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Imaging in lung cancer: positron emission tomography scan

Respiratory Oncology Unit (Dept of Pulmonology), University Hospital Gasthuisberg, Catholic University Leuven, Belgium

CORRESPONDENCE: J.F. Vansteenkiste, Respiratory Oncology Unit (Dept of Pulmonology), University Hospital Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium. Fax: 32 16346803. E-mail: johan.vansteenkiste@uz.kuleuven.ac.be

Keywords: emission computed tomography, induction chemotherapy, lung neoplasms, radiotherapy planning, staging, treatment outcome

Received: June 14, 2001
Accepted June 14, 2001

	Abstract

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 
In the past 5 yrs, positron emission tomography (PET), usually used with ¹⁸F-fluoro-2-deoxy-glucose (FDG), has become an important imaging modality in lung cancer patients.

Currently, the use of FDG-PET in respiratory oncology is mainly for diagnosis and staging. Standard indications are the evaluation of an indeterminate solitary pulmonary nodule or mass, where FDG-PET has proven to be significantly more accurate than computed tomography (CT) in the distinction between benign and malignant lesions. Several studies have also convincingly demonstrated that locoregional lymph node staging by FDG-PET (in correlation with CT images) is significantly superior to CT, with a negative predictive value equal or even superior to mediastinoscopy. FDG-PET also improves extrathoracic staging, through the detection of lesions missed at conventional imaging or characterization of lesions that remain equivocal on conventional imaging. Many European countries now have or plan reimbursement in these indications. Large-scale randomized studies should now focus on the impact this accurate tumour imaging technique has on treatment outcome and cost-efficacy.

Ongoing studies in specialized centres focus on the use of FDG-PET in more advanced clinical applications, such as planning radiotherapy, response evaluation after radiotherapy or (induction) chemotherapy, follow-up and early detection of recurrence, and prognostic information in this in vivo measurement of tumour glucose metabolism.

After a short note on the technique used and a summary of the current common indications of diagnosis and staging, this paper will deal mainly with two of the more advanced clinical applications of FDG-PET in locally advanced nonsmall cell lung cancer: radiation treatment planning and assessment of induction chemotherapy.

Finally, it should be mentioned that a whole new field of applications of positron emission tomography in molecular biology, using new radiopharmaceutical probes, is under extensive investigation. These techniques are promising for future use in very early response monitoring during chemo- or radiotherapy, in evaluation of novel molecular-targeted lung cancer therapies, or even gene therapy.

More than 200,000 new cases of lung cancer are diagnosed in the European Union (EU) each year. This disease is by far the most common cause of cancer-related death in the EU. Due to an increase in smoking amongst females, an increase in overall incidence is to be expected well into the first decades of the 21st century.

Conventional imaging, including chest radiography, computed tomography (CT), ultrasonography, and magnetic resonance imaging, has a major role in the diagnosis, staging, and follow-up of patients with lung cancer. Although these imaging tests allow exquisite anatomic detail, they usually do not provide a definitive diagnosis or staging. Therefore, more invasive tests with tissue sampling are often required. Positron emission tomography (PET) was initially used as a research tool for brain function studies 1, 2 and the assessment of cardiac metabolism 3, 4. In the past 5 yrs, however, >80% of its indications have been as an innovative imaging technique in tumour patients. Different applications in lung cancer are listed in table 1.

Positron-emitting isotopes, such as ¹⁸fluorine, have an excess of protons and are therefore unstable. They decay by emission of a positron, which is the subatomic, positively charged, antiparticle of the negatively charged electron. The positron released in this process has kinetic energy, travels a short distance, and then annihilates with an electron. This annihilation creates two 511 keV photons, emitted in opposite directions. The detection of high numbers of these annihilations by the detector rings of the PET camera generates high-resolution pictures (5–10 mm) indicating the sites of FDG accumulation in the body 12. The preferential accumulation of FDG in neoplastic cells permits differentiation between benign and malignant tissue. In this way, FDG-PET compliments the anatomic information on standard imaging with metabolic information.

