FDG-PET imaging in the management of non-small-cell lung cancer

E. Salminen1,+ and M. Mac Manus2

1Department of Radiotherapy and Oncology, Turku University Hospital, Turku, Finland; 2Radiation Oncology, Peter MacCallum Cancer Institute, Melbourne, Australia

Received 10 August 2001; accepted 14 November 2001.


    Abstract
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 Introduction
 Staging of lung cancer...
 Evaluation of treatment outcome...
 Is PET cost-effective in...
 Appropriate treatment according...
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Lung cancer is currently the leading cause of cancer-related death in both men and women in most Western countries. Tumour stage is the strongest prognostic factor and the most important parameter guiding treatment decision making. Metabolic positron emission tomography imaging with fluorodeoxyglucose (FDG-PET) has consistently proved superior to conventional imaging for staging of non-small-cell lung cancer and provides information of greater prognostic significance than can be obtained using conventional approaches. FDG-PET has been approved in the USA, Germany and the UK as a basic and invaluable tool in the management of lung cancer.

Key words: FDG-PET, non-small-cell lung cancer, outcome, staging, treatment


    Introduction
 Top
 Abstract
 Introduction
 Staging of lung cancer...
 Evaluation of treatment outcome...
 Is PET cost-effective in...
 Appropriate treatment according...
 References
 
Lung cancer is currently the leading cause of cancer-related death in both men and women in most Western countries. Non-small-cell lung cancer (NSCLC) comprises 75–80% of all new cases of lung cancer [1]. Early diagnosis of lung cancer is difficult and screening is limited to clinical studies. Most patients are diagnosed with what is considered a loco-regionally advanced stage of disease and many have extensive disease at presentation. In earlier series, even if a complete resection was performed, >50% of cases relapsed, with the majority of the relapses occurring at distant sites [2, 3]. When surgery is not indicated, patients with non-resectable but loco-regionally confined disease without negative prognostic factors such as weight loss or poor performance status have a chance for prolonged survival and even cure with radical chemoradiotherapy. Current treatment options in NSCLC are presented in Table 1. The combination of radiation to 60–66 Gy and platinum-based chemotherapy is a commonly recommended standard curative approach in inoperable patients [4]. Nevertheless, too many patients treated with radical chemoradiation relapse with disease progression in the thorax or with distant metastasis, suggesting that in many cases the initial staging assessment understimated the true extent of disease.


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Table 1. Treatment options for NSCLC are guided by the known extent of disease
 
Determination of the primary tumour extent and of the extent of nodal involvement is crucial for successful surgery and radical radiotherapy. Accurate staging avoids futile surgery or radical radiotherapy in patients with incurable disease. Tumour stage is the strongest prognostic factor in NSCLC and the most important parameter that guides treatment decision making. Patients with metastases to the mediastinal lymph nodes have an average 5-year survival rate of ~10%, compared with a survival rate of 50% in the absence of mediastinal metastases [5]. Knowledge of the true tumour extent should greatly assist with the choice of management strategies for patients with NSCLC and provide improved results compared with those reported in the literature and characterised by inaccuracy in staging. More accurate definition of tumour and normal tissue volumes and the use of higher radiation doses than before have become feasible with the advanced radiotherapy. Gross tumour volume was the sole independent predictor of survival in NSCLC patitents treated with conformal radiotherapy [6], indicating the importance of accuracy in tumor delineation.

Positron emission tomography (PET) scanning with fluorodeoxyglucose (FDG) utilises the fundamental biochemical differences in glucose metabolism between normal cells and cancer cells to differentiate between benign and neoplastic processes. The glucose analogue 18F-fluoro-2-deoxy-D-glucose is trapped inside tumour cells because these abnormal cells are unable to metabolise FDG after phosphorylation [7]. The accumulation of labelled FDG in cancer cells can be detected with high resolution by the PET camera, and imaging of neoplastic tissue with this method is in many clinical situations more sensitive than with structural imaging with computed tomography (CT) and magentic resonance imaging (MRI). PET has proven to be more sensitive and specific compared with conventional imaging of NSCLC in several crucial areas, principally in staging of the mediastinum [811] and the detection of distant metastases [1217].


    Staging of lung cancer with FDG-PET compared with CT
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Clinical staging of the mediastinum with CT or MRI is based on lymph node size and is therefore unable to identify nodal metastases that are <1 cm in diameter or to differentiate between malignant and enlarged reactive nodes. CT can only detect mediastinal node involvement by tumour in enlarged lymph nodes, although malignant nodes are not necessarily enlarged significantly in all cases and not all enlarged nodes contain tumour. In a large study with clinical-pathological confirmation, no correlation was found between the presence of mediastinal nodal metastases and nodal size [18]. On the other hand, a study that included extensive dissection of mediastinal lymph nodes (18–28 lymph nodes recovered) after CT and FDG-PET staging has shown that enlarged lymph nodes visualised at CT, but negative at PET, were free of metastatic involvement with a sensitivity of 92% [19]. Lung cancer has different histologies, and a reduced sensitivity of FDG-PET to evaluate bronchoalveolar carcinoma has been suggested previously. Acknowledging the limitations of small localised tumours, FDG-PET can detect and stage broncohoalveolar tumours with identical accuracy to other histological types of NSCLC [20].

