18F-FLT PET imaging of cellular proliferation in pancreatic cancer

https://doi.org/10.1016/j.critrevonc.2015.12.014Get rights and content

Highlights

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    There is a potential for integrating other imaging modalities in the management of pancreatic cancer.

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    Standard uptake values from 18F-FLT PET images have been shown to correlate with cellular proliferation in some malignancies.

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    18F-FLT PET in GI malignancies is limited by high physiologic radiotracer uptake in surrounding normal tissues and liver.

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    18F-FLT PET has higher specificity but lower sensitivity compared to 18F-FDG PET for measurement of cellular proliferation.

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    Dynamic imaging with 18F-FLT PET allows an improved understanding of treatment effects and detection of liver metastases.

Abstract

Pancreatic ductal adenocarcinoma is known for its poor prognosis. Since the development of computerized tomography, magnetic resonance and endoscopic ultrasound, novel imaging techniques have struggled to get established in the management of patients diagnosed with pancreatic adenocarcinoma for several reasons. Thus, imaging assessment of pancreatic cancer remains a field with scope for further improvement. In contrast to cross-sectional anatomical imaging methods, molecular imaging modalities such as positron emission tomography (PET) can provide information on tumour function. Particularly, tumour proliferation may be assessed by measurement of intracellular thymidine kinase 1 (TK1) activity level using thymidine analogues radiolabelled with a positron emitter for use with PET. This approach, has been widely explored with [18F]-fluoro-3′-deoxy-3′-l-fluorothymidine (18F-FLT) PET. This manuscript reviews the rationale and physiology behind 18F-FLT PET imaging, with special focus on pancreatic cancer and other gastrointestinal malignancies. Potential benefit and challenges of this imaging technique for diagnosis, staging and assessment of treatment response in abdominal malignancies are discussed.

Introduction

Pancreatic ductal adenocarcinoma carries one of the poorest prognoses amongst gastrointestinal malignancies; with very similar incidence and mortality rates, it is the fourth leading cause of cancer-related death in men and women (Jemal et al., 2011). Unfortunately, most patients (up to 80%) are diagnosed at an advanced stage and palliative chemotherapy is the only option for treatment. There is therefore a clear need to improve the management of pancreatic cancer and considerable effort has been put in the development of novel therapies, albeit with limited success. Implicit in improvements in therapy is the need for advancements in imaging to aid the diagnosis and monitoring of treatment (especially in the identification of early detection of therapy efficacy). Currently, imaging techniques used in patients with pancreatic cancer include abdominal ultrasound (US), computerized tomography (CT), endoscopic ultrasound (EUS) and magnetic resonance (MR) for the diagnostic work-up and CT or MR for the assessment of response to therapy (Seufferlein et al., 2012). Although molecular imaging methods such as positron emission tomography (PET) and functional MR methods can provide functional information on the tumour pathophysiology, their use has been limited; to date, the glucose analogue 2-deoxy-2-[18F]-fluoro-d-glucose (18F-FDG PET) probing the glycolytic pathway, has been the most evaluated tracer in pancreatic cancer. The potential to image tumour proliferation by assessing the turnover of the DNA nucleoside thymidine has been exploited by imaging [18F]-fluoro-3′-deoxy-3′-l-fluorothymidine (18F-FLT), an analogue of thymidine with PET. This review summarizes the current knowledge supporting PET molecular imaging in patients with pancreatic cancer with a focus on the rationale and potential uses and limitations of imaging with 18F-FLT PET pancreatic adenocarcinoma and other gastrointestinal malignancies.

Section snippets

Pancreatic cancer overview

Pancreatic ductal adenocarcinoma is known for its poor prognosis; approximately 45,220 patients are diagnosed annually with pancreatic adenocarcinoma in the United States; almost all of them are expected to die from the disease (Siegel et al., 2013). Five-year survival rate after the diagnosis is around 5% for all the stages: 20% for patients diagnosed with early stage disease and <1% for advanced stages (Oettle et al., 2007, Neoptolemos et al., 2004).

The majority of pancreatic tumours (85%)

Overview of 18F-FLT PET imaging

Thymidine is a native nucleoside, which is exclusively incorporated into the cellular DNA. This property is exploited in titrated thymidine assays, commonly used to measure cellular proliferation (Been et al., 2004). Thymidine is taken up into cells by the nucleoside transporters located in the cell membrane and phosphorylated to thymidine mono-/bi-/tri-phosphate by the cytosolic enzyme thymidine kinase-1 (TK1) (See Fig. 1).

The measurement of intracellular levels of phosphorylated thymidine (as

Background and rationale for use of 18F-FLT PET in pancreatic cancer

In addition to its potential as a marker of cellular proliferation, 18F-FLT PET imaging may have a potential benefit in pancreatic cancer by virtue of it being, like gemcitabine, a substrate of the human equilibrative nucleoside transporter (hENT) family, that have been identified in pancreatic cancer cell lines (Garcia-Manteiga et al., 2003) and in human tissue samples of pancreatic adenocarcinoma (Spratlin et al., 2004). However, the relationship between hENT and 18F-FLT uptake remains a

Challenges for the identification of primary tumours

Although PET is generally combined with other high resolution modalities such as CT, for improvement of the anatomic localisation, characterisation of the metabolic activity remains challenging. Due to the low background activity of 18F-FLT in the thorax, lung cancer has been the main area of development (Yamamoto et al., 2008a, Yamamoto et al., 2007, Yamamoto et al., 2008b, Yap et al., 2006), followed by breast (Smyczek-Gargya et al., 2004), head and neck cancer (Troost et al., 2007) and

Current role of 18F-FLT imaging in gastrointestinal malignancies

The use of 18F-FLT in gastrointestinal cancers is limited in part by the high physiologic uptake in the abdomen (liver, intestines, kidneys and bladder where 18F-FLT is metabolised and excreted), which contrasts with animal xenograft models where the tumours are often grown subcutaneously rather than in the organ of origin of the tumour. Even within these limitations, 18F-FLT has demonstrated mixed utility in several studies, summarised in Table 3.

