COSA:NETs guidelines/Imaging

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Imaging

Introduction

GEP NETs arise from a diverse range of cells involved in neurohormonal regulation of the gastrointestinal tract and vary considerably in clinical presentation, pathology and behaviour. An isolated primary lesion as small as 1cm may secrete the bioactive products responsible for the symptoms that bring approximately 40% of patients to medical attention. The exception is carcinoid syndrome, where symptoms are usually a manifestation of escalating serotonin secretion from hepatic or ovarian metastases bypassing hepatic degradation. In these patients, the burden of disease may range from small volume metastases suitable for resection through to disseminated metastases requiring systemic therapy. The remaining 60% of GEP NETs that are not associated with hormone-related symptoms at diagnosis are usually detected as incidental imaging or surgical findings or due to systemic manifestations of metastatic disease, particularly including abdominal or bone pain.

The purpose and choice of imaging depends upon the particular clinical scenario. The indications for imaging include:

  1. Diagnosis: Evaluation of suggestive symptoms or biochemical abnormalities
  2. Localisation: Detection of a primary GEP NET in the setting of known metastatic disease
  3. Staging: Evaluation of the extent and location of metastatic disease to allow selection and planning of therapy
  4. Biological characterisation: Assessment of the nature of cellular biology, particularly when considering molecular targeted therapies
  5. Treatment monitoring: Assessment of the efficacy of treatment

Both anatomical and functional imaging can perform many of these functions and may be required at one or more points during the course of the disease. The wide variation between patients in course of disease and treatment precludes setting of prescriptive imaging schedules. In addition to imaging to determine the extent of disease, patients with carcinoid tumours may also require periodic echocardiography to detect the possible cardiac complications of carcinoid syndrome.

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Structural Imaging

Multi-slice CT and magnetic resonance imaging are the most sensitive of the widely available anatomical imaging modalities for detecting sites of disease. These techniques are most effective when performed by experienced radiologists using protocols that have been optimised for the evaluation of neuroendocrine tumours.[1] Accordingly, referral to facilties that are experienced in the evaluation of GET NET is encouraged. Whilst most NETs are highly vascular leading to significant contrast enhancement in extra-hepatic disease, the timing of peak enhancement may vary for liver lesions. Therefore multi-phasic imaging protocols may be required to assess this organ.

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Methodological considerations for CT

CT is the anatomical modality of initial choice, and the most widely used, for diagnosis and staging. CT enteroclysis (CTE) has become the imaging modality of choice for the diagnosis and localisation of primary small bowel tumours. Volume challenge of 2L of enteral contrast agent administrated to the small bowel via a naso-jejunal catheter ensures luminal distension, which is a prerequisite for the detection of mural abnormalities and also facilitates the accurate visualisation of intra-luminal lesions. CT acquisition is centred on small bowel loops, reconstructed in thin axial slices and completed by multiplanar views. Image analysis is essentially done in cine-mode on workstations. This technique is usually reserved for patients in whom other techniques have failed to localise the primary lesion in metastatic carcinoid tumours. CTE is favoured over MRE unless radiation dose is a concern.

Staging of known or suspected metastatic disease is a more common indication for CT. The field-of-view for diagnostic studies should include the lower neck (to identify supraclavicular lymphadenopathy, which is a relatively common manifestation of intra-abdominal metastasis), chest, abdomen and pelvis. Studies should be performed with oral contrast and consideration should be given to performing high oral volume (1000-2000cc) polyethylene glycol (PEG) techniques to obtain enteroclysis-type images of the small and large bowel. This allows profiling of the bowel wall against the low attenuation bowel contents, enhancing detection of primary bowel lesions.

All studies should be performed with IV contrast, except when there are recognised contraindications. CT examinations should include an arterial contrast phase through the liver and pancreas and a portal venous phase to cover from the superior liver margin to the pelvis. A non-contrast scan through the liver is also recommended as NET lesions may be relatively hypodense and with post-contrast enhancement may become isodense with liver, decreasing sensitivity if this is the only phase of imaging.

Arterial phase imaging should be individualised by using a region of interest technique on the aorta to maximise and standardise the timing of the arterial phase acquisition. Studies should be obtained on multi-slice CT (MSCT), (16 slice and above), which allow for optimisation of scan protocols with appropriate reformats and the ability to examine and manipulate original data on a dedicated workstation. There is improved resolution and multiple anatomical plane reconstruction, with coronal image reconstruction particularly useful for defining abdominal anatomy.[2]

Initial diagnostic reports should include representative images of target lesions (primary, metastases) with axial measurements saved to an archiving system for future reference. Lesions should be measured in the same post contrast phase with access to the saved measurements from the prior/diagnostic series. The greatest variability in lesion appearances tends to occur in the arterial phase since this is the most time dependent.

