The Evolving Role of Molecular Imaging in Non–Small Cell Lung Cancer Radiotherapy

https://doi.org/10.1016/j.semradonc.2014.12.001Get rights and content

Molecular imaging with positron emission tomography (PET) has dramatically changed the management of patients with lung cancer who are treated with radiotherapy. Uptake of the most widely used PET radiopharmaceutical 18F-fluorodeoxyglucose identifies lung nodules or intrathoracic lymph nodes as likely to be malignant and frequently identifies previously unsuspected sites of malignant disease outside the thorax. Patients with non–small cell lung cancer, especially those with apparently more advanced locoregional disease to start with, are often upstaged, and this has a profound effect on their subsequent management. Better patient selection, primarily by excluding patients with PET-detected advanced disease, and better targeting of radiotherapy to avoid geographic miss have contributed significantly to improvements in outcome in recent series of patients treated with definitive chemoradiation. Advances in motion management with 4-dimensional PET/computed tomography and research into sequential imaging during treatment to permit response-adapted therapy hold promise for further improvements in treatment outcomes. Research involving novel PET tracers that can characterize biological properties of tumors, such as proliferation or hypoxia, may help develop more personalized approaches to patient management in the future.

Introduction

The clinical positron emission tomography (PET) scanner has transformed the world of molecular imaging of cancer. This technology, which first found application in oncology more than 3 decades ago, allows the biodistribution of molecules labeled with positron emitters to be imaged in human beings with a sensitivity and resolution that was previously unparalleled in nuclear medicine. It was soon applied to lung cancer and became an essential imaging tool for staging.1 Together with advances in radiotherapy (RT) planning and delivery systems, better motion management, and the rapidly increasing use of stereotactic body RT (SBRT) for small extracranial tumors, PET has contributed to significant recent improvements in the management of patients with non–small cell lung cancer (NSCLC) treated with RT.

Modern PET/computed tomography (CT) scanners have overcome many of the limitations of earlier stand-alone PET devices and have higher resolution, shorter imaging times, and expanded fields of view. Their increased sensitivity allows the use of lower administered amounts of radiotracer. Most importantly, coregistration of contemporaneously acquired structural (CT) and functional (PET) information in modern PET/CT scanners produces hybrid images of unparalleled accuracy and detail that can portray the location of tumor deposits with high contrast between normal and neoplastic tissue, combined with exquisitely detailed anatomical information. When PET/CT is performed using the tracer 18F-fluorodeoxyglucose (FDG), the resulting images, which include electron density information from the CT component, provide the best available imaging tool for RT planning in NSCLC.2, 3

FDG-PET/CT provides much more accurate staging information than the previous imaging gold standard of CT scanning does (even when augmented by radionuclide bone scanning and liver ultrasound as considered appropriate). Because of this much greater accuracy, PET/CT imaging has become the imaging modality of choice for selecting patients for either surgery or curative intent RT. Patients with extensive PET-detected thoracic or distant metastatic disease can instead receive more appropriate palliative therapies. When used for planning RT in NSCLC, PET/CT can increase the accuracy of tumor targeting while simultaneously reducing unnecessary irradiation of normal tissues.4, 5, 6 PET/CT-based target volume definition leads to much greater reproducibility between observers when compared with that of CT-based planning.7 PET has contributed to a gradual improvement on reported outcomes for patients with locoregionally advanced NSCLC treated with curative-intent chemo-RT in recent years.

Although small cell lung cancer is also imaged sensitively by PET, there have been few prospective studies on this disease.8, 9, 10, 11, 12, 13 This article considers the use of PET in patients with NSCLC and its role in staging, patient selection, and RT target volume delineation. Although FDG is currently the most valuable PET radiopharmaceutical in NSCLC, the potential of other tracers is briefly discussed. Some of the most useful data on PET in lung cancer date from the stand-alone PET era. PET/CT is even more accurate, and as more time elapses, the long-term results of PET/CT are likely to surpass those of separately acquired from PET and CT imaging. Innovations such as time-of-flight and point-spread function further increase signal to background contrast, but at the potential risk of trading higher sensitivity for poorer specificity.14