	Technical aspects

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 
The different acquisition protocols
Whole-body images are most commonly used for clinical oncology studies. In this technique, FDG is injected into the patient outside the PET camera. After an uptake period of 1 h, necessary to obtain a good tumour-to-normal tissue contrast, the patient is positioned in the camera. Since the field of view of the PET camera is only 10–15 cm, different bed positions need to be scanned to obtain a whole-body survey. At the end, the data of the different bed positions are reconstructed to a whole-body image by a computer algorithm, taking into account the physical decay of the FDG tracer during the examination. The advantage of this technique is that it allows a fast acquisition (usually <45 min) of information of the whole body. The disadvantage is that since no attenuation correction is performed, the technique only generates images for visual interpretation, without any quantitative information on FDG-uptake.

Attenuation-corrected images are needed in order to gain more information on FDG uptake. An important number of the emitted photons are absorbed in the patient's body. This absorption depends on the position in the body (e.g. superficial lesions are less attenuated than those situated in deeper layers of the body) and the type of surrounding tissue (e.g. lung tissue is less attenuating than muscle tissue). Since the intensity of the photon emission of a lesion is position dependent, the intensity seen on the nonattenuation corrected whole-body images does not truly reflect the actual FDG uptake. If the images are corrected for photon attenuation by a so-called transmission scan, which estimates the attenuating characteristics of the patient, quantification of the FDG metabolism becomes possible. This transmission scan, which can be performed prior to ("cold transmission") or after ("hot transmission") FDG injection, prolongs the acquisition time substantially. In addition, the use of the transmission scan allows the Standardized Uptake Value (SUV) to be reported. The SUV of a lesion is a semiquantitative index of the glucose utilization that is obtained by normalizing the accumulation of FDG in the lesion to the injected dose and patient body weight 13.

Initially, the transmission scan to correct for photon attenuation could only be performed prior to FDG injection (cold transmission). After FDG injection, the patient had to remain completely still in the PET camera for 1 h, the time needed to obtain a good tumour-to-normal tissue contrast. Acquisition of the emission images, usually limited to two or three bed positions, and whole-body images then completed the examination. A total camera time of nearly 3 h was needed for the entire sequence. With the introduction of hot transmission (i.e. acquisition of transmission images after injection, and alternating with emission images) to the new PET devices and the development of new reconstruction methods to decrease transmission time, whole-body attenuation corrected images can now be obtained in 60–80 min 14, 15.

Methods to facilitate the more widespread availability of ¹⁸F-fluoro-2-deoxy-glucose positron emission tomography imaging
Several factors actually impede the widespread use of FDG-PET as a tool complimentary to CT in the diagnosis and staging of nonsmall cell lung cancer (NSCLC). However, further development of the technique can be expected when commercial isotope distributors will be able to deliver FDG, so that an onsite cyclotron is no longer needed. FDG has a half-life of 110 min, so a practical distribution radius of 200–300 km should be feasible.

Another factor will be the availability of PET cameras. Whether cheaper dual-head gamma camera coincidence imaging (GCI) will be a valid substitute is still uncertain and requires a large amount of carefully controlled clinical studies. Indeed, conclusions on the use of FDG-PET in respiratory oncology are mainly based on studies using high-performance PET cameras (so-called dedicated PET scans), characterized by high resolution and sensitivity. Because of the high cost of a dedicated PET camera, GCI has been examined as a potential alternative. However, the crystals used in these gamma cameras have less stopping power for high energy photons compared to those used in dedicated systems, which results in a decrease in positron emission detection and thus, sensitivity 16. Some studies have already compared GCI with dedicated PET in lung cancer, in a limited number of cases, ranging from 23–31 patients 17–20. Some series, which usually included larger lesions visible on both techniques, suggested that both techniques are equivalent. In a more challenging study, GCI detected 13 (93%) of the 14 lung nodules, 20 (65%) of the 31 metastatic mediastinal nodes, and only 27 (42%) of the 64 distant metastases seen on PET 20. Another study found an 86% overall accuracy in staging lung cancer with FDG-PET, compared to only 64% with GCI 19. This suggests that the sensitivity of GCI clearly decreases for lesions <2 cm. Obviously, this affects the detection of small metastatic deposits in mediastinal nodes or distant sites. Care should therefore be taken when extrapolating the conclusions on clinical decision-making obtained with dedicated PET in a situation where GCI is used.

