Abstract: Molecular imaging is changing diagnostic and treatment paradigms in patients with neuroendocrine tumors through its ability to non-invasively characterize disease, supplementing the traditional role of using imaging for localizing and measuring disease. For patients with metastatic disease, there is an increasing range of therapies but these must be individualized to the specific subtype of tumor expressed, which varies in aggressiveness from well to poorly differentiated phenotypes. Positron emission tomography (PET) is now able to characterize these subtypes through its ability to quantify somatostatin receptor cell surface (SSTR) expression and glycolytic metabolism with SSTR and fluorodeoxyglucose (FDG) PET, respectively. The ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. Through earlier diagnosis, improved selection of the most appropriate therapy and better assessment of therapeutic response for an individual patient, molecular imaging is improving the outcome for patients with NET.
Neuroendocrine tumors (NETs) are a group of tumors that share common clinical features but arise from a variety of different cells within the neuroendocrine system. This results in different clinical phenotypes of unpredictable and unusual biologic behavior. In the last decade, there has been major progress in diagnosis and management, which is resulting in markedly improved patient outcomes. In part, this has been led by advances in nuclear medicine which has improved diagnosis, staging, restaging, and enabled targeted internal delivery of radio-isotopes with peptide receptor radionuclide therapy (PRRT). While NETs have long been recognized as a heterogeneous group of malignancies with considerable variation between patients, advances in molecular imaging are enabling visualization of tumor heterogeneity at different sites within an individual patient. This is enabling a new era of personalized care in which selection of a number of new targeted therapies can be optimized for an individual patient. This is a paradigm change from a prior step-wise approach of first, second, and subsequent lines of chemotherapy, typically chosen on the basis of results from trials of large patient cohorts without regard for an individual’s unique tumor phenotype.
NETs span a spectrum from well- to poorly-differentiated phenotypes, which characterize disease biology and prognosis. Well-differentiated NETs closely resemble normal neuroendocrine cells and tend to have an indolent natural history. In some, the functional activity of the original cells is preserved and amplified, resulting in high and inappropriate secretion of hormones, which can lead to morbidity and even mortality despite slow tumor growth. Like their normal neuroendocrine cells of origin, well-differentiated NETs have high cell surface expression of somatostatin receptors (SSTR), which is a G protein-coupled receptor that functions as an inhibitory signaling pathway. As disease becomes more poorly-differentiated, the cells appear less like normal cells and behave aggressively, with more rapid proliferation and clinical course. Histopathology, with determination of staining for neuroendocrine cell markers such as synaptophysin and chromogranin-A, and markers of cellular proliferation such as Ki-67 antigen, is used to grade the tumor and determine degree of differentiation. According to the European Neuroendocrine Tumor Society (ENETS) grading system, Ki-67 is used to divide tumor grade into three categories, using cut-offs of 2 and 20% (Plockinger et al., 2004). While anatomic imaging has played almost no role in such tumor classification, molecular imaging is able to accurately characterize SSTR expression and glycolytic metabolism, features of well- and poorly-differentiated disease, respectively (Figure 1).
Somatostatin Receptor (SSTR) SPECT and SPECT/CT Imaging
Octreotide, a long acting analogue of somatostatin, was radiolabeled with iodine-123 and subsequently indium-111 (111In) by the Krenning group, enabling non-invasive imaging of somatostatin receptor expression (Krenning et al., 1989; Lamberts et al., 1990). To perform this test, less than ten micrograms of the radiolabeled peptide octreotide is injected intravenously. Despite using a near homeopathic dose of the peptide, whole body images can be obtained owing to the remarkable sensitivity of the gamma camera for detecting radioactive substances. Over the last three decades, 111In-octreotide scintigraphy has become a key imaging modality in staging and restaging NET (Krenning et al., 1993).
Traditionally, a two-dimensional planar whole body image is acquired followed by single photon emission computed tomography (SPECT) through regions of interest. The latter enables three-dimensional reconstruction and improved tumor to background contrast. Hybrid imaging with devices that combine both SPECT and multi-slice CT (SPECT/CT) has significantly improved the technique by enabling precise correlation of function and anatomy. The precise co-registration of the two modalities increases sensitivity by identifying subtle SPECT or CT abnormalities that cannot be discerned on their own (Even-Sapir et al., 2001). Specificity is also increased by confirming physiologic localization to sites such as bowel. Thus, SPECT/CT improves accuracy by increasing both sensitivity and specificity, while also improving diagnostic confidence and reporter agreement (Ingui et al., 2006; Patel et al., 2008).
