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Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy.

Hicks RJ - Cancer Imaging (2010)

Bottom Line: Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the diagnostic sensitivity of FDG PET/CT.High FDG avidity is associated with a poorer prognosis but increases the likelihood of response to chemotherapy.In the future, paradigms guided by clinical and biopsy features should allow personalized imaging paradigms aligned to therapeutic options.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Radiology, University of Melbourne, Centre for Cancer Imaging, Molecular Imaging and Targeted Therapeutics Laboratory, The Peter MacCallum Cancer Centre, East Melbourne, Australia. rod.hicks@petermac.org

ABSTRACT
Imaging of neuroendocrine tumours (NET) poses significant challenges because of the heterogeneous biology of the tumours that are represented by this class of neoplasia. NET can range from benign lesions to highly aggressive cancers. Structural imaging techniques have suboptimal sensitivity in most published series and diagnosis is often delayed until metastatic disease is present. Current guidelines emphasise the importance of functional imaging for evaluating the extent of NET. The mainstay of this type of imaging has been somatostatin receptor scintigraphy (SRS) with [(111)In]diethylenetriaminepentaacetic acid-octreotide (Octreoscan™). Routine use of single-photon emission computed tomography (SPECT) and particularly of hybrid SPECT/computed tomography (CT) has significantly improved localisation of tumour sites and evaluation of somatostatin receptor (SSTR) expression, which is important for predicting the likelihood of response to somatostatin analogues (SSA). Positron emission tomography (PET) can also now be used for evaluating SSTR expression. There are a number of peptides that have been evaluated but [(68)Ga]tetraazocyclodecanetetraacetic acid (DOTA)-octreotate (GaTate) PET/CT, which has been shown to be significantly more sensitive for detecting small lesions than Octreoscan™, is now probably the preferred agent because high uptake in known sites of disease provides a diagnostic pair for assessing suitability of patients for [(177)Lu]DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT). A range of other radiolabelled SSA has also been used for PRRT. Lesions without SSTR expression require alternative imaging and therapeutic strategies. Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the diagnostic sensitivity of FDG PET/CT. High FDG avidity is associated with a poorer prognosis but increases the likelihood of response to chemotherapy. Functioning tumours also require substrates for their secreted products. This can be exploited for NET imaging with amine precursor uptake being imaged using [(18)F]3,4-dihydrophenylalanine and serotonin-secreting tumours being sensitively detected using [(11)C]5-hydroxytryptamine. Both these agents are suitable for imaging with PET. [(123)I]meta-Iodo-benzyl-guanidine (MIBG) SPECT/CT may also be useful as a staging technique, particularly for NET of the sympathetic neuronal chain, and can identify patients who may be suitable for [(131)I]MIBG therapy. In the future, paradigms guided by clinical and biopsy features should allow personalized imaging paradigms aligned to therapeutic options.

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Planar whole-body images in the anterior and posterior projection of a patient with metastatic rectal carcinoid demonstrate intense focal uptake in relationship to multiple bone metastases, particularly in the left scapula and humerus and in the pelvis as well as in soft tissue deposits in the lungs and abdomen, which were better localised on SPECT/CT (not shown).
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Figure 1: Planar whole-body images in the anterior and posterior projection of a patient with metastatic rectal carcinoid demonstrate intense focal uptake in relationship to multiple bone metastases, particularly in the left scapula and humerus and in the pelvis as well as in soft tissue deposits in the lungs and abdomen, which were better localised on SPECT/CT (not shown).

Mentions: Neuroendocrine cells signal to other cells, and thereby control various physiological processes, including digestion, through secretion of chemicals. These chemicals include peptide hormones that bind to stimulatory or inhibitory cell surface receptors. The most ubiquitous inhibitory receptor is the somatostatin receptor (SSTR), which has 5 known subtypes. Somatostatin is a peptide with 2 forms, containing 14 and 28 amino acids, respectively. Both bind to all subclasses of SSTR but are rapidly degraded in the blood by peptidases. Therefore, they tend to act in a paracrine manner, being secreted and acting locally. Various synthetic somatostatin analogues (SSA) have also been made to increase resistance to peptidases and thereby allow systemic delivery by virtue of longer circulation times. These SSA have varying affinity for the different SSTR subtypes. The most widely used is an 8-amino acid peptide, octreotide (Sandostatin®). This peptide has also been radiolabelled as [111In]diethylenetriaminepentaacetic acid (DTPA)-octreotide or Octreoscan™[2]. This agent has highest affinity for SSTR-2 and is suitable for imaging on a gamma camera. Despite malignant change, neuroendocrine tumours (NET) can retain, to a variable degree, the characteristics of the cell type from which they arose, including the capacity to secrete biological products. Whether they are functioning or not, most retain expression of the SSTR, most commonly of subtype 2. They are thus capable of being imaged using [111In]DTPA-octreotide[3], which can identify both the primary tumour and metastatic sites to soft tissue or bone (Fig. 1). This agent can also visualise SSTR expression on normal endocrine organs like the anterior pituitary and thyroid. More recently, octreotide and other SSA have also been labelled with positron-emitting radioisotopes, such as 68Ga, for positron emission tomography (PET).Figure 1


Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy.

