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Prognosis and Reevaluation of Lung Cancer by Positron Emission Tomography Imaging Jeremy J. Erasmus1, Eric Rohren1, and Stephen G. Swisher2 1

Division of Diagnostic Imaging, and 2Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Positron emission tomography (PET) imaging using 18F-2-deoxy-Dglucose, a D-glucose analog labeled with fluorine-18 (FDG-PET), is being evaluated in the assessment of prognosis and therapeutic response in patients with non–small cell lung cancer. FDG-PET imaging has the potential to allow more appropriate selection of patients for surgical resection and for neoadjuvant and aduvant chemotherapy as well as chemoradiation. Currently, the absence of standardization in how FDG-PET images are obtained and interpreted limits its widespread clinical utility. Although prospective multi-institutional trials and standardization of FDG-PET imaging protocols are required for the true utility to be determined, the evolving experience with FDG-PET imaging indicates a greater and integral role in treatment decisions. This article will discuss the assessment of prognosis and treatment response in patients with non–small cell lung cancer using FDG-PET, and will emphasize potential advantages and limitations in clinical management. Keywords: lung cancer; PET-CT; response

Positron emission tomography (PET) using the radiopharmaceutical, 18F-2-deoxy-D-glucose (FDG), a D-glucose analog labeled with fluorine-18 (FDG-PET), is routinely used to improve the detection of nodal and extrathoracic metastases in patients with non–small cell lung cancer (NSCLC) being assessed for curative resection (1–7). In fact, the introduction of FDG-PET imaging in the staging of NSCLC has resulted in a significant change in the stage distribution, with an increased percentage of patients diagnosed with metastatic disease (8). FDG-PET imaging has also been evaluated in a limited number of studies to determine the role of FDG-PET in the evaluation of prognosis and treatment response in patients with NSCLC. In this regard, the potential importance of FDG-PET imaging in patient management is predicated on the fact that the 5-year survival for patients with NSCLC and pathologic stages IA, IB, II, and IIIA disease after complete resection is only 67%, 57%, 47%, and 23%, respectively (9). The ability to identify those patients with NSCLC most at risk for loco-regional recurrence of malignancy and metastatic disease based on FDG uptake by the tumor could be useful to select patients for curative resection as well as those who would potentially benefit from neoadjuvant or adjuvant chemotherapy and/or closer postoperative surveillance. In addition, the early determination of treatment response could allow the institution of more appropriate chemotherapy. The rationale for using FDG-PET imaging in the assessment of prognosis and therapeutic response is that FDG uptake is a function of proliferative activity as well as viable tumor cell number, and can be quantified (10–14). The uptake of FDG can be quantified by using several parameters including standard-

(Received in original form June 30, 2008; accepted in final form August 16, 2008) Correspondence and requests for reprints should be addressed to Jeremy J. Erasmus, M.D., M.D. Anderson Cancer Center, Division of Diagnostic Imaging, Unit 037, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: jerasmus@di. mdacc.tmc.edu Proc Am Thorac Soc Vol 6. pp 171–179, 2009 DOI: 10.1513/pats.200806-059LC Internet address: www.atsjournals.org

ized uptake value (SUV) or local metabolic rate of glucose (Ki 5 influx constant) (10). In NSCLC, use of SUV measurements has been shown to be as accurate and reproducible as more complex quantitative calculations based on dynamic imaging (10). Accordingly, SUV measurements are the most commonly used parameter to evaluate FDG uptake by the tumor. This article will discuss the assessment of prognosis and treatment response in patients with NSCLC as determined by the SUV at diagnosis and after therapy, respectively, and will emphasize potential advantages and limitations of using FDGPET imaging in clinical management.

