Critical Review
The Use of Positron Emission Tomography (PET) in the Staging/Evaluation, Treatment, and Follow-Up of Patients With Lung Cancer: A Critical Review

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Introduction

The availability of clinical positron emission tomography (PET) is increasing rapidly in the developed world (1). This article reviews the role of PET scanning in lung cancer, emphasizing issues relevant to the radiation oncology community. Fused PET/computed tomography (CT) images, acquired using modern hybrid scanners, are the most powerful means currently available for imaging lung cancer and are more accurate than either PET and CT scans acquired separately (2). Advantages of PET/CT include greater precision in localizing suspicious tracer uptake, improving both sensitivity and specificity, more accurate quantification of tracer uptake, and improved radiation therapy (RT) planning. Although stand-alone PET is being superseded by PET/CT, many older studies remain relevant because extensive data are not yet available for hybrid scanners.

Most lung cancers have increased activity of glucose transporters and increased hexokinase activity compared with normal cells. After phosphorylation by hexokinase, fluorodeoxyglucose (FDG) usually accumulates at a higher rate in lung cancer cells than nearby normal tissues. FDG, labeled with the positron-emitting isotope 18F, is the radiopharmaceutical of choice for imaging lung cancer. Other agents, such as 18F-fluorothymidine (FLT) or 18F-misonidazole (FMISO), can provide significant physiological information—for example, by indicating the extent of proliferation (3) or hypoxia (4) in a tumor. Most published studies of PET in lung cancer refer to non–small cell lung cancer (NSCLC), and this review does not consider other tumor types.

Intensity of uptake in a lesion on PET can be assessed using the standardized uptake value (SUV), which is derived by dividing the tissue radioactivity by the injected dose and their weight and multiplying the result by a correction factor. Biological factors, such as obesity and blood glucose levels, influence FDG uptake in tissues. PET imaging is also affected by technical factors, including scanner performance and scan timing after tracer injection. Because of the limited spatial resolution of PET (approximately 5 mm), SUV assessment in small lesions, especially those less than 1cm, is highly inaccurate. Highly FDG-avid tumors smaller than 5 mm may still be visualized qualitatively even if their SUV is grossly underestimated. Lesions can only be detected by FDG-PET if their uptake of FDG differs from surrounding normal tissues. In the brain, where uptake of FDG is normally high, FDG-PET cannot detect small metastases and is inferior to CT or MRI. In other tissues, PET can usually image avid lesions measuring 1 cm or more.

Tracer uptake is underestimated in lesions that move significantly with respiration because counts detected by the scanner are averaged within the volume of movement. Gated-acquisition of PET data can increase the accuracy of assessment of moving tumors (5). Although PET provides only a semiquantitative estimate of lesional tracer uptake, automated SUV-based methods have been used to “objectively” define the margins of lesions for radiation therapy planning. This approach can lead to highly inaccurate delineation of tumor margins if the confounding factors listed earlier are not considered. Nevertheless, SUV assessment can be extremely valuable. Intensity of FDG uptake is a prognostic factor, and changes in SUV can be used to assess response to therapy. SUVmax estimates FDG uptake in the “hottest” region of the tumor. Higher SUVmax levels are associated with worse outcomes in NSCLC (6).

Section snippets

PET in the Evaluation of Pulmonary Lesions

FDG-PET is useful for evaluating undiagnosed pulmonary masses. Approximately 30%–50% of solitary pulmonary nodules (SPNs) in the United States are primary lung cancers. Most lung cancers are FDG avid, and pulmonary lesions with higher FDG uptake are more likely to be malignant. In a meta-analysis of 40 studies, FDG-PET attained sensitivity and specificity of 96.8% and 77.8%, respectively 7 (Table 1). That meta-analysis failed to confirm that semiquantitative image interpretation improved the

FDG-PET staging before surgery in NSCLC

FDG-PET can help prevent unnecessary surgery by detecting intrathoracic lymph node (LN) metastases or distant metastases. Major lung resections are associated with significant perioperative mortality and risks of long-term morbidity. Futile surgery for patients with unresectable NSCLC needlessly exposes patients to these risks and both delays and compromises other therapies such as radical chemoradiation.

CT-determined nodal size (short axis diameter > 1 cm) has been routinely used to decide

Role of PET in Radiation Therapy Planning

The role of PET in RT planning is a topic of intensive research 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39. A summary of significant studies in which the impact of PET on RT planning was studied is shown in Table 3. In the earliest studies, estimates of the influence of PET on treatment volumes were made visually or using simple graphical methods. More recent studies have employed coregistered, separately acquired images or, best of all, integrated PET/CT images. All studies show

Role of PET in Response Assessment in Lung Cancer

Changes in tumor dimensions, measured using structural imaging modalities such as CT and MRI, are widely used for therapeutic response assessment following nonsurgical therapy (44). However, tumors are composed of variable proportions of malignant cells, stroma, and inflammatory cells. Changes in tumor dimensions after therapy reflect the sum total of changes in all of these components and may occur slowly and incompletely. In NSCLC, a residual fibrotic mass often remains after curative

Surveillance after Definitive Therapy

Few studies have addressed the role of PET in longer-term follow-up after definitive treatment of NSCLC. Limited data suggest that PET imaging after lung resection or RT can help confirm or exclude relapse. The extent of relapsed disease, when stratified by FDG-PET into local, locoregional, or metastatic disease, has prognostic significance (55).

Conclusions

Poor patient selection and inappropriate target volume determination, both of which are consequences of inadequate tumor imaging, have undoubtedly contributed to the historically dismal results of radical RT in NSCLC. We now know that about one third of patients treated with radical RT in the pre-PET era had disease that would be considered incurable at the outset with our current treatment protocols. It is also likely that many potentially curable patients did not receive high-dose RT to all

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