Dorota Kendler

68Ga-DOTA-Tyr3-Octreotide PET in Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and CT

The aim of this study was to evaluate the diagnostic value of a new somatostatin analog, 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTA-TOC), for PET in patients with known or suspected neuroendocrine tumors. PET was compared with conventional scintigraphy and dedicated CT. Methods: Eighty-four patients (48 men, 36 women; age range, 28–79 y; mean age ± SD, 58.2 ± 12.2 y) were prospectively studied. For analysis, patients were divided into 3 groups: detection of unknown primary tumor in the presence of clinical or biochemical suspicion of neuroendocrine malignancy (n = 13 patients), initial tumor staging (n = 36 patients), and follow-up after therapy (n = 35 patients). Each patient received 100–150 MBq 68Ga-DOTA-TOC. Imaging results of PET were compared with 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) and 111In-DOTA-TOC. CT was also performed on every patient using a multidetector scanner. Each imaging modality was interpreted separately by observers who were unaware of imaging findings before comparison with PET. The gold standard for defining true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) results was based on all available histologic, imaging, and follow-up findings. Results: PET was TP in 69 patients, TN in 12 patients, FP in 1 patient, and FN in 2 patients, indicating a sensitivity of 97%, a specificity of 92%, and an accuracy of 96%. The FP finding was caused by enhanced tracer accumulation in the pancreatic head, and the FN results were obtained in patients with a tumor of the gastrointestinal tract displaying liver metastases. 68Ga-DOTA-TOC showed higher diagnostic efficacy compared with SPECT (TP in 37 patients, TN in 12 patients, FP in 1 patient, and FN in 34 patients) and diagnostic CT (TP in 41 patients, TN in 12 patients, FP in 5 patients, and FN in 26 patients). This difference was of statistical significance (P < 0.001). However, the combined use of PET and CT showed the highest overall accuracy. Conclusion: 68Ga-DOTA-TOC PET shows a significantly higher detection rate compared with conventional somatostatin receptor scintigraphy and diagnostic CT with clinical impact in a considerable number of patients.

Bone Metastases in Patients with Neuroendocrine Tumor: 68Ga-DOTA-Tyr3-Octreotide PET in Comparison to CT and Bone Scintigraphy

Somatostatin receptor scintigraphy is an accurate imaging modality for the diagnosis of neuroendocrine tumor. Because detection of distant metastases has a major impact on treatment, early diagnosis of metastatic spread is of great importance. So far, no standard procedure has become established for the early diagnosis of bone metastases from neuroendocrine tumor. We compared the diagnostic value of CT with that of the novel somatostatin analog 68Ga-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′′′-tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTATOC) in the detection of such metastases. Methods: Fifty-one patients (22 women and 29 men; age range, 32–87 y) with histologically verified neuroendocrine tumor were included in this study. PET scans were fused with CT scans using a vacuum fixation device. 18F-NaF or 99mTc-dicarboxypropane diphosphonate bone scans or clinical follow-up served as the reference standard. Results: Twelve of the 51 patients had no evidence of bone metastases on any of the available imaging modalities, and 37 patients had 68Ga-DOTATOC PET results true-positive for bone metastases. 68Ga-DOTATOC PET results were true-negative for 12 patients, false-positive for one, and false-negative for another, resulting in a sensitivity of 97% and a specificity of 92%. 68Ga-DOTATOC PET detected bone metastases at a significantly higher rate than did CT (P < 0.001). Furthermore, conventional bone scans confirmed the results of somatostatin receptor PET but did not reveal additional tumors in any patients. Conclusion: 68Ga-DOTATOC PET is a reliable, novel method for the early detection of bone metastases in patients with neuroendocrine tumor. Our results show that CT and conventional bone scintigraphy are less accurate than 68Ga-DOTATOC PET in the primary staging or restaging of neuroendocrine tumor.

