(Chest. 2004;126:1656-1666.)
© 2004
American College of Chest Physicians
Seeking a Home for a PET, Part 3*
Emerging Applications of Positron Emission Tomography Imaging in the Management of Patients With Lung Cancer
Frank C. Detterbeck, MD, FCCP;
Johan F. Vansteenkiste, MD, PhD;
David E. Morris, MD;
Christophe A. Dooms, MD;
Amir H. Khandani, MD, PhD and
Mark A. Socinski, MD, FCCP
* From the Multidisciplinary Thoracic Oncology Program (Drs. Detterbeck, Morris, Khandani, and Socinski), University of North Carolina, Chapel Hill, NC; and Respiratory Oncology Unit (Drs. Vansteenkiste and Dooms), Department of Pulmonology, University Hospital Gasthuisberg, Catholic University, Leuven, Belgium.
Correspondence to: Frank C. Detterbeck, MD, FCCP, Division of Cardiothoracic Surgery, Medical School Wing C - Room 354, CB #7065, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7065; e-mail: fdetter{at}med.unc.edu
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Abstract
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Positron emission tomography (PET) imaging is an important tool to refine the diagnosis and staging approach in patients with a possible lung cancer. In addition, other applications of PET imaging are being explored. Data consistently show that the intensity of uptake on a PET scan correlates with the biological aggressiveness of a tumor. PET imaging for restaging after induction therapy does not appear to be accurate enough to guide management. The results of PET imaging late after completion of treatment are highly predictive of future survival, and changes in PET images after only one cycle of chemotherapy are predictive of how a patient will respond to that planned treatment. PET imaging may allow radiotherapy treatment fields to be planned with greater accuracy, although data on how this affects patient outcomes are not yet available. Further technologic improvements in PET scanners are likely to bring further benefits to the management of patients with lung cancer in the future.
Key Words: lung cancer • positron emission tomography
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Introduction
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Positron emission tomography (PET) imaging became clinically available in a limited number of centers approximately 10 years ago. Much experience has been accumulated since then, providing a fairly clear understanding of the value and limitations of this technology in the evaluation of patients suspected of having lung cancer. A review of the data and a rational definition of the role of PET imaging in the diagnosis and in the staging of patients with lung cancer have been the focus, respectively, of two previous articles: "Seeking a Home for a PET, Part 1: Defining the Appropriate Place for Positron Emission Tomography Imaging in the Diagnosis of Pulmonary Nodules or Masses"1 and "Seeking a Home for a PET, Part 2: Defining the Appropriate Place for Positron Emission Tomography Imaging in the Staging of Patients With Suspected Lung Cancer."2
In addition to these uses of PET imaging, there is a growing interest in the application of PET imaging in other ways to guide management of patients with lung cancer. These other applications are the focus of this review. While the value of PET imaging for these clinical issues is not yet clearly established, a review of the currently available data is needed because these issues present themselves daily to physicians who are involved in the care of patients with lung cancer.
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PET Intensity as a Marker of Biological Behavior
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It is clear to experienced clinicians that there is a wide spectrum of biological behavior among non-small cell lung cancers (NSCLCs), with some showing a high propensity for dissemination and rapid growth, while others follow a more indolent course. While the clinical and pathologic TNM stage is a predictor of prognosis, it does not predict biological aggressiveness well. Although performance status correlates with the rapidity of patients’ demise among those with advanced disease, it would be very useful to have an indicator of biological aggressiveness for earlier-stage patients as well. Because PET imaging reflects a difference in metabolism between normal and cancer cells, it is logical that PET might predict the metabolic rate and the biological aggressiveness of a tumor. Indeed, studies have found that higher PET intensity correlates with more rapid lung cancer cell proliferation345 and more rapid tumor doubling time.6
Strong evidence from a growing number of retrospective studies demonstrates that the intensity of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake of the primary tumor (expressed as the standardized uptake value [SUV]) is highly correlated with disease recurrence and survival (Table 1
).789101112 Survival has been consistently found to be better among patients with less metabolically active tumors when the patients are dichotomized by a threshold SUV value. The differences are statistically significant in these studies even though patients with a range of tumor stages were included. In addition, comparison between studies suggests that there is a correlation between metabolic activity and biological behavior across a continuous spectrum. For example, 2-year survival is 91% for patients with an SUV < 5, 83% for patients with an SUV < 7, and 52% for patients with an SUV < 10 when comparing the studies by Higashi et al,7 Vansteenkiste et al,9 and Ahuja et al,11 respectively. A compelling argument for the prognostic value of PET intensity is the fact that multivariate analysis has found the intensity of PET uptake to be an independent predictor of survival in all studies in which this analysis was done (in addition to stage91011 and performance status9). Furthermore, higher SUV values consistently predicted worse survival among patients of each stage in one study,11 and among resected stage I patients in another study7 (Fig 1
).