	Common clinical indications

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 
The standard clinical indications for FDG-PET imaging in lung cancer patients have been detailed in a recent review 21. In this contribution, these indications will only be repeated briefly, with emphasis on clinical application.

Diagnosis of solitary lung nodule or mass
The problem of differential diagnosis of an indeterminate solitary pulmonary nodule is well known. Calcification or absence of growth over a 2-yr period are highly suggestive of a benign lesion, but calcification or comparator chest radiographs are usually lacking 22, 23. Bronchoscopy is often nondiagnostic and a transthoracic needle-aspiration biopsy has complications, such as pneumothorax, requiring drainage in 5–10% of the procedures 24, and possible false-negative findings, leading to an unacceptable expectation in patients with early-stage lung cancer 25, 26.

FDG-PET has thus been studied extensively as a promising noninvasive imaging test to differentiate between benign and malignant nodules 27–37. Based on 12 well-designed prospective studies, it can be concluded that FDG-PET has proven to be accurate in differentiating benign from malignant lesions as small as 1 cm 21. An overall sensitivity of 96% (range 83–100), specificity of 79% (52–100) and accuracy of 91% (86–100) can be expected.

Potential pitfalls in sensitivity are due to the fact that a critical mass of metabolically active malignant cells is required for PET diagnosis. Therefore, false-negative findings can occur in lesions <1 cm 29, 30, 34, 35, 38, in tumours with low metabolic activity (e.g. carcinoid tumours 30, 39), or in bronchioloalveolar cell carcinoma 38, 40–42.

Errors in specificity are due to FDG uptake in inflammatory conditions, such as bacterial pneumonia 43, pyogenic abscess or aspergillosis, granulomatous diseases, active sarcoidosis 44, tuberculosis, histoplasmosis, coccidiomycosis, Wegener's disease or coal miner's lung. In these lesions, the FDG uptake has been attributed to an increase in granulocyte and/or macrophage activity 45.

Locoregional lymph node staging
The lymph node (LN) extension in NSCLC determines the prognosis and the choice of treatment. Indeed, patients without malignant LNs in the mediastinum are usually treated with straightforward surgical resection. Patients with diseased mediastinal LNs are candidates for induction chemotherapy, followed by surgery and/or radiotherapy 46–50. It is therefore of considerable clinical interest to evaluate these mediastinal LNs as accurately as possible.

CT is the most commonly used noninvasive staging method of the mediastinum, but is far from satisfying and less accurate than invasive surgical staging 51–54. In prospective data from the Radiological Diagnostic Oncology Group, the sensitivity and specificity of thoracic CT were only 52% and 69% 55. The Leuven Lung Cancer Group (LLCG) found that the best results were obtained when LNs 1.5 cm at their maximal cross-sectional diameter were considered to be metastatic 56. Using this criterion, the sensitivity was 69% and the specificity 71%. Because of this very moderate level of accuracy of CT, invasive staging by mediastinoscopy until recently remained the only reliable tool for mediastinal LN staging. The use of FDG-PET as a noninvasive tool for the determination of LN spread has thus been examined in several well-designed prospective studies 27, 57–72. FDG-PET proved to be significantly more accurate than CT in locoregional LN staging. In the distinction between presence (N2-N3) or absence (N0-N1) of mediastinal LN disease, an overall sensitivity of 89% (67–100), a specificity of 92% (79–100) and an accuracy of 90% (78–100) can be expected for FDG-PET, in contrast with a sensitivity of 65% (20–86), a specificity of 80% (43–90), and an accuracy of 75% (52–79) for CT 21. The superiority of FDG-PET can be explained by the fact that the size of LNs on CT is a relative criterion; FDG-PET correctly identifies small malignant nodes and large benign nodes.