68Ga-DOTA-Tyr3-Octreotide PET for Assessing Response to Somatostatin-Receptor–Mediated Radionuclide Therapy

68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid-d-Phe1-Tyr3-octreotide (DOTA-TOC) PET has proven its usefulness in the diagnosis of patients with neuroendocrine tumors. Radionuclide therapy (90Y-DOTA-TOC or 177Lu-DOTA-octreotate) is a choice of treatment that also requires an accurate diagnostic modality for early evaluation of treatment response. Our study compared 68Ga-DOTA-TOC PET with CT or MRI using the Response Evaluation Criteria in Solid Tumors. Furthermore, standardized uptake values (SUVs) were calculated and compared with treatment outcome. Methods: Forty-six patients (29 men, 17 women; age range, 34–84 y) with advanced neuroendocrine tumors were investigated before and after 2–7 cycles of radionuclide therapy. Long-acting somatostatin analogs were not applied for at least 6 wk preceding the follow-up. Data were acquired with a dedicated PET scanner. Emission image sets were acquired at 90–100 min after injection. 68Ga-DOTA-TOC PET images were visually interpreted by 2 experienced nuclear medicine physicians. For comparison, multislice helical CT scans and 1.5-T MRI scans were obtained. Attenuation-corrected PET images were used to determine SUVs. Repeated CT evaluation and other imaging modalities, for example, 18F-FDG, were used as the reference standard. Results: According to the reference standard, 68Ga-DOTA-TOC PET and CT showed a concordant result in 32 patients (70%). In the remaining 14 patients (30%), discrepancies were observed, with a final outcome of progressive disease in 9 patients and remission in 5 patients. 68Ga-DOTA-TOC PET was correct in 10 patients (21.7%), including 5 patients with progressive disease. In these patients, metastatic spread was detected with the follow-up whole-body PET but was missed when concomitant CT was used. On the other hand, CT confirmed small pulmonary metastases not detected on 68Ga-DOTA-TOC in 1 patient and progressive liver disease not detected on 68Ga-DOTA-TOC in 3 patients. Quantitative SUV analysis of individual tumor lesions showed a large range of variability. Conclusion: 68Ga-DOTA-TOC PET shows no advantage over conventional anatomic imaging for assessing response to therapy when all CT information obtained during follow-up is compared. Only the development of new metastases during therapy was detected earlier in some cases when whole-body PET was used. SUV analysis of individual lesions is of no additional value in predicting individual responses to therapy.

Role of radiopharmaceuticals in the diagnosis and treatment of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms characterised by their endocrine metabolism and histological pattern, originating mainly from the gastroenteropancreatic tract (GEP NETs). As opposed to other tumour entities GEP NETs are relatively rare tumours and their diagnosis requires a high index of suspicion. NETs characteristically synthesise, store and secrete a variety of peptides and neuroamines which may lead to clinical syndromes such as the carcinoid syndrome, the Zollinger Ellison syndrome, or the Verner Morrison syndrome [1,2]. However, most GEP NETs are clinically silent until late presentation with metastases. In fact, a delayed diagnosis of NET is typical, resulting in excessive morbidity and mortality and increased probability of metastatic disease. A multidisciplinary approach for therapeutic intervention is necessary. On initial clinical presentation, NETs may be difficult to diagnose because of the large variability in tumour location and the high frequency of small lesions. The proliferation marker Ki-67 (MIB-1) is important in determining tumour grade and prognosis. Once metastasised, the therapeutic options for patients with NETs are limited. Treatment with long-acting somatostatin (SST) analogues results in reduced hormonal (over)production, and thus, relief of symptoms. Surgery is the therapy of choice in localised disease. Chemoembolisation of primary tumour/liver metastases can be attempted in order to reduce the tumour mass for subsequent therapy with radiolabelled peptide analogues in patients with slowgrowing tumours. In patients with poorly differentiated tumours chemotherapy may be considered [3]. However, the management options are manifold, and there are only a few evidence-based controlled studies available. Furthermore, formal guidelines are required. One should be aware that not all centres have the same treatment approach. For example, some believe that the long-acting SST analogues exert a beneficial effect even when the patient does not have symptoms. Positive effects of long-acting octreotide on tumour progression were assessed in the PROMID study recently [4]. In addition, there is not a general agreement as to the scope and timing of tumour debulking surgery and/or chemoembolisation [1]. The assessment of the location and extent of NETs is crucial for clinical management. Although being a heterogeneous group of neoplasms, NETs are characterised by their ability to over-express SST receptors (SSTR) at the cell surface. For localisation, conventional SSTR scintigraphy/positron emission tomography (PET), computed tomograhpy (CT)/magnetic resonance imaging (MRI), fused PET/CT or PET/MRI imaging, endoscopic ultrasound, arterial stimulation and venous sampling are used [5–8]. Other nuclear medicine techniques are also available for rare NETs. Here, we give an overview of the clinical value of radiopharmaceuticals used for diagnosis and treatment of NET patients.