Although there is a strong suggestion that PET intensity may be a way to assess the biological aggressiveness of a tumor, further research is needed before this can be broadly applied clinically. The lack of standardization and poor definition of many details of how PET intensity is measured makes integration of the available knowledge difficult.13 The term SUV is a misnomer because it is not truly standardized with regard to many technical factors and does not allow comparison between scanners at different institutions.14 The period of fasting prior to scanning varied in the different studies between at least 4 h and 6 h. The exclusion serum glucose level, obtained just before FDG injection, is reported in only two articles, at > 6.6 mmol/L7 and > 5.8 mmol/L9, respectively. The dose of FDG injected was mostly fixed at 350 to 370 MBq, except for two studies, where it was a lower average of 185 MBq7 or a higher average of 6.5 MBq/kg,9 respectively. The interval between FDG injection and the emission scan was highly variable between 30 min and 90 min. All authors used a point of maximal FDG uptake within a region of interest, eg, the maximum SUV of the tumor, primarily as measured on transaxial images. Correction of maximum SUV for smaller lesions was not reported. These factors undoubtedly contribute to the different thresholds for dichotomization of patient cohorts used among different studies, in addition to the argument that there is no true cut-off point for SUV but rather a continuous spectrum of a gradually worsening prognosis. Clinical application of PET intensity in selection of patients for neoadjuvant or adjuvant therapy must await standardization of technical factors, consensus regarding definitions and details of the imaging technique, and technologic and software improvements.
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PET for Restaging After Neoadjuvant Therapy
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Induction chemotherapy or chemoradiotherapy followed by resection has been suggested to be of benefit in smaller phase III trials,1516 especially for patients with locally advanced NSCLC, although the value of this approach could not yet be confirmed in a large randomized study.17 The issues regarding restaging are whether PET can reliably predict a pathologic complete response at all sites (potentially making resection unnecessary) or predict clearance of all tumor from the mediastinal nodes (this has been a consistent marker for a good prognosis after resection).18 This is particularly important because restaging by CT has been very unreliable,18 and repeat mediastinoscopy is difficult and not generally performed outside of a few selected centers.18192021
To date, only a few studies have evaluated the reliability of PET scanning in assessing mediastinal downstaging (Table 2
).19202122232425 The reported results vary greatly, yielding the conclusion that PET for restaging of the mediastinum after induction therapy is poorly defined and not reliable enough to base treatment decisions on. In most of the studies, only a minority of patients had mediastinal involvement prior to induction therapy, and the interval between chemotherapy and the PET imaging test was variable. In some studies, the induction therapy included radiotherapy, which in itself can result in FDG uptake. However, the reliability of PET imaging for restaging was not appreciably different among patients receiving chemotherapy alone compared with all patients in the one study19 that examined this. Five of the studies1920212223 were prospective and controlled. The reference standard in all studies was a positive biopsy or a node dissection at thoracotomy. Thus, PET imaging after induction therapy does not reliably allow selection of patients in whom mediastinal clearance has been achieved, or provide a means of avoiding a thoracotomy in those with persistent mediastinal disease.
Another potential application of PET after induction therapy might be to identify those patients in whom a complete pathologic response at all sites of disease has been achieved, thus avoiding resection in these patients. Four studies19222425 have evaluated PET imaging after induction therapy (Table 2). Although the reported sensitivity of PET imaging for residual disease is approximately 90% in these studies, prospective application of this technology is hindered by a high false-negative rate of a negative PET scan, and a high false-positive rate except in those studies1924 in which a high prevalence of residual cancer makes this parameter unreliable.26 Thus, the reliability of PET for the definition of complete response after induction therapy is not high enough to avoid surgery.