SSTR PET/CT Imaging: a Major Advance in Neuroendocrine Imaging
Positron emission tomography (PET) is a fully tomography technique with several orders of magnitude higher sensitivity for detecting radioactive substances over conventional SPECT imaging, in addition to superior spatial and temporal resolution. All PET devices are now integrated with multi-slice CT, unlike SPECT where standalone devices are still widely used. SSTR PET imaging is feasible using gallium-68 (68Ga), a positron emitter, conjugated to octreotide or newer generation peptides such as octreotate (Hofmann et al., 2001). Gallium-68 has ideal characteristics for PET imaging with a short, 68-minute half life and ability to label peptides via a DOTA conjugate. Moreover, it is available on-demand using a small generator which has shelf-life of approximately one year. Several compounds are now in use including [68Ga-DOTA0-Ty3]octreotate (DOTA-TATE, GaTate), [68Ga-DOTA0-Ty3]octreotide (DOTA-TOC, GaToc), and [68Ga-DOTA0-NaI3]octreotide (DOTA-NOC, GaNoc). These have varying SSTR subtype specificity with highest affinity for SSTR2, SSTR5, and SSTR3/5, respectively. SSTR2 is the predominant subtype overexpressed in neuroendocrine tumors, present in more than 90% of gastroenteropancreatic NETs (Reubi et al., 2000), and therefore GaTate is probably the most logical agent for clinical staging. Nevertheless, all these 68Ga compounds have shown high utility for imaging NET and major advantages compared to conventional SPECT or SPECT/CT scintigraphy (Table 1).
SSTR PET/CT represents the new gold standard for imaging diagnosis and staging of NET. The gold standard is, by definition, the best performing test available, and therefore there is no criterion standard against which it can be assessed. This makes assessment of purported accuracy difficult. A recent meta-analysis of 16 studies demonstrated pooled sensitivity and specificity of 93% (95% confidence interval: 91-95%) and 91% (82-97%), respectively (Treglia et al., 2012). The paradox of the gold standard is demonstrated by earlier studies of planar 111In-octreotide demonstrating a sensitivity of 95%, as such results are no longer plausible in the SSTR PET/CT era. For the purpose of assessing SSTR expression, PET/CT has astonishing target-to-background contrast resulting in both high sensitivity and specificity for detection of NET. The intensity of radiotracer uptake as determined by standardized uptake values (SUVs), a semiquantitative measure of regional radiotracer uptake, has been shown to correlate closely with in vivo SSTR cell surface expression as determined by real-time reverse polymerase chain reaction (Boy et al., 2011).
In our experience, false negative or positive results with SSTR PET/CT are rare (Table 2). It is able to resolve lesions as small as 2-3 mm but sensitivity is reduced in lesions smaller than 5-8 mm, particularly when localized within organs of high physiologic activity. PET/CT technology has evolved substantially over the last decade, so the sensitivity for small volume disease is also determined by the equipment used. False positive results are rare with experienced reporters as they usually have only low intensity activity, a distinct pattern of distribution, and different anatomic correlates. Pancreatic uncinate process activity is a well-recognized site of physiologic activity, occurring in approximately 25-30% of patients, and should not be mistaken for malignancy (Hofman et al., 2012). The variability of this pattern of uptake, however, suggests that it might represent hyperplasia of normal cells. Reactive nodes demonstrate low-grade activity as activated lymphocytes express SSTR. This typically occurs in a symmetric distribution in mediastinal and hilar nodes, or within the axilla or inguinal region. Osteoblasts also express SSTR and can result in low-grade uptake at sites of degenerative bony disease, fracture, or vertebral hemangiomas. Benign meningiomas are also frequently visualized and should not be mistaken for cerebral metastases. In children, epiphyseal growth plate activity is apparent. Since the spleen contains T-lymphocytes, splenunculi may be mistaken for intra-abdominal nodes.