False-negative findings can occur when the tumour deposit in the mediastinal nodes is small, especially in so-called "minimal N2", where a reasonable prognosis after surgical resection can be expected 73. False-positive images are possible in LNs containing anthracosilicosis 32 or inflammatory tissue with high metabolic activity. Therefore, the use of mediastinoscopy is still advised to prove N2 or N3 disease in patients with positive mediastinal nodes on PET. Mediastinal mapping by mediastinoscopy is justified before the start of a chemotherapy induction protocol and is needed to ensure that no single patient with N0 or N1 disease is denied the chance of cure by direct surgical resection based on a false-positive PET.

Extrathoracic staging
Patients with extrathoracic metastases are no longer amenable to long-term remission or cure. It should be realized that current standard staging based on clinical and biological factors and imaging tests, such as CT, ultrasound, or bone scintigraphy 74, 75, is far from perfect. After radical treatment for apparently localized disease, 20% of the patients will nonetheless have an early distant relapse 76–78, due to micrometastases already present at the time of initial staging 79, usually in the adrenal glands, bones, brain, or liver 80.

Most organ-specific studies on the detection of distant metastases in lung cancer patients do not have the power of locoregional staging studies. For bone metastasis, one study found an equivalent sensitivity of FDG-PET and standard bone scintigraphy, but a much higher specificity for FDG-PET (98% versus 61%) 81. Another study indicated that FDG-PET was more sensitive than bone scintigraphy and allowed better differentiation between benign and malignant lesions 82.

Adrenal masses, which are found in 20% of NSCLC patients at initial presentation 83–85, are often a diagnostic challenge. FDG-PET can be a useful adjunct to other imaging modalities. Some small series highlight the high sensitivity of FDG-PET in the detection of adrenal metastases 86–88. An equivocal lesion on CT without FDG uptake on PET will usually not be metastatic, but care should be taken in the interpretation of small lesions. With regard to FDG-positive adrenal lesions, pathological proof by, for example, puncture needs to be obtained before a decision about inoperable disease is made 86.

In the evaluation of liver metastasis, the main advantage of FDG-PET is its ability to differentiate between hepatic lesions that were not determined by conventional studies. In one study, FDG-PET accurately indicated liver metastases in two patients with negative conventional imaging and in nine with equivocal findings on conventional liver imaging. In addition, FDG-PET could exclude metastasis in four cases with suspect conventional imaging 89.

FDG-PET can also reveal metastases that otherwise escape clinical detection, e.g. small nodules in the other lung, soft tissue lesions, retroperitoneal LNs, hardly palpable supraclavicular LNs, etc. Because whole-body FDG-PET is able to stage both intra- and extrathoracic sites in one examination and because it is more accurate than conventional imaging, it is reported to change patient management in 19–41% of patients 58, 90–93.

Although numerous data indicate that FDG-PET can complement conventional imaging in the detection of extrathoracic metastases, there is clearly insufficient data to suggest that FDG-PET can replace it. In contrast with the large amount of data on locoregional staging, most of the organ-specific studies are small and do not include an adequate number of small lesions, which really challenge the technique.

	Use of 18F-fluoro-2-deoxy-glucose positron emission tomography in radiotherapy planning

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 
Most of the FDG-PET studies of locoregional NSCLC staging were performed or implemented in a pre-operative setting. However, FDG-PET could be of equivalent interest in radiotherapy planning in nonmetastatic patients not suitable for surgery (e.g. due to cardiopulmonary limitations or contralateral LN disease). Exact definition of the locoregional tumour load will not only influence the treatment intention, i.e. curative or palliative dose, but also the treatment volume and, therefore, the toxicity. Several studies have suggested an important relationship between the irradiated volume and the likelihood of radiation pneumonitis 94–97. Different parameters from dose/volume histograms have been correlated with the incidence of radiation pneumonitis, e.g. the percentage of the lung volume receiving more than 20 Gy (V_lung20) 94. The ability of these parameters to predict the rate of pneumonitis and to guide dose escalation protocols is currently under investigation in prospective studies 98, 99.