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PET After Treatment To Predict Prognosis
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Two studies2027 have reported on the ability of PET to predict a major pathologic response (only microscopic residual cancer) as opposed to a pathologic complete response after induction therapy and before planned surgery in 25 patients and 40 patients, respectively. In one study,20 the sensitivity of PET for a major pathologic response was 100%, and specificity was 58%, with a FN rate of 0% and a 57% FP rate (prevalence of persistent gross cancer was 76%). However, the prognostic value of a major pathologic response was not defined in this study.20 The other study27 reported a FN rate of 44% (gross tumor present despite a major PET response), but found median survival to be better in 40 stage III patients with a major response by PET (76% vs 43%, p = 0.042). Thus, the reliability of PET to predict a major pathologic response is poorly defined and appears to be associated with high FP and FN rates. Although it appears likely that PET can predict prognosis after induction therapy, the data are limited, and whether and how this could be used to define further treatment is unclear.
A PET scan performed late after treatment is useful in predicting prognosis. In a study of 113 patients with all stages of NSCLC who underwent PET at a median interval of 7 months after treatment (surgery, radiotherapy, chemotherapy, or a combination of these), survival among those with a negative PET was good (11 of 13 patients still alive), whereas it was poor in those with persistent PET uptake in the chest (median, 12 months).28 Another study of PET performed > 6 months after treatment in 59 patients found that PET results were predictive of outcome by multivariate analysis, while conventional restaging tests were not (sensitivity, 98%; specificity; 82%; FN and FP rates of 7%).29 This is corroborated by a study of 73 patients with stage I-IIIb NSCLC treated primarily with chemoradiotherapy, in whom PET was performed a median of 2 months (range, 1 to 3 months) after completion of therapy.30 In this study,30 there was poor correlation of the response assessed by CT with that assessed by posttreatment PET (agreement in only 45%). Patients with a complete response, partial response (appreciable decreased intensity), or no response by PET were observed to have 1-year survival rates of 80%, 68%, and 43% (p = 0.0053; Fig 2
). Only the posttreatment PET response was predictive of prognosis by multivariate analysis (not stage, performance status, or weight loss).30 Thus, it appears that PET performed some time after completion of therapy can be useful to predict prognosis, but the optimal timing of the scan, the exact prognosis, and the influence of the patient’s original stage of NSCLC are not well defined.
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Figure 2.. Overall survival according to PET response after treatment in patients with NSCLC. CR = complete response; PR = partial response; NR/PD = no response/progressive disease. Reprinted with permission.30
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Early Changes in PET To Assess Response to Treatment
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Studies31323334 of PET in other types of cancer have suggested that a decrease in PET intensity can be seen after only a few days to weeks of therapy. In fact, a change in PET intensity after 2 to 3 weeks (one cycle of chemotherapy) was the best predictor of response to therapy (better than a PET done after completion of treatment) in studies313234 that have analyzed this. Furthermore, a reduction in PET intensity after treatment initiation correlates well with outcomes and tumor regression in lymphoma,35 osteosarcoma,36 breast cancer,3132 and esophageal cancer.33343738 This suggests that changes in FDG uptake by PET can be seen early enough to predict response to treatment in lung cancer, and thus allow modification of the treatment plan. This is most applicable to the choice of chemotherapy agents, as there are several active, so-called third-generation agents for NSCLC, yet an objective response is realized in only approximately 30% of patients by conventional radiographic criteria.3940
One study41 has addressed early changes in PET uptake in 55 patients with stage IIIb-IV NSCLC treated with palliative chemotherapy. PET imaging was performed 1 week prior to treatment and 3 weeks after the first cycle of chemotherapy. A metabolic response by PET was prospectively defined as a decrease of > 20% from baseline, based on previous studies.1342 The change in PET uptake after one cycle of chemotherapy was very good at predicting a subsequent objective response according to conventional Response Evaluation Criteria in Solid Tumors (RECIST) study criteria.43 PET prediction of nonresponse had a FN rate of 4% (1 of 27), although PET prediction of response had a FP rate of 29% (8 of 28). A metabolic PET response was also predictive of lack of disease progression within the first three cycles of chemotherapy (4% vs 59% in PET responders vs nonresponders, respectively); furthermore, early metabolic PET response predicted better survival (median, 8.2 months vs 5 months; p = 0.01).41 It is unclear in this report whether the FP rate of a metabolic PET response results from inaccuracy of conventional radiographic assessment as opposed to inaccuracy of the PET imaging.41