PROGNOSIS Although the data are varied, patients with primary tumors that are highly metabolic (as indicated by high FDG uptake) tend to have a more aggressive clinical course than those with a low metabolic rate. This observation is reported across the spectrum of disease including early surgically treated stages and advanced inoperable stages of NSCLC (15–22). A recent meta-analysis performed by the European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project concluded that metabolic activity of the primary tumor as determined by the SUV on FDG-PET imaging is a prognostic factor in patients with NSCLC (23). There were 13 eligible studies with a total of 1,474 patients, and 11 of these studies identified a high SUV as a poor prognostic factor for survival. However, the authors recommended that SUV needs to be compared with stage and performance status in a formal analysis to determine if FDG-PET imaging adds prognostic value. In this regard, there is a plan to perform a metaanalysis based on individual patient data, and this endeavor may be of particular importance in the view of the forthcoming seventh edition of the TNM classification for lung cancer (24–26). A review of the individual preliminary studies suggests a possible role for PET as a prognostic marker with the degree of increased FDG uptake in the primary lesion at diagnosis related to survival rate (15, 16, 19, 21, 22, 27–30). The threshold SUV used for univariate analysis in these studies ranged from 3.3 to 20. In a retrospective study by Goodgame and coworkers, an SUV threshold of 5.5 was used to evaluate the prognostic significance of FDG uptake in patients with stage I NSCLC who underwent curative surgical resection (21). Disease-free survival was evaluated in 136 patients, 32 of whom developed recurrence of malignancy after a mean post-resection period of 46 months. Patients with a primary tumor with high FDG uptake (SUV . 5.5) were approximately three times more likely to have recurrences of their disease (21) (Figure 1). In fact, 22 patients (33%) with a high SUV (. 5.5) had disease recurrence, whereas only 10 patients with a low SUV (, 5.5) had recurrence (14%). The 5-year estimates of recurrence rates for patients with high and low SUV were 37% and 14%, respectively (P 5 0.002), with 5-year overall survivals of 53% and 74%, respectively (P 5 0.006). Interestingly, in multivariate analyses based on SUV, Tclassification, age, and histology, high SUV was independently associated with recurrence (P 5 0.002) and mortality (P 5 0.041) (21). Hanin and colleagues reported similar results in

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Figure 1. Prognosis. Image is from an 81-year-old man with history of Stage I (T1N0MO) non–small cell lung cancer (NSCLC). (A) Axial contrastenhanced computed tomography (CT) reveals a spiculated right upper lobe nodule (arrow). (B) Whole-body maximum intensity projection positron emission tomography (PET) image shows focal increased 18F-2-deoxy-D-glucose (FDG) uptake (standardized uptake value [SUV] 5 9) in the right upper lobe nodule (arrow). Transthoracic needle aspiration biopsy confirmed primary lung malignancy. Note absence of nodal and distant metastases. L 5 liver; asterisks indicate renal excretion of FDG. (C) Axial CT 1 year after right upper lobe lobectomy shows a new right lung nodule (arrow). Transthoracic needle aspiration biopsy confirmed metastatic disease. Note primary stage I malignancies that have a high SUV tend to have a higher recurrence rate of malignancy.

a recent retrospective study of evaluating the prognostic value of FDG uptake in 96 patients with predominantly squamous (n 5 47) and adenocarcinomas (n 5 46) stage I and II tumors that were completely resected (22). The median survival of 127 months in patients with stage I tumors and an SUV less than or equal to 7.8 was significantly longer than those with higher FDG uptake (69 mo, P 5 0.001). However, there was no statistical difference observed in patients with stage II tumors (72 mo versus 40 mo), although there was a trend toward reduced survival for highly metabolic tumors (SUV . 7.8). Disease-free survival of 96.1 months for all patients with an SUV less than or

equal to 7.8 was also significantly better than those with more metabolically active tumors (87.7 mo, P 5 0.01). The authors in both preceding studies concluded that FDG uptake is predictive of disease-free survival (21, 22). The authors also postulated that FDG-PET imaging could potentially be useful in determining the selection of patients for postoperative adjuvant chemotherapy. Although the current evidence from clinical trials does not support the use of adjuvant chemotherapy in patients with stage I NSCLC, there may be a survival benefit in the high-risk subset of patients with highly metabolic tumors as determined by a high SUV. Specifically, identifying stage I