Classical radiotherapy planning uses conventional imaging, such as chest radiography and CT, to describe the tumour and to draw the target volume for irradiation. The main limitations of this method are the poor demarcation of some tumours on CT and the inability of CT to distinguish between benign and malignant LNs. FDG-PET might help to limit the volume of normal tissues irradiated in patients, in whom the FDG-PET-defined locoregional tumour spread is smaller than the CT-defined locoregional tumour spread. It might also help to reduce geographical misses outside the radiation fields, in patients in whom the FDG-PET-defined locoregional tumour spread is more extensive than the CT-defined locoregional tumour spread.

One study reported on the additional information generated by FDG-PET in 12 patients with poorly demarcated tumours. CT and FDG-PET volumes corresponded in seven patients, but in three, the CT abnormalities were larger than on FDG-PET, and in two, the abnormalities on FDG-PET extended outside the region of CT changes 100. Another retrospective study highlighted the substantial reduction in radiation fields by FDG-PET, especially in postobstructive atelectasis 101. Due to the occurrence of this in 34 patients, it was concluded that in 10 of 34 cases the size of the treatment field could have been reduced.

With regard to the involvement of LNs, a theoretical study on the potential impact of FDG-PET on the radiation treatment plan of NSCLC patients was carried out at the author's centre 102. The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols were used for the analysis 59, 61. The main advantage of this approach was that invasive surgical staging of 988 LN stations from 105 patients was available, so that the gold standard of pathological information could be used to interpret the radiotherapy study findings.

A theoretical plan was made for 73 patients who had positive LNs present on CT and/or FDG-PET. For each patient, the irradiated volume (gross tumour volume (GTV)) was defined based on CT and FDG-PET (correlated with CT) images. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard (table 2). A GTV based on the tumour and LNs judged to be positive on CT alone would have covered all pathological nodes in 55 of 73 patients (75%). In addition, using FDG-PET data, coverage of pathological LNs would have been present in 65 patients (89%, p=0.0005). The CT-defined volume was identical to the FDG-PET-defined volume in 28 patients, leaving 45 patients (62%) in whom the additional acquisition of FDG-PET data changed treatment volumes. In 16 patients (22%), the FDG-PET-defined volume was larger. In 11 of these, this was proved to be correct by the surgical pathology data, and in the other five, the enlargement was unnecessary in one and still insufficient in four. In 29 patients (40%), the FDG-PET-defined volume was smaller than the CT-defined volume: in 25 cases, this reduction was correct, as the FDG-PET-defined volume covered all pathological nodes; in one patient, the reduction was inappropriate; and in three patients, both the FDG-PET- and the CT-defined volumes were too small. Therefore, according to the pathology data, this change of volume was correct in 36 patients (49%), inappropriate in two (3%) and insufficient in seven (10%). Insufficient correction of the radiotherapy volumes was either due to LN stations with only minimal-N2 disease 73 or localization errors between adjacent nodes (e.g. lower right tracheobronchial level (4R) and subcarinal (7) levels).

View larger version (75K): [in this window] [in a new window]   Fig. 1.— Illustration of the reduction of the radiation treatment volume when using 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET). According to a) computed tomography, malignancy is located in a right upper lobe tumour (T), the right hilar nodes (10R), the right (4R) and left (4L) lower paratracheal nodes, and the subcarinal ones (7). b) FDG-PET correctly excluded lymph node disease in stations 7 and 10R. This reduced the treatment volume by 37%.

Other groups have reported on the feasibility of using FDG-PET information in modern radiotherapy. CT and FDG-PET lung image registration and fusion, based on the chamfer-matching method, could be validated in both anatomic thoracic phantom images and clinical patient images 103. Detailed analysis in five patients indicated a small spatial error (<4 mm) in the coregistration. The authors concluded that coregistration systems could facilitate target definition and treatment planning. Another study came to a similar conclusion for CT and GCI images 104. Three-dimensional (3D) fusion of these images was used for virtual simulation in 12 patients, using four landmarks drawn on the patient's skin. Again, matching error was small (<5 mm). Anatometabolic fusion corrected LN staging in four individuals and extrathoracic staging in one. In these patients, the dose/volume histograms revealed a reduction in V_lung20 by an average of 23%.