Although these results are exciting and suggest that an early PET scan might be useful to tailor chemotherapy treatment, there are many hurdles to more widespread application. At this point, the data in NSCLC are limited to one study.41 The exact timing of PET after injection is important, because scans performed, for example, at 45 min and 60 min after injection have a 16% difference in PET intensity.13 In the study41 mentioned above, dynamic PET imaging was performed, involving serial data acquisition over a 75-min period to address this problem. Accurate positioning of the patient during serial scans may be important to ensure that a change in intensity is measured in the same region. Correction of SUV measurement for the blood glucose level is important,44 although it potentially introduces additional error due to the accuracy of glucose measurement and has been found to have only a small effect on the reproducibility of the measurement when the glucose level is in a normal range (75 to 125 mg/100 mL).13 Furthermore, the effect of chemotherapy (including in some cases steroids) on glucose metabolism in the tumor and normal tissues as reflected by FDG-PET imaging has not been characterized. In addition, research is ongoing regarding technical issues of the acquisition parameters, reconstruction algorithms, and analytic methods to reliably use FDG-PET to monitor response to treatment.44
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PET for Radiotherapy Treatment Planning
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More accurate staging with the use of PET imaging can be of benefit with regard to radiotherapy in several ways. PET can help define the true stage of disease in patients with lung cancer, and thus help select an appropriate treatment, such as definitive radiotherapy, for a particular patient. The role of PET in defining disease stage is the subject of part II of this series.2 In addition, PET may aid in the identification of patients with limited amounts of metastatic disease, with the argument that more aggressive treatment of these sites of disease may be of palliative benefit by providing longer-term control of the disease. Although it has been shown that patients with a limited amount of metastatic disease have a better prognosis,45 there are insufficient data to confirm a survival advantage to aggressive radiation in these situations. Finally, PET can help define local recurrence in patients who may be candidates for retreatment.46
Modern radiotherapy uses three-dimensional conformal treatment planning, based primarily on CT scans, to ensure that the radiotherapy is actually delivered to all of the tumor.47 Furthermore, there has been a trend to using much higher total radiotherapy doses due to poor local control with the traditional dose of 60 Gy. Dose escalation is facilitated by limiting the treatment volume more tightly to the tumor bearing tissues.4849 This raises the question whether PET imaging should be used to assist in radiotherapy treatment planning. PET can be used to define the gross tumor more clearly (eg, differentiation from atelectatic lung), or to determine whether sites of potential nodal involvement (that are not radiographically suspicious) should be treated at a lower dose or not treated at all.
Experience has clearly shown that treatment fields are frequently altered when PET findings are taken into account. This is most often observed when atelectatic lung is present. PET imaging allowed treatment fields to be reduced in 47% of patients with atelectatic lung compared with CT-based treatment planning alone in a retrospective review50 of 17 patients. Other reports515253 have found that PET changed treatment volume and/or fields in approximately half of the patients. Target volume was reduced slightly more frequently (in 24 to 93% of patients),5354 but volumes were also frequently enlarged (in 6 to 76% of patients),55 with no clear or consistent pattern among patients.56 In addition, the PET data acquisition and utilization are often not obtained in the treatment position, and can be misleading for precise tumor targeting particularly when considering respiratory motion.57 Thus, PET data have been primarily used clinically as a complementary imaging modality for tumor targeting and radiotherapy treatment planning.
The use of PET may be most important when elective mediastinal radiation will not be performed or in the setting where neoadjuvant chemotherapy is being used. PET may be useful when nodal sites are marginal on CT scan to ensure that all gross disease can be better identified.49 Recent radiotherapy dose-escalation trials58 are using PET imaging to define the treatment target. However, no data are available yet whether incorporating PET imaging in radiotherapy treatment planning has an impact on survival, toxicity, or local control.
PET imaging may become important in the future as part of "response-adaptive" therapy as a method of identifying the response of different populations of cancer cells to treatment.55 This approach may allow treatment optimization (eg, changes in fractionation schemes or in concurrent chemotherapy regimens) by evaluating early or sequential changes in PET intensity or tumor volume during treatment. New imaging agents such as [18F]fluoromisonidazole may allow identification of hypoxic cells that may require a larger dose per fraction or a higher total dose for effective cell kill,59 taking advantage of the reoxygenation that takes place during radiation. At present, the technical aspects of response-adaptive therapy are not well studied, and the role of this approach remains speculative.