CT is commonly used for assessing disease progression and for therapeutic monitoring where RECIST measures are applied using the revised RECIST guideline.[3]

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MRI and Ultrasound

For evaluation of liver lesions, MSCT (which is readily available, faster and more cost effective for patient and provider) remains the imaging modality of choice. However, if the lesions are in doubt, DCE-MR (MRI with imaging agent such as Primavist) may be useful. Dynamic contrast enhanced–ultrasound (DCE-US) has a niche role for equivocal liver and pancreatic lesions.

It has been suggested that in the liver, MRI has a higher sensitivity than CT for metastatic disease. They usually appear of low signal intensity on T1-weighted sequences and high on T2-weighted sequences relative to the pancreas.[4][5] However, MRI for this purpose is neither funded under the MBS, and is not a prerequisite for surgery. Therefore, for most patients a good quality MSCT is adequate. However, MRI can be helpful in cases where the patient has some underlying hepatic disease or where lesions are not visible on contrast CT but strongly suspected on other criteria.

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Upper GI endoscopy with Ultrasound Capability

The major role of upper gastrointestinal (GI) endoscopy is in the primary detection of small, primary duodenal NETs under direct vision but has been adapted to become an imaging technique through implementation of ultrasound probe near the tip of the device. Upper GI endoscopy combined with endoscopic ultrasound (EUS) has found utility for local staging of small pancreatic lesions, particularly those located in the head and body, lesions in the duodenal wall, and regional lymphadenopathy. Although results of sensitivities as high as 79-100% have been reported,[6] lesion detection rate is much lower when lesions are submucosal (as low as 30-60%). These devices can also be used to obtain minimally-invasive biopsies of structures close to the lumen of the upper gastro-intestinal tract, particularly lesions in the pancreas. As with other operator-dependent studies these cases should be referred to centres with significant experience in such studies.

EUS should generally be preceded by functional and anatomical imaging to guide the operator to interrogate sites of greatest suspicion.

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Functional imaging

Functional imaging is usually performed with radiolabeled somatostatin analogues binding with high affinity to somatostatin receptors subclasses 2 and 5, which have been reported to be expressed on at least 80% of GEP-NETs.[7] This is often used as the first line imaging modality when there is biochemical or histological evidence of GEP-NET. In the context of evolving use of molecular targeted therapies, including use of synthetic peptides, the degree of uptake can also be used to guide therapy. There are other approaches to imaging as outlined in the section on PET/CT.

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OctreoScan®

Currently, Indium-111 pentetreotide (OctreoScan®, Tyco) is the only radiolabeled somatostatin analogue to be listed on the Australian Register of Therapeutic Goods (ARTG). It is reimbursed under the Medicare Benefits Schedule for the following indications:

(a) Detection of suspected gastro-entero-pancreatic endocrine tumour, based on biochemical evidence, but negative or equivocal conventional imaging; or
(b) Exclusion of additional disease sites in patients with surgically amenable gastro-entero-pancreatic endocrine tumour based on conventional techniques.

These indications were established prior to recent advances in the management of GEP-NET including evolving concepts in palliative surgery and medical management detailed elsewhere. Biological characterisation of lesions has diagnostic, prognostic and therapeutic implications. OctreoScan® should be considered to select patients suitable for molecular targeted therapy using somatostatin analogues as either long-acting or radiolabeled agents within the broader context of current therapeutic options.

Availability of In-111 pentetreotide imaging is currently limited in the community as the cost of the radiopharmaceutical alone exceeds by several hundred dollars the Medicare Benefits Schedule fee for the entire procedure. Many imaging facilities therefore either do not offer this as a service or charge significant out-of-pocket expenses to the patient to cover this shortfall. The scanning procedure is also time consuming for both patient and staff, as it involves injection followed by imaging at several time points over at least two days. This should be performed in accordance with the guidelines issued by the various nuclear medicine societies, especially with regard to dose of radiopharmaceutical, imaging time-points, and use of single-photon emission computed tomography (SPECT). Sensitivity and specificity of this technique is enhanced by coregistered CT (SPECT/CT), which should be considered as the ideal standard for In-111 pentetrotide imaging protocols.

In some New Zealand centres preference has currently been given to technetium - 99m (99mTc) tektrotyd for functional imaging with SPECT/CT.