PET has emerged as the most accurate non-invasive method available to characterise mediastinal lymph node status in the preoperative staging of NSCLC [19, 21–23]. The use of PET in preoperative staging resulted in a different stage from that determined by standard methods in about half of patients, with the stage lowered in 20% and raised in 41% of patients. In surgically managed patients, PET has been shown to improve sensitivity and specificity of mediastinal node assessment by 10–20% compared with structural imaging techniques, and to change and improve patient management in 15–30% of cases. A meta-analysis [12] has firmly established the superior accuracy of metabolic staging compared with anatomical staging in the detection of mediastinal nodal metastases. Overall, the sensitivity, specificity and accuracy of FDG-PET for staging mediastinal lymph nodes was 96, 93 and 94%, respectively. This has been confirmed recently with a German meta-analysis, including >1000 patients and also evaluating the sensitivity, specificity and accuracy in other metastatic sites, with the same conclusion: high diagnostic efficacy of FDG-PET is superior to conventional imaging in lung cancer [17].

Most patients with NSCLC considered for radical radiation therapy have stage III disease following conventional staging procedures. Most of these patients ultimately die of distant metastases, and it is therefore likely that conventional staging often underestimates the true extent of disease at presentation. In the series reported by Mac Manus and co-workers [24], there was an increase in the incidence of PET detection of distant metastases with increasing pre-PET stage from stage I (7.5%) to stage II (18%) to stage III (24%, P = 0.016). Additionally, in stage IIIA and IIIB, 26 and 21% of patients, respectively, had unsuspected metastases detected by PET. In no case was the PET-detected metastasis found to be false positive. In the meta-analysis [17], unexpected extrathoracic metastases were detected in 12% of lung cancer patients with FDG-PET, and the therapeutic management was changed in 18% of patients due to FDG-PET staging [17].


    Evaluation of treatment outcome with PET
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Preoperative evaluation has shown that FDG uptake by tumour, assessed by PET, can provide important prognostic information which could be useful in clinical decision-making [25, 26]. PET imaging may allow the differentiation between tumour and atelectasis resulting in a smaller target volume in patients with broncial obstruction and sparing of normal lung tissue, and may guide the appropriate inclusion or exlusion from treatment of involved and uninvolved lymph nodes [27]. In a study of tumour coverage with radiation fields [23], gross tumour would have been missed in 20% of cases without PET. Evaluation of response to therapy with PET after treatment appears to be more accurate than with CT and is strongly predictive for survival in NSCLC in published and preliminary studies [28, 29]. Early evaluation, within 2–3 months of treatment, has been predictive for outcome [29], as has been late evaluation over 6 months after treatment [28]. Common guidelines for the use of FDG-PET in monitoring of tumour response after chemotherapy have been recommended by an EORTC committee [30].


    Is PET cost-effective in the management of NSCLC?
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PET may represent a major advance in the management of lung cancer since significant benefits for patients can be obtained with more appropriately targeted treatments. PET may also benefit healthcare providers by leading to an overall reduction in treatment costs because significant numbers of patients will receive less expensive palliative therapies rather than more expensive radical treatments.

New forms of technology, such as PET, can be widely implemented only when they are proved to be cost-effective [31]. In the USA, FDG-PET, when available, has become a standard investigation in the diagnosis of solitary lung nodules and in the pre-operative staging of lung carcinoma. The cost benefits of PET have been largely attributed to the reduction in the number of patients with unresectable mediastinal disease who earlier underwent unnecessary attempts at curative surgery [32]. Additional savings could result if PET is used to exclude patients with occult distant metastases from surgery [33]. A recent analysis on cost-effectiveness by Dietlein et al. [34] shows that the use of FDG-PET leads to cost savings and additional life-expectancy in the case of an intermediate pre-test probability of malignancy, and that the use of FDG-PET was most cost-effective in potentially operable lung cancer patients with normal mediastinal lymph nodes on CT. In the US, Medicare and many third-party insurers have approved reimbursement for PET with 18F-fluorodeoxyglucose for the staging of NSCLC. In the UK, the Royal Society of Surgeons has accepted PET as part of the recommended staging for pre-surgical evaluation in lung cancer, and the use of FDG-PET for lung cancer staging is now contained within the guidelines issued by the British Thoracic Society and the Society for Cardiothoracic Surgeons [35], as it is in the recommendations of the German Consensus Conference [17]. Ongoing prospective studies will further clarify the issue of cost-effectiveness. For most indications, FDG-PET is used in addition to other diagnostic modalities.


    Appropriate treatment according to the true extent of lung cancer
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FDG-PET should lead to better clinical practice with more accurate targeting of radical therapies towards those patients who may benefit from them [36]. Potentially curable patients who are candidates for radical radiation therapy will have improved treatment planning with a reduced risk of geographic miss and less unnecessary irradiation of normal tissues (Table 2). Patients with extensive disease will receive more appropriately palliative treatments in line with their specific needs. Selected patients may be candidates for investigational aggressive therapies targeted to their metastatic disease. Future technical developments with novel tracer markers will enable even more rapid and accurate staging. These changes will promote better outcomes for lung cancer patients and will also lead to more cost-effective management of this disease [34, 36].


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Table 2. The role of PET in improvement of the diagnosis of lung cancer, staging, treatment planning and response evaluation
 

    Footnotes
 
+ Correspondence to: Dr E. Salminen, Department of Radiotherapy and Oncology, Turku University Hospital, Kiinamyllynkatu 4–8, 20520 Turku, Finland. Fax: +358-2-2334702; E-mail: eevsal@utu.fi Back


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