Leo J. Hofland

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

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

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

[111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation.

Somatostatin receptor-positive human tumors can be detected using radioiodinated analogues of somatostatin, both in vitro and in vivo. [123I-Tyr3]-octreotide has been successfully used in the visualization of somatostatin receptor-positive tumors by gamma camera scintigraphy, but this radiopharmaceutical has some major drawbacks, which can be overcome with other radionuclides such as 111In. As starting material for a potentially convenient radiopharmaceutical, a diethylenetriaminopentaacetic acid (DTPA) conjugated derivative of octreotide (SMS 201-995) was prepared. This peptide, [DTPA-D-Phe1]-octreotide (SDZ 215-811) binds more than 95% of added 111In in an easy, single-step labeling procedure without necessity of further purification. The specific somatostatin-like biologic effect of these analogues was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in a dose-dependent fashion by octreotide, [DTPA-D-Phe1]-octreotide and non-radioactive [115In-DTPA-D-Phe1]-octreotide. The binding of [111In-DTPA-D-Phe1]-octreotide to rat brain cortex membranes proved to be displaced similarly by natural somatostatin as well as by octreotide, suggesting specific binding of [111In-DTPA-D-Phe1]-octreotide to somatostatin receptors. The binding of the indium-labeled compound showed a somewhat lower affinity when compared with the iodinated [Tyr3]-octreotide, but indium-labeled [DTPA-D-Phe1]-octreotide still binds with nanomolar affinity. In conjunction with in vivo studies, these results suggest that [111In-DTPA-D-Phe1]-octreotide is a promising radiopharmaceutical for scintigraphic imaging of somatostatin receptor-positive tumors.

The Medical Treatment of Cushing’s Disease: Effectiveness of Chronic Treatment with the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery

BACKGROUND The role of dopamine agonists in the treatment of Cushings disease (CD) has been previously debated. AIM The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term (12-24 months) treatment with cabergoline in patients with CD. PATIENTS AND METHODS 20 patients with CD unsuccessfully treated by surgery entered the study. Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, until urinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsiveness to treatment was evaluated according to changes in urinary cortisol excretion. A decrease greater than 25% was considered as a partial response, whereas complete normalization was considered as a full response at short-term evaluation; persistence of normal cortisol excretion was the only criterion to evaluate the response at long-term evaluation. RESULTS After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment. Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escape was observed in five patients after 6-18 months. Among the 10 long-term responsive patients, eight were followed for 24 months, whereas the remaining two were followed for 12-18 months, due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24 month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) without significant side effects, was obtained in eight of 20 (40%) patients. CONCLUSIONS The results of this study demonstrated that cabergoline treatment is effective in controlling cortisol secretion for at least 1-2 yr in more than one third of a limited population of patients with CD. If this evidence is confirmed by additional studies, this agent may be considered as a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery.

Somatostatin analogs in the diagnosis and treatment of cancer

Over the past few years, significant progress has been made in our understanding of the biology and functional significance of somatostatin receptors (sst) on human tumors. Somatostatin analogs, such as octreotide, bind predominantly to sst(2) and successfully control hormone hypersecretion in patients with acromegaly, islet cell tumors and carcinoids, and (temporary) control of tumor growth is often also seen. Furthermore, sst(2) on tumors can be imaged in vivo after the injection of radionuclide-coupled octreotide. Targeted chemo- and radiotherapy, in which somatostatin analogs coupled to a chemotherapeutic agent or a radionuclide are selectively internalized by sst-positive tumors, are now being studied for their effect on tumor growth. Knowledge about the differential anti-tumor effects of the sst subtypes on tumor cells might have clinical significance after the development of new subtype-specific somatostatin analogs.

Coexpression of Dopamine and Somatostatin Receptor Subtypes in Corticotroph Adenomas

CONTEXT Previous studies have demonstrated the expression of somatostatin receptor subtypes (mainly sst(5)) and dopamine (DA) receptor subtypes (mainly D(2)) in smaller series of human corticotroph adenomas. In line with these findings, sst(5) and D(2)-targeting agents have already been used clinically in patients with Cushings disease (CD) and have shown promising results in subsets of patients. To what extent these receptor subtypes are coexpressed within individual adenomas, is not known however. OBJECTIVE The aim of the study was to investigate the (co-)expression of both sst and DA receptors in a large series of human corticotroph adenomas. DESIGN We performed in vitro analysis of corticotroph adenoma tissue obtained via transsphenoidal adenomectomy. SETTING The study was conducted at two university medical centers. PATIENTS Adenoma tissue from 30 patients with CD was analyzed in this study. RESULTS Analyzed by quantitative RT-PCR, D(2) and sst(5) were significantly (co-) expressed in the majority (60%) of adenomas, whereas 23% of adenomas only expressed D(2), but not sst(5). The remaining 17% of adenomas did not significantly express either sst(5) or D(2). Overall, expression of sst(1-4) and D(4) was low to nondetectable. Corticotroph adenomas with invasive growth invariably showed loss of sst(5) and D(2) expression. Autoradiography revealed clear D(2) and/or SS-14 binding in a subset of cases, which correlated well with their respective mRNA data. CONCLUSIONS Sst(5) and especially D(2) are highly expressed in the majority of human corticotroph adenomas, with coexpression of sst(5) and D(2) being a common phenomenon. These findings support the current studies with sst(5) and D(2)-targeting agents in patients with CD and highlight the rationale behind sst(5)-D(2) combination therapy.