[18F]choline positron emission tomography in prostate cancer patients with biochemical recurrence after radical prostatectomy: influence of antiandrogen therapy - a preliminary study.

ObjectiveOur purpose was to evaluate whether antiandrogen therapy (AAT) influences [18F]choline PET results in patients with biochemical recurrence after radical prostatectomy (RPE). MethodsThrough a retrospective study we evaluated two groups of patients, both with histologically proven carcinoma of the prostate, who had undergone RPE and a subsequent [18F]choline PET because of biochemical failure (<4 ng/dl). One group consisted of 13 patients under AAT at the time of the PET examination (age range, 55–80 years; median, 68). The other group who had not undergone AAT consisted of 22 patients (age range, 48–72 years; median, 67). Our results were correlated with follow-up information related to histopathology, changes in prostate-specific antigen levels, other imaging modalities and clinical examination. Mean follow-up was 27 months. ResultsIn patients who had undergone AAT, [18F]choline PET was true positive in eight out of 10 patients. The overall sensitivity in this group was 80%. In two cases [18F]choline PET turned out to be false negative, missing local relapse. Of the patients treated only with RPE, 10 out of 20 turned out to be true positive, resulting in a sensitivity of 50%.In all, in four patients biochemical recurrence could not be correlated to pathological findings in any of the available modalities. The difference in sensitivity between patients with and without AAT was statistically not significant (P=0.235). ConclusionIn patients with biochemical recurrence during AAT after RPE, [18F]choline PET can yield true-positive findings, even at prostate-specific antigen values of less than 4 ng/dl, and is an accurate technique for the detection of recurrence.

First experience with proteasome inhibitor treatment of radioiodine nonavid thyroid cancer using bortezomib.

PURPOSE Radioiodine nonavid thyroid cancer (TC) is a rare disease entity with a poor prognosis. Despite a multimodal therapeutic approach including surgery, chemotherapy, and external beam radiation, radioiodine nonavid TC accounts for a high number of TC-associated deaths. The aim of this investigation was to evaluate the response rate of progressive TC patients to treatment with the proteasome inhibitor bortezomib. MATERIALS AND METHODS Seven patients with inoperable, metastasized progressive TC proven to be radioiodine nonavid were included into this pilot study. Patients received bortezomib intravenously with a standardized dose of 1.3 mg/m on days 1, 4, 8, and 11. All patients underwent 3 therapeutic cycles with an interval of 10 days. [F]2-deoxy-2-fluoro-D-glucose positron emission tomography (F-FDG PET) and measurements of thyroglobulin levels were performed before, during, and after therapy, with a 6-week interval to post-therapeutic follow-up. RESULTS Stable disease was seen after proteasome inhibitor therapy in 4 of the 7 patients. Two of the 7 patients showed decrease of maximum standardized uptake value in both post-therapeutic follow-up investigations, and one of these cases also had decreasing thyroglobulin levels. Two patients experienced stable disease during the posttherapeutic follow-up. Two patients showing a mixed response had an improvement in their clinical situation. One patient had rapidly progressive disease, and died 3 months after the last therapeutic cycle. Adverse events included mild polyneuropathy in 2 patients and alterations of the blood count up to WHO (World Health Organization) grade 2 in 5 patients. CONCLUSION Proteasome inhibitor treatment with bortezomib is a promising therapeutic approach in TC patients without an established treatment alternative. The development of a specific therapeutic regimen for the treatment of radioiodine nonavid TC is warranted.