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patients who are at highest risk of relapse could help determine which patients are most likely to benefit from adjuvant chemotherapy. For instance, in the study by Ohtsuka and coworkers, evaluating the prognostic significance of FDG uptake in patients with pathologic stage I adenocarcinomas who underwent curative resection, the poorer disease-free survival associated with a high SUV (. 3.3) occurred in patients with both stage IA and IB disease, and suggests that these patients could be candidates for adjuvant chemotherapy (19). In addition, none of the patients with stage IB and an SUV less than 3.3 developed disease recurrence, raising the possibility that these patients may not benefit from adjuvant therapy. It is important to understand that while adjuvant chemotherapy can result in a significant and clinically meaningful survival advantage in patients with stage II–IIIA NSCLC after resection, subset analyses of stage IB patients, and a large trial of only stage IB patients, have failed to show a significant survival advantage in this population (31). However, in a retrospective study by Cerfolio and colleagues of 315 patients with NSCLC in which the disease-free survival for patients with high and low SUV within each stage who underwent complete resection was analyzed, patients with stage IB and stage II disease with an SUV of greater than the median for their respective stages had a lower disease-free survival at 4 years (32). The differences in diseasefree survival in patients with stage IB (92% for the low SUV group versus 51% for the high SUV group) and stage II disease (64% for the low SUV group versus 47% for the high SUV group) were significant (P 5 0.005 and P 5 0.044, respectively). Stratified by stage, the actual 4-year survival for patients with stage IB NSCLC was 80% versus 66%, for stage II disease it was 64% versus 32% and for stage IIIA it was 64% versus 16% for the low and high SUV groups, respectively. The SUV also independently predicted the likelihood of metastases occurring to lymph nodes, as well as to distant metastatic sites; that is, patients with a high SUV (> 10) were more likely to have advanced stage. In fact, SUV was an independent predictor of a tumor’s in vivo aggressiveness, and was the best predictor of disease-free survival and overall survival. That is, patients with the same disease stage who had complete resection but who had a higher SUV were more likely to have cancer recurrence (significant for stages IB and II) and shorter survival (significant for stage IB, II, and IIIA disease) compared with those with a low SUV. Most of the studies demonstrating a correlation between survival and FDG uptake have been focused on patients with early-stage NSCLC. In a phase II study of 31 patients with inoperable stage III NSCLC, patients treated with three cycles of neoadjuvant chemotherapy followed by consolidation radiotherapy had FDG-PET imaging performed before and after chemotherapy (33). All the tumors had marked increased uptake of FDG (median SUV 11.3) before chemotherapy. After three cycles of neoadjuvant chemotherapy, 10 patients had a complete response to therapy as defined by an SUV less than 2.5. These patients had a significantly longer time to progression (median 19.9 mo) and overall survival (median . 49 mo) than the patients with an SUV greater than 2.5 after induction therapy (9.8 mo and 14.4 mo, respectively) (33). Furthermore, in a prospective study of the prognostic usefulness of FDG-PET after the completion of definitive radiotherapy (n 5 10) or chemoradiotherapy (n 5 63) in a group of patients in which the majority had advanced-stage NSCLC (pre-treatment stage I in 13 patients, II in 14 patients, III in 46 patients), the authors reported a significant association between the qualitative decrease in FDG uptake within the primary tumor and mediastinal lymph nodes and patient outcome (34). In addition, the study also confirmed previous observations of the superior prognostic value of FDG-PET compared with CT imaging after

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therapy (34). In fact, a single early post-treatment PET was found to be a better predictor of survival than CT response, stage, or pretreatment performance status. However, data from a retrospective study of 214 patients with advanced-stage NSCLC (stage IIIA, IIIB, and IV) who underwent FDG-PET imaging at the time of diagnosis are in contrast with the preceding two studies and other studies reporting a significant relationship between increased FDG uptake and adverse prognosis (35). In the study by Hoang and colleagues, univariate and multivariate analysis did not provide evidence that survival for patient subgroups defined by the median SUV of 11.1 were significantly different (35). In this regard, 158 (74%) of the 214 patients died and 56 patients were alive at 27 months (range, 3– 140 mo) after the diagnosis of NSCLC. The median survival of the 106 patients with the primary tumor having an SUV less than 11.1 was 16 months, and 12 months in the 108 patients with an SUV greater than 11.1. A possible explanation for the absence of correlation between survival and FDG-PET activity as measured by SUV in the primary tumor for patients with stages III and IV disease, could be the short survival times and high mortality in patients with advanced-stage NSCLC. Because of the inherent limitations of data obtained from retrospective studies with small numbers of patients, it is uncertain how to appropriately incorporate FDG-PET into the treatment algorithm of patients with NSCLC. In this regard, several questions that reflect the current dilemma of clinicians involved in the treatment of patients with NSCLC are worthy of consideration (32). In particular, should patients with an early clinical stage NSCLC and a primary tumor with a high SUV be more extensively imaged before resection to detect occult metastases? Would a patient with an early-stage lung cancer who has a high SUV benefit more from adjuvant therapy than one with a low SUV, and would this patient also benefit from neoadjuvant therapy? Should the SUV be considered together with the clinical stage in determining therapy? Should patients with a high SUV have more intensive postoperative surveillance? While the definitive answers to these questions require multi-institutional prospective randomized trials, the evolving experience with FDG-PET imaging indicates a greater and integral role in treatment decisions, particularly in patients with early-stage lung cancer.

