Staging of non-small cell lung cancer: clinical value of positron emission tomography and mediastinoscopy
http://www.100md.com
《血管的通路杂志》
Department of Cardiothoracic Surgery, University Hospital Wuerzburg, Germany
Abstract
We report about a MEDLINE research from 2000 to 2005 with the key words ‘positron emission tomography AND/OR mediastinoscopy’. The search identified 448 potential studies. Out of the published data sensitivity, specificity, positive and negative predictive value, and accuracy for mediastinal lymph node staging by FDG-PET ranged from 58%–94%, 76%–96%, 43%–95%, 56%–98% to 74%–91%, respectively. With corresponding values of 80%–96%, 100%, 100%, 92%–97%, and 94%, respectively, for mediastinoscopy. FDG-PET improved the rate of detection of local and distant metastases in 12% to 62% and changed the management of treatment in 8% to 60% of patients with NSCLC. Our study shows that in the diagnostic strategy of patients with NSCLC, additional FDG-PET can prevent non-therapeutic thoracotomy in a significant number of cases. If FDG-PET imaging and CT scan is negative for mediastinal lymph node involvement routinely mediastinoscopy can be omitted and thoracotomy can immediately be performed. In patients with negative FDG-PET scan, but positive CT scan, histologic verification by invasive methods can individually be considered. Patients with positive FDG-PET scan mediastinoscopy still remain a reliable standard for exact lymph node staging. By incorporating FDG-PET in clinical staging unnecessary exploratory thoracotomies, and mediastinoscopy, can be omitted.
Key Words: Non-small cell lung cancer; [18F]Fluoro-2-deoxy-D-glucose positron emission tomography; Mediastinoscopy; Staging
1. Introduction
Pathologic staging in patients with newly diagnosed non-small cell lung cancer (NSCLC) is of substantial importance determining the best possible therapeutic option, clarifying operability, detecting prognosis, and is essential in clinical trials comparing different management strategies, and enables universal communication regarding the efficacy of different treatments in specific patient groups. The likelihood of the surgical cure of primary NSCLC is strongly dependent on the local extent of the cancer, particularly whether or not the mediastinal lymph nodes are involved with cancer or whether extrathoracic metastases are present [1]. Mediastinal lymph node involvement is reported to be present in 28% to 38% of NSCLC at the time of diagnosis, and if present has an important bearing on the treatment plan [2]. Complete pathologic staging as derived from complete mediastinal lymph node dissection is the accurate way of providing definitive staging information. Additional FDG-PET diagnostics leads to avoid ineffective therapies, particularly unnecessary thoracotomy.
The purpose of this review is to assess on the basis of published studies the value of FDG-PET and of mediastinoscopy in lymph node staging in patients with NSCLC as well as to question to what extent FDG-PET may bypass mediastinoscopy in some cases.
2. Methods
We performed a MEDLINE analysis restricted to the years 2000 to 2005 with the key words ‘positron emission tomography AND/OR mediastinoscopy’ (448 hits). The diagnostic value of FDG-PET, CT, and mediastinoscopy were defined by sensitivity, specificity, positive and negative predictive value, and accuracy, respectively.
3. Results
The MEDLINE search identified 448 potential studies. We selected 28 articles (3 meta-analyses, 17 prospective and 8 retrospective articles). All other studies were excluded after scanning their abstracts, including studies written in another language other than English or German, or because of insufficient data reported, respectively.
3.1. 2-[18F]Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)
Positron emission tomography, a non-invasive imaging modality with the metabolic tracer F-18-fluorodeoxyglucose allows for functional characterization of tissues. The amount of FDG taken up by the abnormal lesion can be represented by semiquantitative measures, such as the standard uptake value (SUV) or ratio (SUR), and made comparable between patients [3]. The use of FDG-PET must take into account the significance of false-positive (i.e. pneumonia, granuloma/sarcoidosis/tuberculosis/aspergillosis/histoplasmosis, pulmonary hamartoma, inflammation or inflammatory response such as bronchiectasis and atelectasis) and false-negative results (atypical carcinoid, NSCLC 1 cm in size or less, and bronchoalveolar carcinomas) (Table 1).