An individual dosimetric approach to 153Sm-EDTMP therapy for pain palliation in bone metastases in correlation with clinical results.

BackgroundThe clinical results of therapy using 153Sm ethylenediamine-N,N,N′N′-tetrakis(methylene phosphonic acid) (153Sm-EDTMP) were correlated with radiation dose indices in metastases, with the intention of improving the therapeutic efficacy. MethodsFifty-six patients with disseminated bone metastases were treated. Prior to therapy, whole-body scans and single photon emission computed tomography (SPECT) of the trunk were performed. Whole-body retention of 99mTc labelled phosphonates was compared with 153Sm-EDTMP retention after therapy. Estimations of the volumes of bone lesions were done by SPECT. Assuming a solid tumour but a thin metabolically active boundary zone between tumour and healthy bone that absorbed the beta radiation, we estimated an ‘irradiated volume’ by using a spherical shell model of 6 mm thickness. Local tracer uptake in lesions was assessed by regions of interest techniques on conjugated views of whole-body scans with homogenous attenuation correction. Calculation of the dose index by applying the Medical Internal Radiation Dosimetry (MIRD) scheme was done retrospectively in 10 patients and prospectively in 22 cases. Depending on changes in pain/mobility scores, results were classified as ‘very good’, ‘good’ and ‘no response’. ResultsA mean dose index ≥10 per lesion was estimated under the condition of a homogenous uptake within the idealized, spherical, tumour volume. Assuming that the uptake of the radiopharmaceutical occurs mostly within an outer shell of the tumour, dose indices to this ‘irradiated volume’ can increase to more than twice that value. ConclusionVery good clinical results for bone pain palliation by using 153Sm-EDTMP therapy could be found in patients receiving a dose index >15 per lesion. Even this approximate dosimetric approach, considering the individual differences in tumour spread and the varying intensity of 153Sm uptake, could improve the impact of 153Sm-EDTMP for pain control in cancer patients.

Detection of Sarcomatoid Lung Metastasis With 68GA-PSMA PET/CT in a Patient With Prostate Cancer.

A 70-year-old man with prostate cancer (adenocarcinoma; pT3aN0Mx; GS: 4 + 4) underwent radical prostatectomy and lymph node dissection in February 2008. In December 2009, biochemical recurrence occurred and prostate-specific antigen progressively increased to 4.63 ng/mL despite local salvage radiotherapy and androgen deprivation. Ga-PSMA PET/CT showed a positive left iliac lymph node and a pathological left pulmonary lesion, which was highly positive in a subsequent F-FDG PET/CT. Lymph node resection confirmed an adenocarcinoma metastasis of the prostate cancer and lung surgery demonstrated a sarcomatoid metastasis of prostate cancer. After surgery, prostate-specific antigen decreased to 0.03 ng/mL.

153SM-EDTMP for Pain Relief in Malignant and Benign Bone and Joint Diseases

Management of bone pain in patients with disseminated skeletal metastases and also in patients with widespread benign inflammatory joint diseases unresponsive to all conventional treatment is a significant clinical problem.

Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study)

Background Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles. Methods Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2) and docetaxel (75 mg/m2 d1) q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly). The primary endpoint was radiological response according to RECIST. Results 40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95%) underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months. Conclusions Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected. Trial Registration EU Clinical Trials Register; Eudract-Nr: 2006-004639-31