18F-FLT PET in pancreatic cancer: current experience

In two different pancreatic cancer cell lines

Conclusions

The main role of 18F-FLT PET in pancreatic cancer is likely to be in detecting response to treatment. To improve the interpretation of results, investigators need to better understand the relative contribution of the multiple processes involved in tumour 18F-FLT uptake. The extent to which 18F-FLT uptake in pancreatic tumours reflects cellular proliferation needs to be validated in tissue resection specimens and correlated with proliferation markers such as MIB-1. 18F-FLT PET may be especially

Conflict of interest

Authors declare no conflict of interest.

Funding

A.L. is part-funded by the ESMO Translational Fellowship Programme and Pancreatic Cancer Research Fund (PCRF).

Angela Lamarca Dr. Lamarca is a Medical Oncologist, specialising in gastrointestinal malignancies (mainly hepato-pancreato-biliary and neuroendocrine tumours). She is currently completing a Clinical Research Fellowship at The Christie NHS Foundation Trust (funded by ESMO Translational Fellowship programme and Pancreatic cancer Research Fund) where she is involved in imaging and therapeutic research and clinical trial design.

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    • Cited by (0)

    Angela Lamarca Dr. Lamarca is a Medical Oncologist, specialising in gastrointestinal malignancies (mainly hepato-pancreato-biliary and neuroendocrine tumours). She is currently completing a Clinical Research Fellowship at The Christie NHS Foundation Trust (funded by ESMO Translational Fellowship programme and Pancreatic cancer Research Fund) where she is involved in imaging and therapeutic research and clinical trial design.

    Marie-Claude Asselin Dr. Asselin is a Senior Lecturer in Quantitative Imaging at The University of Manchester, UK. She is currently involved in the development and application of quantification methods, in particular pharmacokinetic analyses, for PET imaging of cellular proliferation, tumour hypoxia, perfusion and efflux transporters in cancer and cerebral diseases, both preclinically and clinically.

    Prakash Manoharan Dr. Manoharan is a Consultant radiologist and nuclear medicine physician and is the clinical service lead for MRI and diagnostic nuclear medicine. He is dually accredited in Radiology and Nuclear Medicine, with sub speciality fellowships in Nuclear Medicine (UK), Oncology body MRI/CT (UK) and Nuclear Medicine/PET CT/ advanced radionuclide therapy (University of Michigan, Ann Arbor, USA). Dr Manoharan’s main research activity is in the role of functional and molecular imaging in Oncology, especially looking at imaging biomarkers of response to therapy or intervention. He developed and delivers neuroendocrine tumour molecular imaging and targeted therapy at The Christie.

    Mairéad McNamara Dr. McNamara is a Senior Lecturer/Honorary Consultant in Medical Oncology (University of Manchester/The Christie NHS Foundation Trust). She treats patients with a diagnosis of Hepato-pancreato-biliary cancer and Neuroendocrine tumours and she leads and participate in clinical trials in this subject area. She completed a 3-year clinical research fellowship in “Princess Margaret Cancer Centre”, Toronto, Canada (2011–2014) in Gastrointestinal tract cancers and Central Nervous System tumours. She also has a degree in Biochemistry and a Ph.D. in Pharmacology (National University of Ireland, Galway).

    Ioannis Trigonis Dr. Trigonis is a Medical Oncologist with clinical research experience in proliferation imaging of lung and other tumours using FLT PET. His special interests include evaluating response to radiotherapy using PET.

    Richard Hubner Dr. Hubner is a Medical Oncologist specialising in the treatment of patients with hepato-pancreatico-biliary (HPB) tumours, and is a member of a specialist HPB MDT which relies on multiple imaging modalities to advice on best practice management of patients with pancreatic cancer.

    Azeem Saleem Dr. Saleem is a translational imaging Oncologist and Head of Oncology and Respiratory Medicine Applications at Imanova Centre for Imaging Sciences, London; a joint venture of Medical Research Council, UK, Imperial College London, Kings College London and University College London. London. He holds Honorary Senior Clinical Lectureship at Imperial College, London and at the University of Manchester and is an Honorary Senior Oncology Physician at Imperial Healthcare NHS Trust. He collaborates closely with academia and industry in the integration of molecular imaging in early phase clinical trials and in the development of novel molecular imaging biomarkers and methodology.

    Juan Valle Prof Valle is a Professor in Medical Oncology at The University of Manchester. He leads and participates in phase Ib to III clinical trials in the field of hepato-pancreato-biliary cancers (hepatocellular carcinoma, pancreas and biliary tract) and neuroendocrine tumours; he collaborates closely on research with the Cancer Research UK Manchester Institute laboratories and the Wolfson Molecular Imaging Centre. He is also a regular faculty member at National and International congresses, seminars and symposia in the field of HPB and neuroendocrine tumours.

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