3.2. Cervical and anterior mediastinoscopy
In the work-up for a thoracotomy in patients with NSCLC mediastionoscopy is considered to be an accurate method, providing a high negative and positive predictive value, and a low morbidity and mortality rate. The only anatomic contraindication is the presence of a permanent tracheostomy. Anterior mediastinoscopy is performed when the primary lesion originates in the left upper lobe or left hilium, or when there is suspicious adenopathy in the anterior mediastinum or aortopulmonary window [4]. But mediastinosocopy can lead to false-negative results, because not all lymph node stations could easily be reached (i.e. subcarinal area, paraesophageal area, and pulmonary ligament). Furthermore, mediastinoscopy is associated with a low but present risk of serious complications (in 0.5% of the patients), including hemorrhage, mediastinitis, pneumothorax, or vocal cord paralysis (Table 2).
4. Discussion
Many authors propose that only patients with positive FDG-PET scan do require mediastinoscopy before exploration for resection and mediastinal lymph node dissection, others recommend performing mediastinoscopy on every patient with potentially operable NSCLC [5,6]. This advice is justified because of the fact that the use of FDG-PET can lead to false-positive and false-negative results. A positive FDG-PET scan result does not necessarily represent malignant disease, and histological confirmation is always warranted.
4.1. FDG-PET versus CT-scan
CT-scan is neither sufficiently sensitive nor specific in identifying lymph node metastases. FDG-PET provides information regarding the functional activity of a malignant lesion rather than strictly anatomic information as is provided by computed tomography (CT) [7]. Several studies have shown that FDG-PET is superior to CT scan in staging mediastinal lymph node involvement in patients with NSCLC (Table 3).
Cerfolio et al. [8] prospectively assessed the role of FDG-PET and CT scan in staging 400 patients with NSCLC. Suspicious N2 lymph nodes by either chest CT or by FDG-PET scan were biopsied. In this study, it could be demonstrated that FDG-PET had a higher sensitivity (71% vs. 43%, P<0.001), positive predictive value (44% vs. 31%, P<0.001), negative predictive value (91% vs. 84%, P=0.006), and accuracy (76% vs. 68%, P=0.037) than CT scan for N2 lymph nodes. Similarly, FDG-PET had a higher sensitivity (67% vs. 41%, P<0.001), but lower specificity (78% vs. 88%, P=0.009) than CT scan for N1 lymph nodes. Furthermore, the authors could show that FDG-PET was most commonly falsely negative in the subcarinal station and the aortopulmonary window lymph node stations [8]. Hellwig et al. investigated 20 studies for FDG-PET imaging (n=1292 patients) and found a sensitivity of 88%, specificity of 92%, and accuracy of 91%, respectively, versus 19 studies for CT-scan (n=1268 patients) with a sensitivity of 65%, specificity of 76%, and accuracy of 73%, respectively [9]. Birim et al. found 17 studies with 833 patients. Sensitivity and specificity were determined using the area under the receiver operating characteristic (ROC) curve. The point on the ROC with equal sensitivity and specificity for FDG-PET was 0.9. For CT it was 0.7. The difference was highly significant (P<0.0001) [1].
Several trials could prove a significant improvement of integrated PET-CT compared to FDG-PET alone (Table 4).