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Technologic Advances in PET Scanning
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Although PET imaging has been in clinical use since the early 1990s, there is still great potential for technologic advances in this imaging technique. In broad terms, efforts to improve PET can be divided into progress in image resolution to provide better definition of the location of a focus of abnormal FDG uptake, and in the development of new tracer molecules that provide a picture of other aspects of cellular biochemistry besides glucose metabolism.
PET and CT images provide complementary information, namely a metabolic and a morphologic-anatomic evaluation of body tissues. In fact, a major limitation of PET imaging alone is the lack of anatomic information. It is now well established that the interpretation of results is better when both PET images and CT images are viewed side by side, instead of PET images alone.606162636465 For example, the sensitivity, specificity, and accuracy of establishing the N stage of lung cancers is better for PET and CT viewed together vs PET alone (Table 3
).606162636465 Such visual correlative reading of PET images represents a minimum standard.
Technologic developments allow PET and CT images to be superimposed on one another (fusion PET/CT), either by digital software or by scanning the patient with an integrated scanner that is able to acquire both CT and PET images practically simultaneously. Data comparing fusion images to visual correlation of PET and CT primarily involves determination of the N stage (Table 4
).60626366 The results of such studies are conflicting, with some authors6263 finding no significant differences in accuracy, whereas others have reported greater specificity67 or greater accuracy60 with fusion images. The latter two studies can be questioned because they are either retrospective67or involve a much lower accuracy of nodal staging by visual correlative PET60 than what is generally reported.686970 Regarding the assessment of the T stage, a prospective study60 with 40 NSCLC patients found that an integrated PET-CT scanner provided significantly more accurate differentiation of chest wall or mediastinal infiltration and differentiation between tumor and adjacent inflammation or atelectasis than CT alone (p = 0.001), PET alone (p < 0.001), or visual fusion of PET and CT (p = 0.013). Nevertheless, at least for the time being, visual correlation of PET and CT images in experienced hands is probably sufficient in many situations.71 Forthcoming prospective studies on larger numbers of patients, optimally also focusing on patient outcome, are needed to determine whether digital fusion should become the new standard approach.
One of the limitations of the current generation of PET cameras is the ability to image small lesions. Detection limits are primarily determined by the ratio of radioactivity in the target vs adjacent background, and to a lesser extent by the target size. False-negative results typically occur in lesions smaller than twice the spatial resolution of the PET camera (5 to 8 mm for current full-ring PET machines). Thus, the reliability of PET imaging is limited for lesions < 1 to 1.5 cm. Future improvements in this field could be achieved by increasing the number and sensitivity of the detectors in the PET camera, which might allow a spatial resolution of 3 to 4 mm. However, there is a limit to how well PET imaging can ever be expected to pinpoint a lesion due to the distance a positron travels before colliding with an electron, thereby generating the photons that are detected.
An improvement in thoracic imaging that is potentially of great importance is the development of reliable and efficient techniques of respiratory gating. Because of respiratory motion, the volume of a lung lesion is overestimated, while the FDG intensity is underestimated (both visually and in the determination of the SUV). This is especially the case for lower lung field lesions, because of the diaphragm excursion during breathing. In the setting of use of FDG-PET for radiotherapy planning, a feasibility study72 found that the reduction in smearing of FDG intensity through the use of respiratory gating resulted in a better target-to-background ratio of the lesion, a more accurate measurement of its SUV, and a better delineation of the lesion resulting in a reduction of the target volume. Among several technical issues, one of the problems with respiratory gating is that it substantially increases overall scan time. Further technical improvements and extensive prospective experience will be needed before this technique will enter clinical lung cancer imaging.
New tracers other than FDG hold promise for the future, but the current clinical experience is still limited. New tracers will be important for understanding the mechanisms and different cellular pathways in oncology. It is hoped that new tracers will increase the accuracy of diagnosis, staging, and assessment of treatment response by PET. Compared to FDG, new tracers should have at least similar sensitivity and preferably better specificity, in order to overcome the FP findings with FDG.