THERAPEUTIC RESPONSE FDG-PET imaging, by identifying those who have had a pathologic response to treatment, may have a role in patients with locally advanced but potentially resectable NSCLC who have completed neoadjuvant therapy (36–42). Specifically, patients with advanced disease (stage IIIA and IIIB) can, after neoadjuvant treatment, have tumor responses that enable subsequent curative resection. Because metabolic response to therapy can occur earlier and may be more accurate than anatomical response, FDG-PET imaging could potentially improve the assessment of residual tumor viability and be useful in selection of patients for resection (Figure 2). Although not used in the routine evaluation of tumor response in patients with NSCLC after neoadjuvant treatment, small studies indicate a potentially important role for FDG-PET imaging. In a study by Eschmann and coworkers of 70 patients with advanced NSCLC (stage III) who had neoadjuvant radio-chemotherapy, the difference between initial FDG uptake and uptake after induction chemotherapy was predictive for long-term survival (42). Patients with normal FDG uptake or an 80% or more decrease in tumor SUV had a significantly longer survival than those below this threshold. Interestingly, the few patients who underwent surgical resection in spite of PET findings of progressive disease had

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Figure 2. Therapeutic response. Image is from a 61-yearold man with right upper lobe NSCLC and ipsilateral mediastinal (N2) nodal metastases being evaluated for curative surgical resection after neoadjuvant chemotherapy. (A) Axial contrast-enhanced CT before neoadjuvant chemotherapy reveals a large right upper lobe mass and enlarged right lower paratracheal nodes (arrow). (B) Axial integrated PET-CT after neoadjuvant therapy shows mass has decreased in size. There is increased FDG uptake in the right lung malignancy and right paratracheal nodes suspicious for residual, viable malignancy (arrow). Endobronchial ultrasound-guided biopsy confirmed persistent metastatic disease in the right paratracheal nodes and patient was treated with definitive chemoradiation therapy. Note if N2 nodes have persistently high SUV patients should not be precluded from resection without pathologic confirmation of metastatic disease, as increased FDG uptake does not reliably indicate residual disease.

only slightly longer survival than patients who did not undergo resection, which raises the question whether exclusion of such patients from resection would be appropriate (42). Furthermore, in a prospective trial of 93 patients with NSCLC and biopsyproven stage IIIA N2 disease, patients underwent initial clinical staging with mediastinoscopy, integrated PET-CT, and CT. Repeat evaluation was performed 4 to 12 weeks after neoadjuvant chemoradiation therapy (40). Integrated PET-CT was better than CT in evaluating these patients after neoadjuvant chemoradiation therapy. ROC curve analysis showed that a decrease of 75% or more in SUV of the primary tumor indicated a high likelihood of a complete response (Figure 3), and a decrease by more than 50% in the N2 node SUV indicated a high likelihood that there was no residual metastatic disease in the node. In this regard, the median decrease in SUV in the patients with N2 disease and complete response was 87%, compared with 52% in those with residual N2 disease (40). However, if the N2 nodes had a persis-

tently high SUV, pathologic confirmation of metastatic disease was recommended, as increased FDG uptake did not reliably indicate residual disease. This strategy is supported by the results of a small study by Ohtsuka and colleagues evaluating FDG-PET imaging for pathologic tumor response and lymph node staging after neoadjuvant treatment of NSCLC, in which the sensitivity (0.61), specificity (0.69), PPV (0.36), NPV (0.86), and accuracy (0.67) for lymph node staging were poor (43). The interpretation of SUV measurements after neoadjuvant therapy (especially after protocols including radiotherapy) can be difficult and can be confounded by different factors including tumor cell differentiation and macrophage infiltration. In fact, animal studies have shown that up to 30% of the FDG uptake in a tumor may be caused by the macrophage/monocyte system, and that some tumors retain high SUV measurements at the end of therapy even with histopathologic complete remission at the time of resection (43–46). Accordingly, FDG-PET imaging