4.2. Mediastinoscopy
Mediastinoscopy, first described by Carlens and associates in 1959, is an invasive procedure with a low but present risk of serious complications. In many clinics mediastinoscopy is not a standard procedure for mediastinal lymph node staging. The utility of mediastinoscopy in the presence of normal-sized mediastinal lymph nodes is more controversial. Even patients with peripheral T1 tumors and no mediastinal adenopathy according to CT may be found to have positive mediastinal lymph nodes in up to 20% of cases. Because N2 disease is a strong marker for probable occult distant metastatic disease, many thoracic surgeons routinely perform mediastinoscopy, which provides the opportunity to consider induction therapy before thoracotomy [10]. Therefore, lymph node sampling or lymph node dissection by means of invasive procedures (cervical and/or anterior mediastinoscopy) provides the definitive possibility for pathologic staging. Daniels et al. investigated 76 patients with NSCLC and performed mediastinoscopy on every patient with potentially operable NSCLC (except for T1 squamous cell carcinoma). Ten percent of the patients were prevented from exploratory thoracotomy by the routine use of mediastinoscopy. The authors conclude that mediastinoscopy should be performed on every patient with possibly operable NSCLC, regardless of the outcome of CT, except for patients with T1 squamous cell carcinoma [6]. Because it is neither practical nor economical to recommend mediastinoscopy for all candidates for surgery, Kimura et al. have developed – in a prospective study with 121 patients – indication criteria for cervical mediastinoscopy. Patients with resectable NSCLC were chosen for mediastinoscopy when at least one of three clinical indicators was present: (1) computed tomographic evidence of mediastinal adenopathy, (2) elevated levels of serologic tumor markers, and (3) diameters of primary cancers 2 to 3 cm. Pathologic examinations after mediastinoscopy indicate that the diagnostic sensitivity and negative predictive value for the postulated indication criteria were 95.8% and 97.4%, respectively. Using three indicators for N2 prediction the authors avoided 37% unnecessary mediastinoscopies. FDG-PET was less effective than the three criteria, yielding 70% (diagnostic sensitivity), 86% (specificity), and 84% (accuracy), respectively [11].
4.3. Comparison of FDG-PET to mediastinoscopy
Several reports tried to answer the question whether FDG-PET can reduce the need for mediastionoscopy in patients who are potentially eligible for a curative resection and to what extent FDG-PET is able to affect management of treatment. Actually, only prospective studies that compare FDG-PET scanning to detect lymph node metastases versus other methods do provide a truly definitive answer. In the year 2001, Poncelet et al. tried to assess – in a prospective study with 64 patients – the effectiveness of FDG-PET in mediastinal lymph node staging for NSCLC and compared it to conventional clinical and surgical staging. This study showed that FDG-PET imaging strength lies in its very high negative predictive value and increased sensitivity. Combinded with chest CT-scan preoperatively, it may alleviate the need for surgical staging when FDG-PET studies of the mediastinum are negative. However, with a positive FDG-PET scan result, further diagnostic procedures should be pursued in order to avoid overstaging and allow better surgical patient selection [12]. On the other hand, Gonzalez-Stawinski et al. compared prospectively the efficacy of FDG-PET to mediastinoscopy in 202 patients with known NSCLC. Of the 65/202 patients (32.2%) with positive results of FDG-PET, only 29 patients had positive results of mediastinoscopy in the corresponding nodal station. Of the 137 patients with negative results of FDG-PET, 16 patients (11.7%) were demonstrated to have N2 or N3 disease. Therefore, the authors concluded that FDG-PET neither confirms nor excludes involvement of the mediastinum in patients with NSCLC and cervical mediastinoscopy with lymph node biopsy remains the criterion standard for mediastinal staging. In this study the false-positive results (55.4%) of mediastinal FDG-PET included granulomatous inflammation, sinus histiocytosis, and silicosis [5]. Also Kernstine [13] could demonstrate results with 237 patients (sensitivity of FDG-PET of 68%, specificity of 82%, positive predictive value of 54%, and negative predictive value of 89%). On the basis of these results, the author concluded, that relative to mediastinoscopy FDG-PET alone is not sufficient to accurately stage the mediastinum and that mediastinoscopy should