SSTR PET/CT provides additional information in a high proportion of cases and this confers a high management impact. In the initial cohort of 59 patients imaged at our center, we found a 47% high management impact, defined as an inter-modality change of therapy (Hofman et al., 2012). This high impact was demonstrable in a cohort that had undergone extensive prior investigation including multiple imaging and invasive procedures such as endoscopic ultrasound or surgery. This high impact also occurred in patients with either a negative or positive 111In-octreotide SPECT/CT study, suggesting redundancy of this technique. Other studies also demonstrated a high management impact of SSTR PET/CT (Table 3).
PET SSTR imaging has particular utility in localizing the primary site of disease, which can be occult on anatomic imaging or conventional scintigraphy. This has a major impact in patients with a functional tumor and consequent endocrine syndrome who can be potentially cured following excision of localized disease (Figure 2). In patients with known metastatic disease, localization of an occult primary site of disease remains of value. This is because excision of the primary site, particularly small bowel, should be considered for symptom relief (Plockinger et al., 2009). Furthermore, identification of the primary site provides prognostic information, which may modify treatment plan. In a series of 59 patients with unknown primary site after conventional work-up including multi-slice CT, MRI, abdominal ultrasound and/or endoscopic ultrasound, Ga-68 DOTA-NOC localized the primary in 59%, most commonly in the pancreas and small bowel (Prasad et al., 2010). Our experience suggests that SSTR PET should be employed early in the patient work-up to avoid morbidity and expense of multiple imaging and invasive investigations.
Despite this strong evidence base including demonstration of high management impact, SSTR PET imaging is not widely available, even in centers with PET/CT equipment. This is, in part, a consequence of both regulatory requirements and funding mechanisms. In some jurisdictions, regulatory requirements mandate licensing and testing of radiotracers by a process similar to that used for pharmaceuticals. The cost of this process means that such radiotracers are unlikely to be commercial viable within such jurisdictions. Given that current PET technology uses minute (homeopathic) doses of the actual peptide, the risk is inordinately small (Langstrom et al., 2009), and is insignificant when presented with a patient who might otherwise undergo futile and hazardous surgery or systemic therapy. In other jurisdictions, such as our own in Australia, current reimbursement for conventional 111In-octreotide imaging does not extend to SSTR PET, despite our ability to perform the newer superior test at no additional cost. Others have also favorably compared the cost of these investigations (Schreiter et al., 2012).
FDG PET/CT for Imaging Glycolytic Metabolism
18F-fluorodeoxyglucose (18F-FDG) is a glucose analogue that is widely used for cancer imaging on the basis that tumors use primarily glycolytic metabolism for proliferation. Well-differentiated NETs are typically not visualized on FDG PET owing to their slow rate of proliferation. Conversely, poorly differentiated rapidly proliferating disease has high FDG activity, while SSTR PET has more limited sensitivity (see Figure 1). Thus, the combination of both SSTR and FDG is needed to detect both well- and poorly-differentiated phenotypes (Kayani et al., 2008).
The presence and intensity of uptake on FDG PET/CT is a powerful and independent prognostic factor in patients with neuroendocrine tumors. A prospective trial of 98 patients with neuroendocrine tumors has demonstrated its strong prognostic value (Binderup et al., 2010). Patients with FDG avidity were associated with a significantly higher risk of death (hazard ratio of 10.3). Twenty three percent of the cohort with FDG positivity died during the one-year follow-up compared with 2% of FDG negative patients. This prognostic value exceeded traditional markers such as Ki-67, chromogranin-A, and presence or number of hepatic metastases. Surprisingly, patients with a Ki-67 below 2% who would be previously defined as ENETS Grade 1 and consequently considered to have indolent disease, had a rate of FDG positivity (40%) and adverse outcome. These findings suggest that biopsy is limited by substantial sampling error and that a low threshold for performing FDG PET/CT should be considered. Our current suggested molecular imaging pathway is illustrated in Figure 3.
Imaging Tumor Heterogeneity with SSTR and FDG PET/CT
In patients with metastatic disease, the management plan is conventionally based on the results of biopsy from a single site of disease. This is usually performed by CT- or ultrasound-guided biopsy of a site deemed most accessible and least likely to result in a complication. Alternatively, histopathology is available following surgical excision of a portion of total tumor burden. The histopathologic results then direct subsequent therapy on the presumption that all sites of metastatic disease have a similar phenotype. It is, however, increasingly recognized that analysis of a single tumor biopsy samples may present a major challenge to personalized medicine and biomarker development (Gerlinger et al., 2012).
