patients with progressive disease after an initial radiologic or clinical response were treated with additional cycles of (177)Lu-octreotate. The intended cumulative dose of additional therapy was 14.8 GBq in 2 cycles. Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of >or=25% and <50%). RESULTS: Median time to progression (TTP) after regular therapy was 27 mo. In 4 patients, the intended cumulative dose was not achieved (2 had progressive disease, 2 had long-lasting thrombocytopenia). Hematologic toxicity grade 3 was observed in 4 patients, and grade 4, in 1. The median follow-up time was 16 mo (range, 1-40 mo). No kidney failure or myelodysplastic syndrome was observed. Renewed tumor regression was observed in 8 patients (2 partial remission, 6 minor response), and 8 patients had stable disease. Median TTP was 17 mo. Treatment outcome was less favorable in patients with a short TTP after regular cycles. Treatment effects in patients with pancreatic neuroendocrine tumors were similar to those in patients with other gastroenteropancreatic neuroendocrine tumors. CONCLUSION: Most patients tolerated additional cycles with (177)Lu-octreotate well. None developed serious delayed adverse events. Additional cycles with (177)Lu-octreotate can have antitumor effects, but effects were less than for the regular cycles. This may be because of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. We conclude that this salvage therapy can be effective and is safe.

Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors.

Somatostatin receptor imaging (SRI) with [(111)In-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 [(68)Ga-DOTA(0),Tyr(3)]octreotate or [(68)Ga-DOTA(0),Tyr(3)]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 (111)In-, (90)Y-, or (177)Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]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 [(177)Lu-DOTA(0),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 [(177)Lu-DOTA(0),Tyr(3)]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 for endocrine tumors.

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

Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,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.

Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours.

PURPOSE: Treatment with the radiolabelled somatostatin analogue (177)Lu-octreotate results in tumour remission in 47% of patients with gastroenteropancreatic neuroendocrine tumours. Adding capecitabine to (177)Lu-octreotate, as a radio-sensitiser, may enhance these anti-tumour effects. We now present the short-term toxicity profile of this novel combination. METHODS: Seven patients were treated with 7.4 GBq (177)Lu-octreotate and capecitabine (1650 mg/m(2) per day) for 2 weeks with an intended number of four cycles. Toxicity, and especially haematological and renal parameters, were monitored on a weekly basis for the first two cycles and 4 and 6 weeks after subsequent cycles. RESULTS: None of the patients had hand-foot syndrome. One patient had grade 1 stomatitis occurring after one of four cycles. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia, but none had grade 4 anaemia. One patient had grade 2 thrombocytopenia after the fourth cycle, and one had grade 3 thrombocytopenia. Grade 4 thrombocytopenia did not occur. No significant changes in serum creatinine levels were observed. None of the patients had symptoms of cardiac ischaemia. CONCLUSIONS: Treatment with the combination of (177)Lu-octreotate and capecitabine was feasible and safe considering acute and subacute side effects. We therefore started a randomised, controlled clinical trial to compare this combination with (177)Lu-octreotate as single agent with regard to anti-tumour effects and side effects.

Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate.

INTRODUCTION: Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). MATERIALS AND METHODS: All (177)Lu-octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. RESULTS: Four hundred seventy-nine patients received a total of 1,693 administrations of (177)Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of (177)Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. CONCLUSION: Hormonal crises after (177)Lu-octreotate therapy occur in 1% of patients. Generally, (177)Lu-octreotate therapy is well tolerated.

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 (111)In, (90)Y, or (177)Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with (111)Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like (90)Y and (177)Lu were developed. Reported anti-tumour effects of [(90)Y-DOTA(0),Tyr(3)]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [(177)Lu-DOTA(0),Tyr(3)]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 [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [(177)Lu-DOTA(0),Tyr(3)]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.