Håkan Örlefors

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/m2) 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 O6-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 O6-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.

Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors.

PURPOSE Carcinoid tumors, especially those of midgut origin, produce serotonin via the precursors tryptophan and 5-hydroxytryptophan (5-HTP). We have evaluated the usefulness of positron emission tomography (PET) with carbon-11-labeled 5-HTP in the diagnosis and treatment follow-up evaluation of patients with neuroendocrine tumors. PATIENTS AND METHODS PET using 11C-labeled 5-HTP was compared with computed tomography (CT) in 18 patients (14 midgut, one foregut, one hindgut carcinoid, and two endocrine pancreatic tumors [EPT]). In addition, 10 of 18 patients were monitored with PET examinations during treatment. RESULTS All 18 patients, including two with normal urinary 5-hydroxyindole acetic acid (U-5-HIAA), had increased uptake of 11C-labeled 5-HTP in tumorous tissue as compared with normal tissue. Liver metastases, as well as lymph node, pleural, and skeletal metastases, showed enhanced 5-HTP uptake and PET could detect more lesions than CT in 10 patients and equal numbers in the others. Tumor visibility was better for PET than for CT due to the high and selective uptake of 5-HTP with a high tumor-to-background ratio. Binding studies indicated an irreversible trapping of 5-HTP in the tumors. Linear regression analyses showed a clear correlation (r = .907) between changes in U-5-HIAA and changes in the transport rate constant for 5-HTP during treatment. CONCLUSION PET with 11C-labeled 5-HTP demonstrated high uptake in neuroendocrine gastrointestinal tumors and thereby allowed improved visualization compared with CT. The in vivo data on regional tumor metabolism, as expressed in 11C-5-HTP uptake and transport rate, provided additional information over conventional radiologic techniques. The close correlation between the changes in 11C-5-HTP transport rate and U-HIAA during medical treatment indicates the potential of 11C-5-HTP-PET as a means to monitor therapy.

The role of PET in localization of neuroendocrine and adrenocortical tumors.

Abstract: Positron emission tomography (PET) supplies a range of labeled compounds to be used for the characterization of tumor biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow up, and clinical research. The first routinely used PET tracer in oncology, 18F‐labeled deoxyglucose (FDG), was successfully used for diagnosis of cancer, reflecting increased expression of glucose transporter in cancerous tissue. This tracer, however, usually does not show sufficient uptake in well‐differentiated tumors such as neuroendocrine tumors. We developed a tracer more specific to neuroendocrine tumors—the serotonin precursor 5‐hydroxytryptophan (5‐HTP) labeled with 11C—and demonstrated increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was so selective and the resolution was so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. To further improve the method, especially to reduce the high renal excretion of the tracer producing streaky artifacts in the area of interest, we introduced premedication by the decarboxylase inhibitor carbidopa, leading to a six‐fold decreased renal excretion while the tumor uptake increased three‐fold, hence improving the visualization of the tumors.

Bilateral Adrenalectomy for Ectopic Cushing’s Syndrome—Discussions on Technique and Indication

BackgroundTumors producing adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) often remain undiagnosed until severe Cushing’s syndrome appears, and it may be difficult to distinguish from Cushing’s syndrome due to pituitary tumors. Many patients suffer from disease spread, with metastases in the liver or other locations, and the main symptoms may be mineral disturbances, diabetes mellitus, or psychological symptoms from the severe hypercortisolism. Bilateral adrenalectomy may alleviate this situation, but is sometimes a troublesome procedure in these severely ill patients.MethodsWe have retrospectively investigated 8 patients with ectopic Cushing’s syndrome who have undergone bilateral adrenalectomy at the University Hospital in Uppsala. In addition, another 5 patients who underwent bilateral adrenalectomy for other reasons (recurrent pituitary Mb Cushing or bilateral hyperplasia) were scrutinized for technical considerations. Indications, timing of surgery, and operative procedures were studied to identify signs that may support our approach to management in the future.ResultsCurative surgery was not possible in any of the cases with ectopic Cushing’s syndrome. Of the 13 operated patients, handport-assisted laparoscopic adrenalectomy was successfully performed bilaterally in 5 patients and unilaterally in combination with contralateral open surgery in 1 patient; conventional open surgery was performed on 7 patients, 3 of which were conversions from intitial handport-assisted procedures. Non-fatal complications occurred in 4 out of 10 patients.ConclusionsWe conclude that bilateral handport-assisted laparoscopic adrenalectomy is safe, and that all surgical techniques in these severely ill patients may be troublesome and technically demanding. Early surgical intervention may reduce the technical disadvantages. Moreover, bilateral adrenalectomy can substantially reduce the symptoms of Cushing’s syndrome, although effects on mortality are not obvious.

