Lung cancer is the most commonly diagnosed cancer, accounting for 11.6% of all cases, and the leading cause of cancer death (18.4% of all cancer deaths).1 It is classified as non-small cell lung cancer (NSCLC), which accounts for 85–90% of all lung cancers, small-cell lung cancer (SCLC), and neuroendocrine tumours (NET).2 For all subtypes, early and accurate diagnosis and staging is essential to increase the likelihood of survival. The first step in the diagnostic process is a chest X-ray to detect abnormal areas in the lung, but its low resolution means that around 25% of lung cancers are not detected by this method (false negatives).3 Low-dose helical computed tomography (CT) has become the recommended imaging modality for lung cancer diagnosis and staging, and is associated with a 20% reduction in lung cancer deaths compared with annual chest radiographs.4 However, low-dose CT has limitations: the use of the radiotracer 18F fluorodeoxyglucose (FDG) has a high rate of nodule detection, leading to false positives that necessitate follow-up CT scans, and the associated expense and increased radiation dose; the cost and risks of biopsy of benign nodules; and a small, but not negligible, risk of cancer associated with multiple follow-up CT scans.5
Due to the limitations of CT, examination with FDG positron emission tomography (PET)/CT is becoming an increasingly important tool in the clinical staging of patients with lung cancer since it combines anatomic information from CT and metabolic details from PET. However, false positives can occur since inflammatory or infectious conditions also have high metabolic rates, and therefore have high 18F-FDG uptake.6 New radiotracers targeting different aspects of lung cancer biology are, therefore, in clinical development. For example, the combination of dual-tracer PET/CT and 18F-fluorothymidine may improve diagnostic accuracy.7
Single-photon emission computed tomography (SPECT) is another useful imaging modality for the diagnosis of lung cancer.8 A hexosamine pathway tracer, 99mTc-ethylenedicysteine-glucosamine (99mTc-EC-G), has been developed as a more specific alternative to 18F-FDG in the detection and staging of NSCLC using SPECT. A recent phase II clinical study found that 18F-FDG PET/CT and 99mTc-EC-G SPECT/CT were equivalent in terms of detecting primary and metastatic tumours.9
Screening for brain metastases is also an important aspect of lung cancer diagnosis and screening. Around 10–20% of NSCLC patients have brain metastases at the time of diagnosis and around 40% will develop them during the course of their disease.10 Screening for brain metastases is important, as it could change the treatment plan for a patient with otherwise early stage disease. Gadolinium enhanced magnetic resonance imaging (MRI) is more sensitive than contrast-enhanced computed tomography (CE-CT); however CE-CT is often used because of contra-indications to MRI or lack of access to MRI.11
The role of imaging has expanded beyond diagnosis and staging; molecular imaging can also provide useful information about tumour biology. Overexpression and/or mutations of the receptor tyrosine kinase (RTK) subfamilies, such as epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), are associated with tumour growth, differentiation, proliferation, apoptosis, and invasiveness. Therapies that target these signalling pathways have shown excellent outcomes in lung cancer but at present, there is no way of predicting which patients will respond best to therapy and monitoring the development of resistance, A number of radiolabelled antibodies are currently in development for use with PET imaging patients with in lung cancer.12
In NSCLC, activation of the c-Met signalling pathway can cause cancer progression and may facilitate acquired resistance to EGFR-targeted therapy. A SPECT peptide tracer targeting the cMet receptor, 99mTc-HYNIC-cMBP, produced clearer images in less time than currently used tracers and was more rapidly eliminated from the body, reducing radiation exposure.13
A novel PET radiotracer, 18F-ODS2004436, which selectively targets and binds to forms of EGFR that contain activating mutations, is currently being evaluated in an early stage phase I clinical trial. If successful, this approach will complement mutation analysis in the prediction of responsiveness to EGFR tyrosine kinase inhibitors (TKIs) and the selection of patients that respond well to those kinase inhibitors that specifically target forms of EGFR with activating mutations.14
Hypoxia is also an important factor that is closely associated with radiotherapy and chemotherapy resistance, metastasis and prognosis. Investigations into molecular imaging tracers for hypoxia are less advanced than other parameters, although recent studies suggest that 18F fluoromisonidazole (18FFMISO)-PET is a promising radiotracer whose uptake is strongly associated with poor prognosis.15,16
Advances in technology have enabled other new applications for PET/CT imaging, including quantitative assessment of response to treatment, determining patient prognosis, and predicting treatment outcome in NSCLC.17 In a retrospective study, NSCLC patients treated with nivolumab underwent pre-treatment FDG-PET to assess tumour burden. A significant association was found between tumour burden and overall survival.18 Another study has shown that tumour PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients using 89Zr-nivolumab.19 This has important implications for predicting responses to immune checkpoint inhibitors.