Somatostatin receptor scintigraphy: Its value in tumor localization in patients with cushing's syndrome caused by ectopic corticotropin or corticotropin-releasing hormone secretion

PURPOSE To assess the feasibility of somatostatin receptor scintigraphy for patients with Cushings syndrome caused by tumors secreting ectopic corticotropin or corticotropin-releasing hormone (CRH). PATIENTS AND METHODS Ten patients with Cushings syndrome, nine with ectopic corticotropin-secreting tumors and one with a CRH-secreting tumor, were consecutively studied. For comparison purposes, eight patients with corticotropin-secreting pituitary tumors and one patient with an autonomous adrenal adenoma were investigated. In vivo tumor localization was performed for all patients using a radionuclide-coupled somatostatin analog. The results obtained with this technique were compared with those obtained with conventional imaging techniques. For some patients, the clinical effects of octreotide therapy were evaluated. RESULTS Somatostatin analog scintigraphy successfully identified the primary ectopic corticotropin-secreting and CRH-secreting tumors or their metastases, or both, in 8 of 10 patients; in 2 patients with corticotropin-secreting bronchial carcinoids, the tumors could not be visualized. Normal scans were obtained for the 8 patients with corticotropin-secreting pituitary tumors and the one patient with an adrenal adenoma. CONCLUSION Somatostatin analog scintigraphy can be included as a diagnostic step in the workup of Cushings syndrome patients with a suspected ectopic corticotropin-secreting tumor or a CRH-secreting tumor.

Pre-clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers for somatostatin receptor-targeted scintigraphy and radionuclide therapy

We have evaluated the potential usefulness of radiolabelled [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide as radiopharmaceuticals for somatostatin receptor–targeted scintigraphy and radiotherapy. In vitro somatostatin receptor binding and in vivo metabolism in rats of the compounds were investigated in comparison with [111In‐DTPA0] octreotide. Comparing different peptide–chelator constructs, [DTPA0,Tyr3]octreotide and [DOTA0, Tyr3]octreotide were found to have a higher affinity than [DTPA0]octreotide for subtype 2 somatostatin receptors (sst2) in mouse AtT20 pituitary tumour cell membranes (all IC50 values obtained were in the low nanomolar range). In vivo studies in CA20948 tumor‐bearing Lewis rats revealed a significantly higher uptake of both 111In‐labelled [DOTA0,Tyr3]octreotide and [DTPA0,Tyr3]octreotide in sst2‐expressing tissues than after injection of [111In‐DTPA0]octreotide, showing that substitution of Tyr for Phe at position 3 in octreotide results in an increased affinity for its receptor and in a higher target tissue uptake. Uptake of 111In‐labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide in pituitary, pancreas, adrenals and tumour was decreased to less than 7% of control by pre‐treatment with 0.5 mg unlabelled octreotide/rat, indicating specific binding to sst2. Comparing different radionuclides, [90Y‐DOTA0,Tyr3]octreotide had the highest uptake in sst2‐positive organs, followed by the [111In‐DOTA0,Tyr3]octreotide, whereas [DOTA0, 125I‐Try3]octreotide uptake was low compared to that of the other radiopharmaceuticals, when measured 24 hr after injection. Renal uptake of 111In‐labelled [DTPA0]octreotide, [DTPA0, Tyr3]octreotide and [DOTA0,Tyr3]octreotide was reduced over 50% by an i.v. injection of 400 mg/kg d‐lysine, whereas radioactivity in blood, pancreas and adrenals was not affected. Int. J. Cancer 75:406–411, 1998.

Medical treatment of cushing's disease

CONTEXT Cushings disease (CD) is associated with serious morbidity and, when suboptimally treated, an increased mortality. Although surgery is the first-line treatment modality for CD, hypercortisolism persists or recurs in an important subset of patients. Considering the deleterious effects of uncontrolled CD, there is a clear need for effective medical therapy. OBJECTIVE In this review, we discuss molecular targets for medical therapy, efficacy, and side effects of the currently used drugs to treat hypercortisolism and focus on recent developments resulting from translational and clinical studies. EVIDENCE ACQUISITION Selection of publications related to the study objective was performed via a PubMed search using relevant keywords and search terms. MAIN FINDINGS Medical therapy for CD can be classified into pituitary-directed, adrenal-blocking, and glucocorticoid receptor-antagonizing drugs. Recent studies demonstrate that somatostatin receptor subtype 5 (sst(5)) and dopamine receptor subtype 2 (D(2)) are frequently (co-)expressed by corticotroph adenomas. Pituitary-directed therapy with pasireotide and cabergoline, targeting sst(5) and D(2), respectively, is successful in approximately 25-30% of patients. Adrenal-blocking drugs can be effective by inhibiting steroidogenic enzyme activity. Finally, the glucocorticoid receptor antagonist mifepristone induces clinical and metabolic improvement in the majority of patients. Each drug can have important side effects that may impair long-term treatment. Generally, patients with moderate to severe hypercortisolism need combination therapy to normalize cortisol production. CONCLUSION Medical therapy for CD can be targeted at different levels and should be tailored in each individual patient. Future studies should examine the optimal dose and combination of medical treatment modalities for CD.

Neuroendocrine tumor markers

Tumor markers used in the diagnosis and follow-up of patients with neuroendocrine tumors are in most instances not specific for a given tumor and circulate under normal conditions in the serum, making their use as an early diagnostic tool difficult (low sensitivity). By combining hormone measurements with tissue responsiveness, demonstrations of inappropriate secretions of PTH, insulin, and gastrin during hypercalcemia, hypoglycemia, and hyperacidity, respectively, become highly sensitive and specific diagnostic tests. The application of polyclonal antibodies in RIAs of hormones, such as ACTH, insulin, and gastrin, increase the diagnostic level of hormone measurements in patients with neuroendocrine tumors. Other markers, such as chromogranin A, neuron-specific enolase, and alpha-subunit, as well as peptide receptor visualization, are of increasing importance in the diagnosis and follow-up of neuroendocrine and non-neuroendocrine tumors.