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175 b Figure 3. Therapeutic response. Image from an 85-year-old woman with T3N0M0 NSCLC being evaluated for surgical resection. (A) Chest radiograph shows a large right upper lobe mass. (B) Axial integrated PET-CT before therapy shows marked increased uptake of FDG (SUV 17.3) in large necrotic lung mass. (C) Axial integrated PET-CT after completion of low-dose neoadjuvant therapy with carboplatin and docetaxel shows marked decrease (65%) in FDG-uptake (SUV 6.1) associated with minimal decrease in size of the mass. The patient underwent surgical resection and histopathologic examination showed extensive necrosis and less than 5% viable tumor. The patient is disease-free 1 year after resection. Note that there is generally a significant association between marked decrease in FDG uptake within the primary tumor and patient outcome.

should not be used in isolation in therapeutic decisions concerning eligibility for surgical resection or dose-escalated radiotherapy after neoadjuvant treatment of NSCLC. This recommendation is supported by the findings of a study by Poettgen and coworkers that correlated PET/CT imaging and histopa-

thology after neoadjuvant therapy in NSCLC (44). Forty-six patients with stage IIIA and IIIB disease were resected after neoadjuvant therapy and there was pathologic complete response of the primary tumor in 19 patients (41%). The primary tumor in these patients had a broad range of SUV measurements (0.4–9.8, mean 3.0) with 44% having a post-induction SUV greater than 2.5 and indicative of residual, viable tumor. In patients with advanced-stage NSCLC, tumor progression can occur in up to one third of patients after initiation of chemotherapy (47). Early determination of this therapeutic failure would assist clinical decisions concerning discontinuation of ineffective treatment and institution of alternative therapy. However, there have been comparatively few studies assessing the value of early FDG-PET in assessing tumor response while patients are still receiving therapy (37, 48). A decrease in FDGuptake before and after one cycle of chemotherapy may predict outcome with improved survival directly related to the magnitude of decreased uptake. In a recent prospective study of 57 patients with stage IIIB or IV unresectable NSCLC who underwent restaging FDG-PET after only one cycle of platinum-based chemotherapy, a fall in SUV of 20% or greater in the primary tumor was an independent predictor of long-term survival (48). This metabolic response correlated highly with best response to therapy according to RECIST as determined on serial CT scans, and was associated with a higher overall survival than in nonresponders (median survival of 252 d, versus a median survival of 151 d for patients without a metabolic response on PET restaging). In addition, in a prospective study of 47 patients with locally advanced but potentially resectable stage IIIA N2 NSCLC who were receiving neoadjuvant chemotherapy, a reevaluation FDG-PET performed after one cycle of induction chemotherapy showed that a decrease in FDG uptake of 35% or greater correlated with increased survival (P 5 0.03) (37). In this study, FDG-PET was better than CT in monitoring response, and also enabled a prediction of survival early during the initiation of therapy. A difficulty in the use of FDG-PET in the assessment of early therapeutic response in patients with NSCLC is that there is no consensus on the timing of performance of FDG-PET imaging or the most appropriate criteria for assessment of tumor response by FDG-PET. In addition, SUV determination is limited by reproducibility between centers because of the lack of standardization of the acquisition and processing protocols (i.e., standardization of scanning methods, including time to imaging after FDG administration, is required for SUV measurements to be comparable). For instance, patients referred to tertiary healthcare centers for therapy often present with PET-CT imaging performed at outpatient imaging centers that do not follow the standardized protocols used at these centers. In this regard, it is important that both the preoperative PET-CT data and post-therapeutic followup data be performed on comparable equipment using comparable protocols. To address the issue of reproducibility of data, the

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Figure 4. Recurrent malignancy. Image from a 74-yearold woman with history of middle lobe NSCLC cancer 4 years after resection and chemoradiation therapy. (A) Axial contrast-enhanced CT shows atelectatic and consolidative opacities due to radiation-induced lung injury. (B) Axial integrated PET-CT shows focal increased FDG uptake in radiation fibrosis (arrow). Recurrence of malignancy was confirmed by transthoracic needle aspiration biopsy. Note physiologic FDG uptake in myocardium (*).