Hicks RJ - Cancer Imaging (2010)

Planar whole-body images in the anterior and posterior projection of a patient with metastatic rectal carcinoid demonstrate intense focal uptake in relationship to multiple bone metastases, particularly in the left scapula and humerus and in the pelvis as well as in soft tissue deposits in the lungs and abdomen, which were better localised on SPECT/CT (not shown).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967140&req=5

Figure 1: Planar whole-body images in the anterior and posterior projection of a patient with metastatic rectal carcinoid demonstrate intense focal uptake in relationship to multiple bone metastases, particularly in the left scapula and humerus and in the pelvis as well as in soft tissue deposits in the lungs and abdomen, which were better localised on SPECT/CT (not shown).
Mentions: Neuroendocrine cells signal to other cells, and thereby control various physiological processes, including digestion, through secretion of chemicals. These chemicals include peptide hormones that bind to stimulatory or inhibitory cell surface receptors. The most ubiquitous inhibitory receptor is the somatostatin receptor (SSTR), which has 5 known subtypes. Somatostatin is a peptide with 2 forms, containing 14 and 28 amino acids, respectively. Both bind to all subclasses of SSTR but are rapidly degraded in the blood by peptidases. Therefore, they tend to act in a paracrine manner, being secreted and acting locally. Various synthetic somatostatin analogues (SSA) have also been made to increase resistance to peptidases and thereby allow systemic delivery by virtue of longer circulation times. These SSA have varying affinity for the different SSTR subtypes. The most widely used is an 8-amino acid peptide, octreotide (Sandostatin®). This peptide has also been radiolabelled as [111In]diethylenetriaminepentaacetic acid (DTPA)-octreotide or Octreoscan™[2]. This agent has highest affinity for SSTR-2 and is suitable for imaging on a gamma camera. Despite malignant change, neuroendocrine tumours (NET) can retain, to a variable degree, the characteristics of the cell type from which they arose, including the capacity to secrete biological products. Whether they are functioning or not, most retain expression of the SSTR, most commonly of subtype 2. They are thus capable of being imaged using [111In]DTPA-octreotide[3], which can identify both the primary tumour and metastatic sites to soft tissue or bone (Fig. 1). This agent can also visualise SSTR expression on normal endocrine organs like the anterior pituitary and thyroid. More recently, octreotide and other SSA have also been labelled with positron-emitting radioisotopes, such as 68Ga, for positron emission tomography (PET).Figure 1

Bottom Line: Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the diagnostic sensitivity of FDG PET/CT.High FDG avidity is associated with a poorer prognosis but increases the likelihood of response to chemotherapy.In the future, paradigms guided by clinical and biopsy features should allow personalized imaging paradigms aligned to therapeutic options.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Radiology, University of Melbourne, Centre for Cancer Imaging, Molecular Imaging and Targeted Therapeutics Laboratory, The Peter MacCallum Cancer Centre, East Melbourne, Australia. rod.hicks@petermac.org

ABSTRACT
Imaging of neuroendocrine tumours (NET) poses significant challenges because of the heterogeneous biology of the tumours that are represented by this class of neoplasia. NET can range from benign lesions to highly aggressive cancers. Structural imaging techniques have suboptimal sensitivity in most published series and diagnosis is often delayed until metastatic disease is present. Current guidelines emphasise the importance of functional imaging for evaluating the extent of NET. The mainstay of this type of imaging has been somatostatin receptor scintigraphy (SRS) with [(111)In]diethylenetriaminepentaacetic acid-octreotide (Octreoscan™). Routine use of single-photon emission computed tomography (SPECT) and particularly of hybrid SPECT/computed tomography (CT) has significantly improved localisation of tumour sites and evaluation of somatostatin receptor (SSTR) expression, which is important for predicting the likelihood of response to somatostatin analogues (SSA). Positron emission tomography (PET) can also now be used for evaluating SSTR expression. There are a number of peptides that have been evaluated but [(68)Ga]tetraazocyclodecanetetraacetic acid (DOTA)-octreotate (GaTate) PET/CT, which has been shown to be significantly more sensitive for detecting small lesions than Octreoscan™, is now probably the preferred agent because high uptake in known sites of disease provides a diagnostic pair for assessing suitability of patients for [(177)Lu]DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT). A range of other radiolabelled SSA has also been used for PRRT. Lesions without SSTR expression require alternative imaging and therapeutic strategies. Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the diagnostic sensitivity of FDG PET/CT. High FDG avidity is associated with a poorer prognosis but increases the likelihood of response to chemotherapy. Functioning tumours also require substrates for their secreted products. This can be exploited for NET imaging with amine precursor uptake being imaged using [(18)F]3,4-dihydrophenylalanine and serotonin-secreting tumours being sensitively detected using [(11)C]5-hydroxytryptamine. Both these agents are suitable for imaging with PET. [(123)I]meta-Iodo-benzyl-guanidine (MIBG) SPECT/CT may also be useful as a staging technique, particularly for NET of the sympathetic neuronal chain, and can identify patients who may be suitable for [(131)I]MIBG therapy. In the future, paradigms guided by clinical and biopsy features should allow personalized imaging paradigms aligned to therapeutic options.

Show MeSH
Related in: MedlinePlus