Imaging in lung cancer still has challenges to overcome. Respiratory motion during PET imaging can cause image blurring and affect the measurement of tracer uptake. New digital PET technology will be used within hybrid PET/MR systems that gives improved motion correction.20 In addition, new PET imaging features. There is still a need for validation studies of new radiotracers and newer PET/CT scanners with improved sensitivity and spatial resolution to enable better tumour detection. Since almost every patient with lung cancer is scanned with PET/CT, techniques for large-scale management of these data for quantitative image analysis is also needed.17
In summary, advances in multimodal molecular imaging is enabling us to better stratify patients with lung cancer in clinical trials of new immunotherapeutic agents, facilitate response prediction and help clinicians with treatment decisions for individual patients.
1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
2. Davidson MR, Gazdar AF, Clarke BE. The pivotal role of pathology in the management of lung cancer. J Thorac Dis. 2013;5 (Suppl 5):S463–78.
3. Bradley S, Abraham S, Grice A, et al. Sensitivity of chest X-ray for lung cancer: systematic review. Br J Gen Pract. 2018;68(Suppl 1):bjgp18X696905.
4. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409.
5. Jett JR, Limitations of screening for lung cancer with low-dose spiral computed tomography. Clin Cancer Res. 2005;11:4988s–92s.
6. Kubota R, Kubota K, Yamada S, et al. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–12.
7. Crandall JP, Tahari AK, Juergens RA, et al. A comparison of FLT to FDG PET/CT in the early assessment of chemotherapy response in stages IB-IIIA resectable NSCLC. EJNMMI Res. 2017;7:8.
8. Piai DB, Quagliatto R Jr, Toro I, et al. The use of SPECT in preoperative assessment of patients with lung cancer. Eur Respir J. 2004;24:258–62.
9. Dai D, Rollo FD, Bryant J, et al. Noninferiority of (99m)Tc-Ethylenedicysteine-Glucosamine as an Alternative Analogue to (18)F-Fluorodeoxyglucose in the Detection and Staging of Non-Small Cell Lung Cancer. Contrast Media Mol Imaging. 2018;2018:8969714.
10. Moro-Sibilot D, Smit E, de Castro Carpeno J, et al. Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: Analysis from the European FRAME study. Lung Cancer. 2015;90:427–32.
11. Schoenmaekers J, Dingemans AC, Hendriks LEL, Brain imaging in early stage non-small cell lung cancer: still a controversial topic? J Thorac Dis. 2018;10:S2168–s71.
12. Wei W, Ni D, Ehlerding EB, et al. PET Imaging of Receptor Tyrosine Kinases in Cancer, Mol Cancer Ther, 2018;17:1625–36.
13. Han Z, Xiao Y, Wang K, et al. Development of a SPECT Tracer to Image c-Met Expression in a Xenograft Model of Non-Small Cell Lung Cancer. J Nucl Med. 2018;59:1686–91.
14. Cochet A, Isambert N, Foucher P, et al. Phase 0/1 of positron emission tomography (PET) imaging agent [18F]-ODS2004436 as a marker of EGFR mutation in patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 36:15(Suppl):e24184.
15. Li L, Wei Y, Huang Y, et al. To Explore a Representative Hypoxic Parameter to Predict the Treatment Response and Prognosis Obtained by [(18)F]FMISO-PET in Patients with Non-small Cell Lung Cancer. Mol Imaging Biol. 2018;20:1061–7.
16. Vera P, Thureau S, Chaumet-Riffaud P, et al. Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by (18)F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study). J Nucl Med. 2017;58:1045–53.
17. Konert T, van de Kamer JB, Sonke JJ, et al. The developing role of FDG PET imaging for prognostication and radiotherapy target volume delineation in non-small cell lung cancer. J Thorac Dis. 2018;10:S2508–s21.
18. Ito K, Tang R, Schoder H, et al. Prognostic value of total lesion glycolysis on pretreatment F-18 FDG PET/CT in patients with advanced NSCLC treated with nivolumab. J Nucl Med. 2018;59(Suppl 1):206.
19. Niemeijer AN, Leung D, Huisman MC, et al. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018;9:4664.
20. Kolbitsch C, Neji R, Fenchel M, et al. Respiratory-resolved MR-based attenuation correction for motion-compensated cardiac PET-MR. Phys Med Biol. 2018;63:135008.