Variable results have been reported with 11C-choline and 11C-thymidine. However, the short half-life of the 11C label (20 min) together with the creation of labeled metabolites in the blood preclude its general and whole-body applicability. To overcome these limitations, other potential tracers of cell proliferation have been investigated. The most exciting new tracer is 3'-[18F]fluoro-3'-deoxy-thymidine (FLT). FLT undergoes the same first metabolic step as thymidine: after intracellular entry, FLT is phosphorylated by thymidine kinase-1, an enzyme only expressed and functional during the DNA S-phase of the cell cycle. The resulting FLT monophosphate is intracellularly trapped and accumulated but not incorporated into DNA. Thus FLT uptake is correlated with DNA synthesis and cell growth, just as FDG uptake correlates with glucose use. Initial experience in patients with a solitary pulmonary nodule (SPN) or NSCLC confirmed the good correlation between FLT uptake and proliferation rate as measured by 67Ki immunohistochemistry (r = 0.92 and 0.84).7374 In the differentiation of a SPN, FLT yielded a specificity of 100% but a sensitivity of only 86% due to FN results in slowly proliferative tumors (low 67Ki index). A prospective study by Buck et al75 showed that FLT uptake is better correlated with proliferation rate than FDG uptake (r = 0.92 vs r = 0.59). Therefore, FLT may be of greater value than FDG for the restaging of patients who have undergone induction chemoradiotherapy for NSCLC, and FLT is probably complementary to FDG in the baseline diagnostic workup of an SPN or NSCLC.
Finally, a whole new field using PET in molecular applications such as measurements of blood flow or regional hypoxia is under exploration. Tumor hypoxia, if present, is an independent negative prognostic factor of clinical outcome. Several PET radiotracers, such as 18F-MISO,59 124I-IAZG,76 and Cu-ATSM,77 showed potential for hypoxia imaging but are still under investigation. This molecular imaging in oncology is in its infancy compared with neurology and psychiatry, where these features have led to major breakthroughs in fundamental science and clinical practice.
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Conclusions
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The ability to image cells based on their metabolism opens up a host of possibilities that goes far beyond greater accuracy in diagnosis and staging. PET imaging has great potential to tailor treatment strategies based on tumor characteristics in an individual patient, although these potential applications of PET are not yet ready for widespread use. The data are particularly strong that PET imaging can predict the biological behavior of a lung cancer. What is missing is standardization of how this is measured, and thoughtful deliberation of how this prediction should be used to alter treatment plans.
PET imaging does not appear to be accurate enough to restage patients after neoadjuvant therapy with confidence. However, there appears to be hope that early changes in PET scans can predict response to a particular chemotherapeutic agent. Much work is still needed to define how this should be assessed, how reliable the prediction is, and how to best use the data to improve outcomes.
The use of PET imaging in radiotherapy treatment planning should result in better tumor targeting. This is particularly intriguing given the data suggesting better outcomes with more aggressive radiotherapy, involving higher doses, three-dimensional treatment planning, and also reduced field size. However, it remains to be demonstrated how much the addition of PET to radiotherapy treatment planning will affect patient outcome (ie, local control, reduced toxicity, and survival).
Finally, technologic improvement in PET scanners will make images easier to interpret. Although it appears to be far in the future, new markers offer a unique tool to further the understanding of how cancer cells grow and spread, and thereby develop more effective treatments.
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Footnotes
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Financial disclosure: The authors have not received anything of financial value either directly or indirectly from a commercial or other party related directly or indirectly to the subject of this article submission.
Abbreviations: FDG = 2-[18F]fluoro-2-deoxy-D-glucose; FLT = 3'-[18F]fluoro-3'-deoxy-thymidine; NSCLC = non-small cell lung cancer; PET = positron emission tomography; SPN = solitary pulmonary nodule; SUV = standardized uptake value
Learning Objectives: 1. To recognize that PET scanning has potential utility in lung cancer management beyond diagnosis and staging. 2. To understand that PET intensity correlates with biological aggressiveness. Early changes in PET activity may predict a response to therapy. 3. To understand that PET scanning is not reliable enough yet to be used in place of surgery for restaging after neoadjuvant therapy. PET scanning may be useful in better defining radiation therapy fields.
Received for publication April 21, 2004.
Accepted for publication April 21, 2004.
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Abstract
Introduction