The combination of SSTR and FDG PET is providing major new insights by identifying patients with populations of well and poorly differentiated disease at different sites (Figure 4). Both of these studies can be performed on a single day owing to the short half-life of Ga-68. This enables whole body lesion characterization and offers advantages over using histopathologic examination of a random site to guide patient management. When histopathologic confirmation is required, directed biopsy of sites of discordant phenotype can be useful to confirm PET findings. Our evolving experience suggests that the combination of SSTR and FDG can be superior to histopathology by demonstrating tumor homogeneity or characterizing intra-individual tumor heterogeneity and thereby directing appropriate therapy.
Directing Management with Molecular Imaging in Patients with Metastatic Disease
Intra-individual tumor heterogeneity may explain the difficulties encountered in validation of oncologic biomarkers owing to sampling bias when using a single site, and may explain unpredictable therapeutic response when using conventional treatment paradigms. As described above, the combination of SSTR and FDG PET enables powerful whole body lesion characterization, enabling identification of targets and assisting with selection of the most appropriate therapy for an individual patient.
The identification of high SSTR expression by octreotide scintigraphy can be used to select patients for clinical treatment with somatostatin analogues such as long-acting formulations of octreotide. Use of 111In- octreotide scintigraphy has evolved as an effective mechanism to identify patients who are likely to benefit from treatment (Janson et al., 1994). This is highly effective in controlling symptoms caused by hypersecretion of hormones and may also have a role as anti-proliferative agent in selected patients (Rinke et al., 2009). This provides the basis for theranostics, a portmanteau of therapeutic and diagnostic, in which imaging is used to identify the target that treatment is subsequently directed against. In this instance, imaging identifies patients with sufficient SSTR expression that are likely to benefit from SSTR agonist therapy.
SSTR imaging also enables selection of patients for peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues. For this therapy, the same peptides used for imaging are labeled with beta, Auger, or alpha emitters that cause DNA damage through their particulate emission. 177Lu-DOTA-Octreotate (LuTate) has been shown to improve survival and markedly improve quality of life with a very low incidence of adverse effects (Kwekkeboom et al., 2008; 2005). Other effective agents include yttrium-90 (90Y) and 111In (Hicks, 2010). In addition to selecting patients suitable for PRRT, SSTR PET can help personalize dosimetry. We have demonstrated with SSTR PET/CT that sequestration of radiotracer within tumor causes a sink effect that decreases concentration of activity in healthy organs such as the kidney (Beauregard et al., 2012). Accordingly, compared to a fixed dose PRRT protocol, an adjusted-dose regimen tailored to SSTR PET/CT findings may allow increasing administered dose without adding to toxicity in normal tissues.
Patients with FDG positive but SSTR PET negative disease cannot be effectively targeted with either octreotide or PRRT, as the negative SSTR PET indicates that the obligatory target is not expressed. Such patients may benefit from conventional chemotherapy or newer biologic agents such as everolimus or sunitinib, which inhibit m-TOR and tyrosine kinase, two pathways involved in NET proliferation, respectively (Raymond et al., 2011; Yao et al., 2011). In patients with dominant liver disease, directed therapy such as transarterial chemo-embolization (TACE) or SIR-Spheres, which are microspheres impregnated with yttrium-90, can also be considered. Surgery remains an option in patients with limited metastatic disease.
Conventional paradigms suggest that patients with higher grade, poorly differentiated disease (ENETS Grade 3 or 2), as marked by FDG positivity, have a poor prognosis and are not likely to benefit from either somatostatin analogue therapy or PRRT. These patients are typically treated with chemotherapy or biologic therapies, but responses are often limited or short lived. However, if all sites of higher grade disease retain sufficient SSTR expression as evidenced by concordant FDG and SSTR PET uptake, then there is potential to target these sites of aggressive disease with PRRT. Indeed, it is our experience that many such patients have striking responses to PRRT, including those who have failed conventional therapies.
Molecular imaging has identified a new subgroup of patients with both well- and poorly-differentiated disease at different sites. This helps explain why in some patients, there is regression at some sites and progression at others following therapy. Given that death is usually related to the poorly-differentiated disease, it is imperative that these are sites that are targeted first. In patients with mixed disease and symptoms due to hypersecretion of hormones, octreotide or PRRT may still be indicated as the well-differentiated cells are the likely source.