All patients on long-acting somatostatin analogues should have these ceased for a minimum of 4 weeks and preferably 4-6 weeks prior to OctreoScan® imaging. Short-acting octreotide can be instituted to control breakthrough hormone-related symptoms but also needs to be withheld for 8-12 hours prior to tracer administration.

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PET/CT

PET/CT imaging (Positron emission tomography/Computed tomography) is not currently approved nor funded for the evaluation of neuroendocrine tumours but can be useful to both detect and biologically characterise lesions. None of the PET radiopharmaceuticals listed below, other than FDG, are registered on the ARTG for any purpose, and no formal reimbursement mechanisms for their use exist. The rarity of GEP NET combined with the current regulatory arrangements pertaining to reimbursement of PET/CT make it unlikely that any of the techniques described below will be routinely available in Australia or New Zealand in the near future. However, physicians and patients should be aware that, based on preliminary data, PET/CT is probably the functional imaging technique of choice for diagnosis and staging of GEP NET at the present time. Nevertheless, availability is limited, formulations are often non-standardised, and access is generally restricted to research institutions. In the absence of regulatory approvals and supporting pivotal trials, this consensus document can report the admittedly highly encouraging research findings, but cannot recommend their use outside of compassionate or research settings.

PET/CT can be performed using a number of different tracers including:

  • 18F-fluorodeoxyglucose (FDG)
  • 68Ga- pentetreotide (or other somatostatin analogues such as DOTANOC and DOTATATE)
  • 18F-dihydrooxyphenylalanine (F-DOPA)
  • 11C-5-hydroxytryptophan
  • 64Cu-octreotide.

FDG is the most commonly used PET tracer in Australia because of its availability and general utility in cancer imaging. However, this tracer appears less effective as a general screening tool in GEP NETs compared to other common cancers because of their relatively low glucose utilisation.[8] However, FDG PET/CT is probably superior to OctreoScan® in the setting of poorly-differentiated neuroendocrine carcinomas with high mitotic activity (Ki-67 >20%) since such tumours tend to have lost somatostatin receptor expression. Although insulinoma is reported to have low somatostatin receptor expression in up to 50% of cases, FDG PET is not a suitable alternative as patients with this tumour can seldom safely fast sufficiently to prepare for this scan and high insulin levels drive FDG into cardiac and skeletal muscles decreasing the availability for tumour uptake.

FDG PET/CT may also be useful subsequent to somatostatin analogue imaging in well-differentiated neuroendocrine carcinomas, particularly those with a Ki-67 >5%, as this may provide prognostic information and impact on therapeutic choices. For well-differentiated NET (Ki-67 <2%), FDG-PET is not indicated unless there are significant morphological abnormalities with low radiolabeled somatostatin analogue avidity, indicating possible heterogeneity in tumour biology. Otherwise FDG PET can be useful to select patients who may be more likely to respond to cytotoxic chemotherapy, and monitor for response.[9]

PET/CT scanning with 68Ga-octreotide analogues has been reported to demonstrate greater sensitivity and specificity in detecting SRS expressing lesions than In-111 octreotide[10] and is also substantially more convenient for patients, with the scanning procedure from injection to completion of imaging being completed within 2 hours. Multiple reports have concluded that PET/CT with 68Ga-octreotide analogues should be the functional imaging agent of choice, particularly for patients in whom the primary lesion has not been detected or for identification of further lesions when this may influence choice of treatment.

Patients from New Zealand are able to access 68Ga-octreotide analogue PET/CT in Australia (Peter Mac, Melbourne) if they satisfy the criteria set up by the regional Variance Committees.

For carcinoid tumours 18F-DOPA provides an alternative to 68Ga-octreotate.[11] A disadvantage of 18F-DOPA PET/CT compared to somatostatin receptor imaging is that it does not provide information about patient suitability for treatment with agents such as 177Lu-octreotate. The other agents listed above have been less well characterised.

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MIBG

Metaiodobenzylguanidine (MIBG) is concentrated to varying extent by up to 70% of carcinoid tumours. When radiolabelled with iodine-123, MIBG is also used in the diagnostic workup of carcinoid tumours.[12] However, its diagnostic use is generally confined to those tumours that do not express sst-2 or sst-5 receptors. Some institutions use iodine-131 MIBG as a palliative therapeutic option.

This agent is neither approved nor funded for such use.

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Imaging for response

The use of morphological and functional imaging in follow up is somewhat dependent on the initial site(s) of disease, the type of therapy received and the expected mechanism of response.