Two retrospective studies examined the utility of FDG-PET during CT-based radiation treatment planning. In one, it was reported that FDG-PET data influenced 34% (12 of 35) of the treatment plans examined and resulted in enlarged portions of the beam aperture (margins of tumour spread), 15 mm 105. In the other, the influence of viewing coronal thoracic FDG-PET images at the time of radiotherapy planning on the anterior-posterior treatment fields of 15 nonoperated patients was assessed 106. It found that four of 15 patients (27%) would have had different treatment volumes based on complimentary FDG-PET information.

Modern radiotherapy in NSCLC uses 3D conformal techniques and dose escalation, which shows irradiation of gross disease only, thereby eliminating the elective nodal irradiation in an attempt to minimize the volume of normal tissues irradiated and keep toxicity within acceptable levels 107. When this type of planning is intended, the mediastinal tumour spread should be known as precisely as possible in order to avoid, on the one hand, geographical misses and, on the other, to maximally reduce the volumes of normal tissues irradiated. Future prospective comparative studies are clearly shown to determine the best use of FDG-PET in this setting and its potential advantages in terms of reduced toxicity, treatment intensification, better local control and increased survival.

	Assessment of response after induction chemotherapy

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 
If the mediastinoscopy in potentially operable NSCLC patients is positive for N2 disease, the results of direct surgical resection (or radiotherapy) are very disappointing 73, 108–110, mainly due to systemic relapses 111. Effective systemic therapy (induction chemotherapy (IC)), followed by resection with mediastinal dissection, is probably a better treatment option for these patients 46–50, 112. In these treatment regimes, it is well known that clearance of viable tumour cells in the mediastinum (downstaging) and pathological response in the primary tumour, are very important for prognosis 113–118. In US data, the estimated 5-yr survival rate of patients with a pathological complete response (pCR) was 54%, while it was only 15% in those without pCR 119.

The presence of downstaging and primary tumour response is usually assessed in the resection specimen post surgery. Ideally, however, this information should be available pre-operatively, in order to select the patients with downstaging or good pathological response for radical surgery with mediastinal dissection and to avoid this major treatment in those unlikely to benefit. CT has not been proven to be a good tool for this purpose. It is well known that patients with little decrease in measurements on the CT can nonetheless have mediastinal LN downstaging or primary tumour response, while those with important decrease can still have metastatic LNs or viable tumour. However, re-mediastinoscopy after induction is often difficult or incomplete, due to fibrosis caused by the chemotherapy and by extensive sampling during the first mediastinoscopy.

Based on favourable experience with FDG-PET in initial LN staging in NSCLC at diagnosis 59, 62, a prospective protocol was started in 1996 to assess cisplatin-based IC in stage IIIA-N2 NSCLC. The specific question to be studied concerned whether FDG-PET after IC would be more reliable than CT in the evaluation of mediastinal LN downstaging, and if some FDG-PET findings would be predictive for outcome after the entire combined modality therapy. The results of the pilot project have been published recently 120. Fifteen patients were examined. They all had a negative standard staging for extrathoracic metastases 75 and surgically proven IIIA-N2 NSCLC. Patients were treated with three cycles of IC, consisting of the standard LLCG schedule at that time, based on vindesine, ifosfamide and cisplatin 121. Evaluation of response after IC on CT was carried out according to standard response criteria 122 and patients without enlarged LNs on CT were considered to have LN downstaging. Responding patients went on to surgery with LN dissection or radical radiotherapy (25 to 33 fractions of 2 Gy) in cases with insufficient cardiopulmonary fitness. In patients without a clear response, radiotherapy for consolidation usually consisted of 13–17 fractions of 3 Gy.