PET-Guided Surgery — High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours

Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

Gastrin-releasing-peptide in neuroendorine tumours.

In a substantial proportion of cases with endocrine malignant disease the primary lesion cannot be localised and the pathologist hesitates upon the origin of the tumour. Well differentiated neuroendocrine carcinomas of the small bowel can usually be identified by the strong serotonin immunoreactivity, but foregut carcinoids may also stain positive for serotonin and the differential diagnosis between the various foregut tumours may be difficult. We examined if immunostaining for gastrin-releasing-peptide (GRP) may aid in establishing the origin of an unknown neuroendocrine tumour. Tumour tissue from 79 patients (27 lung carcinoids, 4 thymic carcinoids, 4 gastric neuroendocrine tumours, 17 pancreatic well differentiated neuroendocrine carcinomas, 1 duodenal well differentiated neuroendocrine tumour and 26 well differentiated neuroendocrine carcinomas of the small bowel) were immunostained with antibodies against GRP and serotonin. Positive staining for GRP was found in 12/27 lung carcinoids. All other tumour types were consistently GRP-negative (p < 0.0001). We conclude that immunostaining for GRP may aid in defining the origin of the tumour, and that GRP-immunoreactivity increases the suspicion of a lung carcinoid.

Whole-Body PET with [11C]-5-Hydroxytryptophan for Localization of Neuroendocrine Tumors.

Purpose: [11C]-5-Hydroxytryptophan (5-HTP) has previously been shown to be an excellent tracer for localization of neuroendocrine tumors, especially hormone-producing midgut carcinoids. To improve the clinical usefulness of 5-HTP PET in a diagnostic setting, we wanted to develop a whole-body scanning approach.Methods: The patients received 200 mg carbidopa orally as premedication to block physiological decarboxylation, thereby improving tumor/background contrast. Two hundred to 800 MBq of 5-HTP was injected in a forearm vein. Ten minutes post-injection emission scanning was performed, covering thorax and abdomen in whole-body mode. In a GE4096 scanner (10 cm FOV), a protocol of up to 6 bed positions with timeframes of 5, 7, 10, 10, 15, and 20 minutes was used. In a Siemens CTI Ecat HR+ scanner (15.5 cm FOV), 4 bed positions with timeframes of 7, 10, 15, and 20 minutes was used. Transmission scans were performed for 2–4 minutes for each bed position and segmented for attenuation correction. Comparison with CT, octreotide scintigraphy, and surgical end points were made.Results: So far 50 patients referred for staging of carcinoid tumors, localization of ectopic ACTH-producing tumors or endocrine pancreatic tumors have been investigated. 5-HTP generally shows more lesions than CT and in some cases more lesions and lesions at an earlier stage than octreotide scintigraphy. Clinical trials have been set up to define the role of 5-HTP whole-body scans in routine clinical use.Conclusions: Whole-body PET with 5-HTP is a promising new approach in diagnostic imaging of neoplasias of neuroendocrine origin, evidently changing treatment planning in selected patient groups. (Clin Pos Imag 1999;2:338) All rights reserved.