RECIST[3] is still the standard for anatomical response assessment but many patients derive significant biochemical and symptomatic benefit, particularly from molecular targeted therapies even in the absence of morphological response. Molecular imaging and clinical responses are often more marked than the apparent morphological responses. Imaging should thus be integrated with clinical and laboratory assessment when planning ongoing management. No firm recommendations can currently be made as therapeutic monitoring and surveillance paradigms are still being defined. Based on the cost, availability and diagnostic sensitivity of available techniques, and the generally indolent nature of most GEP NET, assessment of therapeutic response can be usefully performed at 3 months with a combination of clinical review, laboratory testing, including known tumour hormone measures in any given patient, diagnostic CT or hybrid OctreoScan® SPECT/CT. In responding patients, 3 monthly laboratory testing and clinical review, 6 monthly CT and annual functional imaging is probably sufficient to determine the need for further treatment.

Specific considerations regarding response to treatment and assessment prior to surgical or targeted therapy are outlined below.

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Diagnostic approach flow chart

Figure 1: Flow chart illustrating suggested diagnostic approach to GEP NET (Modified from Wong et al, 2009). [13]


Diagnostic approach to carcinoid tumours.jpg


* Ga-68 somatostatin analogue imaging (*Ga-68 DOTA-octreotide or *Ga-68-DOTA-octreotate) currently has limited availability but preliminary data suggests substantially higher sensitivity than In-111 octreotide/OctreoScan® and could be considered in cases where OctreoScan® scanning is negative or, if available, in place of Octreoscan®.

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Transmission of electronic imaging

Because patients with neuroendocrine tumours are often managed by multiple clinicians and frequently require treatment in a number of healthcare settings, images should be stored in an electronic format that is compliant with DICOM standards. Ideally these should be both archived on PACS and provided to the patient on a CD that can be imported into dedicated image viewing workstations or viewed on personal computers. The indolent progress of some NETs mandate that images be kept for far longer than is generally required for most cancers.

An Australasian College of Radiologists’ working group is currently finalising recommendations for standardising transmission of electronic imaging.

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References

  1. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008 Jan;9(1):61-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18177818.
  2. Rockall AG, Reznek RH. Imaging of neuroendocrine tumours (CT/MR/US). Best Pract Res Clin Endocrinol Metab 2007 Mar;21(1):43-68 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17382265.
  3. 3.0 3.1 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009 Jan;45(2):228-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19097774.
  4. Owen NJ, Sohaib SA, Peppercorn PD, Monson JP, Grossman AB, Besser GM, et al. MRI of pancreatic neuroendocrine tumours. Br J Radiol 2001 Oct;74(886):968-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11675319.
  5. Semelka RC, Custodio CM, Cem Balci N, Woosley JT. Neuroendocrine tumors of the pancreas: spectrum of appearances on MRI. J Magn Reson Imaging 2000 Feb;11(2):141-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10713946.
  6. Rösch T, Lightdale CJ, Botet JF, Boyce GA, Sivak MV Jr, Yasuda K, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med 1992 Jun 25;326(26):1721-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1317506.
  7. Horton KM, Kamel I, Hofmann L, Fishman EK. Carcinoid tumors of the small bowel: a multitechnique imaging approach. AJR Am J Roentgenol 2004 Mar;182(3):559-67 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14975946.
  8. Adams S, Baum R, Rink T, Schumm-Dräger PM, Usadel KH, Hör G. Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the imaging of neuroendocrine tumours. Eur J Nucl Med 1998 Jan;25(1):79-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9396878.
  9. Oberg S, Wenner J, Johansson J, Walther B, Willén R. Barrett esophagus: risk factors for progression to dysplasia and adenocarcinoma. Ann Surg 2005 Jul;242(1):49-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15973101.
  10. Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, et al. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur J Nucl Med 2001 Sep;28(9):1319-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11585290.
  11. Koopmans KP, de Vries EG, Kema IP, Elsinga PH, Neels OC, Sluiter WJ, et al. Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study. Lancet Oncol 2006 Sep;7(9):728-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16945767.
  12. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AK. Gastrointestinal carcinoids: the evolution of diagnostic strategies. J Clin Gastroenterol 2006 Aug;40(7):572-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16917396.
  13. Wong M, Kong A, Constantine S, Pathi R, Parrish FJ, Verma R, et al. Radiopathological review of small bowel carcinoid tumours. J Med Imaging Radiat Oncol 2009 Feb;53(1):1-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19453523.


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