FDG-PET images were acquired before and after IC. The images pre- and post-IC were interpreted prospectively, blinded to surgical pathology data and used for study purpose only. Patients with FDG uptake in the mediastinum that was not higher than mediastinal blood pool activity, were considered to have LN downstaging. The response of the primary tumour was expressed as the per cent decrease in its SUV, according to the formula 100–(SUV_post/SUV_pre)x100. Primary tumour response on FDG-PET was defined as a drop of 50% in SUV.

CT correctly predicted mediastinal LN downstaging in six of nine operated cases, but erroneously suggested downstaging in one and persistence of metastatic mediastinal nodes in two. FDG-PET, in contrast, was correct in all instances.

FDG-PET was also superior in determining the prognosis after IC. Patients with either presence or absence of downstaging on CT had a similar survival, but there was a significant difference in survival after the entire combined modality treatment between the groups with or without downstaging on FDG-PET (p=0.01). The same finding was present when looking at primary tumour response. No significant difference in survival emerged between patients who had a decrease of the product of the two perpendicular diameters of >50% (i.e. response) or not on CT. Looking at FDG-PET response, however, a significant difference in survival between the groups with or without a 50% decrease in SUV of the primary tumour after IC was noted (p=0.02). One of the possible explanations why FDG-PET response is of considerable importance is that a high SUV after IC means persistence of highly proliferative, probably chemoresistant tumour cells, which could be responsible for the (systemic) relapse after treatment.

These promising initial findings led to the conclusion that FDG-PET had the potential to become a reliable noninvasive technique to assess IC, to select patients for intensive locoregional treatment after IC, and for the initiation of a larger prospective multicentre study.

Interim results of this study have recently been reported at another meeting 123. Although the accuracy of FDG-PET in assessing downstaging slightly decreased, the value in prediction of prognosis seems to be confirmed, as illustrated in figure 2. When response on FDG-PET after IC is defined as both mediastinal clearance and a decrease of >50% of the SUV of the primary tumour, a highly significant prognostic discrimination is found (p=0.008). Conversely, CT has only limited value (p=0.10), as already noted from past experience.

View larger version (14K): [in this window] [in a new window]   Fig. 2.— Survival according to response assessment after induction chemotherapy in stage IIIA-N2 nonsmall cell lung cancer assessed either on a) computed tomography (CT) (–––: overall CT response; - - -: no CT response; log-rank p=0.1) or b) 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) (–––: overall PET response; - - -: no PET response; log-rank p=0.008) (interim results of ongoing study adapted from 123).

	Conclusions and prospects

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

View larger version (17K): [in this window] [in a new window]   Fig. 3.— Possible implementation of 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) in nonsmall cell lung cancer (NSCLC) management. LN: lymph node; M+: metastasis.

Finally, a whole new field using molecular probes in positron emission tomography is under exploration. An important number of new tracers is under investigation. It is hoped that positron emission tomography examinations with these molecular tracers will become sufficiently reliable and manageable to evaluate receptors, transport proteins or intracellular enzymes. This is of major importance to assess the large number of novel molecular-targeted lung cancer therapies, which are coming into phase II and III trials now 124.

	Acknowledgements

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 
The authors want to thank the numerous other coworkers involved in the ¹⁸F-fluoro-2-deoxy-glucose positron emission tomography research programme of the Leuven Lung Cancer Group (LLCG) (in alphabetic order): Data-nursing LLCG (B. Anrys, D. Strens), Nuclear Medicine (P. Dupont, L. Mortelmans, S. Stroobants), Pathology (E. Verbeken), Pneumology (M. Demedts, K. Nackaerts), Radiology (J. Bogaert, W. De Wever, J. Verschakelen), Radiotherapy (Y. Lievens, L. Van Uytsel), Thoracic Surgery (P. De Leyn, G. Deneffe, T. Lerut, D. Van Raemdonck).

	References

TOP Abstract Technical aspects Common clinical indications Use of 18F-fluoro-2-deoxy... Assessment of response after... Conclusions and prospects Acknowledgements References

 

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