Assessing Response to Therapy
Response assessment is pivotal to enable a change of strategy if treatment is failing and to avoid the morbidity and cost of ineffective therapy. This is particularly important in NET given the heterogeneity of disease and the array of therapies available. Conventional imaging paradigms rely on measuring a change in size or contrast enhancement on CT or MRI. This is typically performed after at least three months of therapy with changes in size used as proxy for response. The limitations of CT and MRI for response assessment are increasingly evident in the molecular imaging era (Table 4). Inaccurate assessment of disease aggressiveness at presentation can also result in inaccurate conclusions of therapeutic response. For example, disease of low proliferative index that does not diminish following a course of chemotherapy can be erroneously classified as a treatment failure. The lack of change, however, might be merely a reflection of a well-differentiated phenotype that would not have changed in size over many years even without treatment; a negative FDG PET/CT at baseline can be useful to predict this temporal change.
Tumor size can increase or remain unchanged despite actual response due to cystic, myxoid, or fibrotic change (Figure 5). In such instances, patients can be miscategorized as having a poor response or progressive disease, resulting in inappropriate cessation of effective therapy. Moreover, in patients with multiple sites of disease, identification of the relevant target lesion to follow can be difficult. There is a bias to selecting lesions which are easy to measure such as nodes or liver lesions whereas osseous or sub-cm disease evident on baseline molecular imaging is overlooked. Identification of liver metastases, which are prevalent in NET, generally relies on a three phase contrast CT. Lesions appear different in size on each phase, and small changes in timing or technique of contrast administration can result in apparent change in size. In patients with carcinoid heart disease, contrast timing will be unavoidably altered due to changes in underlying physiology. Measurement is also subject to substantial reporter variability, especially when lesions have irregular shape or when patients are positioned differently. Despite all these limitations, studies to date rely primarily on anatomic measurement, such as the Response Evaluation Criteria in Solid Tumors (RECIST), to assess response (Eisenhauer et al., 2009). Inaccuracy of such methods may explain why factors such as progression free survival can be discordant with measures of overall survival.
Molecular imaging enables measuring a change in target following therapy in addition to size. With SSTR and FDG PET/CT changes in SSTR expression and glycolytic metabolism can be measured non-invasively. This can be quantified using semi-automated tools, which trace the tumor boundaries enabling measurement of both target intensity and size. This can be performed easily in three dimensions providing volumetric measurements. Very high tumor to background contrast makes measurement highly reproducible. Results can be displayed in maximum intensity projection (MIP) images, which provide a whole body overview that are intuitively understood by both physicians and patients (Figure 6). Changes can also be assessed early as metabolic changes typically precede anatomic changes by weeks or months. Perhaps most importantly, molecular imaging enables characterization of changes in poorly- and well-differentiated phenotypes at different sites. This is pivotal to redirect appropriate management.
Molecular imaging is improving outcomes in patients with neuroendocrine tumors, through improved diagnosis, staging, and ability to better assess response to treatment. For staging, the role of imaging is changing from one of lesion counting to lesion characterization. SSTR and FDG PET/CT are able to quantify sites of well and poorly differentiated disease, respectively. The ability to perform this as a whole body study in patients with metastatic disease is highlighting the limitations of histopathology obtained from a single site. By identifying patients with aggressive phenotype, FDG PET/CT has powerful independent prognostic utility, while SSTR PET/CT is able to direct patients to octreotide or PRRT. The combination is leading to recognition that some patients have heterogeneous disease phenotypes and is enabling better restaging by quantifying changes in target expression rather than size alone. This is leading to better individualized therapy and improving patient outcomes.
Prof. Rodney J. Hicks is the recipient of a Translational Research Grant from the Victorian Cancer Agency, which sponsored his research in neuroendocrine tumors.
R.J.H. is on the Advisory Boards of both Novartis and Pfizer but receives no payment for these services. M.S.H. reports no conflicts of interest.
Rodney J. Hicks, M.B.B.S., M.D., Professor and Director, Centre for Cancer Imaging, Peter MacCallum Cancer Centre and Co-Chair, Neuroendocrine Service, University of Melbourne, St. Andrews Place, East Melbourne, Victoria 3185, Australia.
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