European Organization for Research and Treatment of Cancer PET Study Group and the Cancer Imaging Program of the National Cancer Institute have guidelines for the use of FDGPET imaging in the determination of prognosis and response to therapy in anticancer studies (12, 49). The use of FDG-PET to determine selection of appropriate therapy and as a surrogate measure of therapeutic efficacy in patients with NSCLC requires that the recommendations pertaining to the standardization of patient preparation, image acquisition and reconstruction, and FDG-PET timing relative to therapy, be implemented (49). In addition, an agreement on the optimal cutoff levels for determination of response is required for FDG-PET to be comparable and widely applicable clinically.

RECURRENT LUNG CANCER Because there may be a survival benefit in retreating patients with recurrent NSCLC after resection, repeat surgery, chemo-

therapy, or radiotherapy have used in selected patients (50–53) (Figure 4). FDG-PET imaging can detect local recurrence of malignancy after surgical resection, chemotherapy, or radiotherapy, and this can occur before anatomic changes are visible on conventional imaging (54–58). In this regard, Keidar and colleagues used PET-CT imaging to evaluate 42 patients with NSCLC at least 6 months after initial therapy (surgery, n 5 25; surgery and radio- or chemotherapy, n 5 15; radiotherapy and chemotherapy, n 5 2) who had an uncertain diagnosis of recurrent disease or its extent after routine clinical and CT evaluation (57). Twenty-five patients had recurrence of NSCLC and the sensitivity, specificity, and positive and negative predictive values of PET-CT for diagnosis of recurrence were 96%, 82%, 89%, and 93%, respectively. Hicks and coworkers also studied patients with suspected recurrence more than 6 months after definitive curative treatment (surgery, n 5 18; surgery and chemoradiotherapy, n 5 12; radical radiotherapy with or with-

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out concurrent chemotherapy, n 5 33) (59). Relapse of NSCLC occurred in 42 of the 63 patients. PET was positive for recurrent malignancy in 41 (sensitivity 98%), while CT indicated relapse in all 42 patients. Seventeen of the 63 patients (27%) had no evidence of relapse and PET was negative in 14 of these patients (specificity 82%). By contrast, CT indicated recurrence of malignancy in 15 of the 17 patients. Importantly, PET imaging resulted in a significant change in the management of 40 patients (63%), including a change from curative to palliative therapy in 6 patients and palliative to curative therapy in 3 patients. Although the results of the preceding study indicate high sensitivity and specificity for the detection of recurrent malignancy, PET imaging was performed more than 6 months after therapy, and this may have reduced the confounding variable of therapeutic-induced inflammation and macrophage infiltration. In fact, diagnostic difficulties over the presence or absence of persistent or recurrent cancer can frequently arise when PET imaging is performed soon after completion of radiotherapy. However, Hicks and colleagues, in a recent study of 73 patients with NSCLC treated with radical radiotherapy, reported that the ability of FDG-PET performed a median of 70 days (range, 39–123 d in 90% of patients) after completion of radical radiotherapy to assess therapeutic response was not confounded by radiation-induced inflammatory change (59). FDG-PET imaging not only improves detection of recurrent disease, but may also provide prognostic information that is useful in selecting patients for repeat surgical resection. In a prospective study of 62 patients with NSCLC who had undergone surgical resection, Hellwig and coworkers showed that not only was PET imaging able to detect tumor recurrence with a high sensitivity (93%), specificity (89%), and accuracy (92%), but was also able to predict which patients would benefit most from surgical retreatment (58). In those patients retreated surgically, lower FDG uptake (SUV , 11) was predictive of a longer median survival (46 mo) than in those patients with a higher SUV (3 mo) (58).

CONCLUSIONS FDG-PET imaging is currently being evaluated in the assessment of prognosis and therapeutic response in patients with NSCLC. FDG-PET imaging has the potential to allow more appropriate selection of patients for surgical resection and neoadjuvant and adjuvant therapy, as well as an earlier assessment of the response to chemotherapy. However, currently it is unclear as to how to optimally incorporate FDG-PET imaging into clinical decisions regarding therapy. Although prospective multi-institutional trials and standardization of PET imaging protocols are required for the true utility to be determined, the evolving experience with FDG-PET imaging indicates a greater and integral role in treatment decisions. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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