Section snippets

Characterizing Lung Nodules With PET/CT

By the time a radiation oncologist sees the patient, the diagnosis of lung cancer is usually established and the patient has often already been determined not to be a surgical candidate because of disease extent or medical comorbidities. However, the literature on PET evaluation of pulmonary nodules contains lessons that are valuable when RT is being considered for a patient with NSCLC. High FDG uptake in a nodule is strongly correlated with malignancy, especially in the presence of known lung

Intrathoracic Lymph Node Evaluation With PET/CT

In modern RT regimens for NSCLC, elective nodal irradiation is rarely used, and therefore, accurate noninvasive characterization of intrathoracic nodes is essential for target volume definition. The planning target volume (PTV) must include all positive lymph nodes and should also exclude uninvolved nodes to minimize toxicity. CT performs very poorly in this regard because lymph node size, with an arbitrary cutoff point (usually short axis diameter of 1 cm), is used to categorize nodes as

Detection of Distant Metastasis by PET

The rate of detection of unsuspected distant metastasis by PET is highest in patients with more locoregionally advanced disease, the very group of patients most likely to be considered for RT,43 with >20% of patients with apparent stage III disease found to have metastasis on PET imaging (Fig. 1). A meta-analysis of 581 patients with lung cancer indicated that overall 12% had PET-detected distant metastasis.44 Studies of individual organs at risk for metastasis show that PET- and

Use of PET to Select Patients for Curative RT

A key role of PET in NSCLC is in patient selection for RT. Patients with stage IIIA or IIIB NSCLC are candidates for potentially curative RT or chemo-RT if they have disease that can be encompassed within a tolerable treatment volume and if they have a relatively good performance status. Patients with stages I-II NSCLC may also be candidates for curative RT if they cannot undergo resection because of medical comorbidities, such as severe chronic pulmonary disease. Complete surgical staging is

Use of PET to Assess the Biology of NSCLC

PET scans can give useful insights into tumor biology in NSCLC. Tumors with high standardized uptake value (SUV) levels on FDG-PET scans tend to be more rapidly growing and have higher proliferation markers, including Ki67, as discussed earlier. Resected early-stage tumors with a high SUV are more likely to relapse with distant metastases,68, 69 as are FDG-avid tumors treated with RT in medically unresectable patients.70, 71, 72 It has been reported that in patients with locoregionally advanced

Defining the PTV With PET/CT

When defining the PTV in NSCLC, CT and FDG-PET data are both required; CT data are required to provide detailed information on the electron density, anatomy, and structure of tissues and FDG-PET data are required to identify a primary tumor and its extensions as neoplastic, to help define the volume that contains the entire tumor over time as it moves with respiration, and to characterize intrathoracic nodes. When PET was first used to assist RT planning, PET and CT scans were viewed side by

Motion Management in the PET/CT Era

The relatively long acquisition time of a PET scan, over several respiratory cycles, means that the PET scan can indicate the average position of a tumor expanded by the blurring effects of motion. With an appropriate expansion to account for microscopic disease extension, this PET GTV can be used to help generate an internal target volume. The internal target volume can then form the basis of the PTV and enable a treatment plan to be produced that should, ideally, include the whole tumor

Interim Target Volume Definition and Response-Adapted RT

Once the target volume has been established before chemo-RT with FDG-PET/CT, patients with locoregional advanced NSCLC typically proceed with 6-7 weeks of chemo-RT without additional diagnostic imaging. A patient׳s individual biological response to treatment is unknown until the posttherapy scan, and modifications outside the “one-size-fits-all” dose and fractionation schema are not routinely made. It has already been established that PET imaging after the completion of chemo-RT in NSCLC is

Conclusions

PET and PET/CT have profoundly changed the management of lung cancer with curative-intent RT. FDG-PET provides invaluable information that complements information from structural imaging and other sources such as biopsy results. This added information can affect the management of patients at all points of their clinical course, including diagnosis, staging and selection of therapy, and RT planning, allowing response-adapted changes in treatment delivery, and then response assessment after

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