continue to be performed in potentially operable cases. The author summarized the impact of FDG-PET in the clinical management: (1) it is useful in diagnosis and staging, though it neither diagnoses nor excludes the presence of malignancy; (2) it can discriminate less suitable candidates for surgical resection, estimated to be 20% to 25% of potential surgical patients; and (3) it may provide helpful prognostic information in additional to the staging information. Even Verhagen et al. assessed prospectively the impact of adding FDG-PET to full conventional clinical staging. The authors concluded that by incorporating FDG-PET in clinical staging, 15% of patients with NSCLC are upstaged due to unexpected extrathoracic metastases. In case of a negative mediastinal FDG-PET scan, mediastinoscopy can only be omitted in the presence of a non-centrally located primary tumor and without FDG-PET positive N1 nodes [10]. The PLUS (PET in LUng cancer Staging; multicenter trial with 188 patients) study was designed to work with routine clinical workup of patients with suspected NSCLC. The authors compared the current strategy of conventional diagnostic methods with a strategy in which FDG-PET was added to non-invasive diagnostic techniques. The results showed that addition of FDG-PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected NSCLC [15]. Also, the American College of Surgeons Oncology Group undertook a trial to ascertain whether FDG-PET could detect lesions that would preclude pulmonary resection in a group of patients with documented or suspected NSCLC. They found that in patients with suspected or proven NSCLC considered respectable by standard staging procedures, FDG-PET can prevent non-therapeutic thoracotomy in a significant number of cases. By correctly identifying advanced disease (stages IIIA, IIIB, and IV) or benign lesions, FDG-PET potentially avoided unnecessary thoracotomy in 1 of 5 patients [7]. Furthermore, several studies pointed out that by adding FDG-PET to conventional staging the management of treatment is changed in 8% to 60% of patients and prevents unnecessary invasive exploratory thoracotomy, and mediastinoscopy in 12% to 62% (Table 5).
5. Conclusions
In conclusion, the results of these studies indicate that in patients with NSCLC incorporating FDG-PET in clinical staging can prevent unnecessary invasive procedures in a significant number of cases. If FDG-PET imaging and CT scan is negative for mediastinal lymph node involvement routinely mediastinoscopy can be omitted and thoracotomy can immediately be performed. In patients with negative FDG-PET scan, but positive CT scan, histological verification by invasive methods can individually be considered. In patients with positive FDG-PET scan mediastinoscopy still remains the definitive method for exact lymph node staging.
References
Birim , Kappetein AP, Stijnen T, Bogers JJC. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann Thorac Surg 2005; 79:375–381.
Fritscher-Ravens A, Bohuslavizki KH, Brandt L, Bobrowski C, Lund C, Knfel WT, Pforte A. Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 2003; 123:442–451.
Dhital K, Saunders CAB, Seed PT, O'Doherty MJ, Dussek J. [18F] Fluorodeoxyglucose positron emission tomography and its prognostic value in lung cancer. Eur J Cardio-thorac Surg 2000; 18:425–428.
Kernstine KH, McLaughlin KA, Menda Y, Rossi NP, Kahn DJ, Bushnell DL, Graham MM, Brown CK, Madsen MT. Can FDG-PET reduce the need for mediastinoscopy in potentially resectable nonsmall cell lung cancer. Ann Thorac Surg 2002; 73:394–402.
Gonzalez-Stawinski GV, Lemaire A, Merchant F, O'Halloran E, Coleman RE, Harpole DH, D'Amico TA. A comparative analysis of positron emission tomography and mediastinoscopy in stagning non-small cell lung cancer. J Thorac Cardiovasc Surg 2003; 126:1900–1905.
Daniels J, Rijana H, Postmus P, van Mourik J. Mediastinoscopy as a standardised procedure for mediastinal lymph node staging in non-small cell lung carcinoma. Eur J Cardiothoracic Surg 2001; 19:377–378.
Reed CE, Harpole DH, Posther KE, Woolson SL, Downey RJ, Meyers BF, Heelan RT, MacApinlac HA, Jung SH, Silvestri BA, Siegel BA, Rusch VW. Results of the American College of Surgeons Oncology Group Z0050 trial: The utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg 2003; 126:1943–1951.
Cerfolio RJ, Ojha B, Bryant AS, Bass CS, Bartalucci AA, Mountz JM. The role of FDG-PET scan in staging patients with nonsmall cell carcinoma. Ann Thorac Surg 2003; 76:861–866.
Hellwig D, Ukena D, Paulsen F, Bamberg M, Kirsch CM. Metaanalyse zum stellenwert der positronen-emissions-tomographie mit F-18-Fluordes- oxyglukose (FDG-PET) bei lungentumoren. Pneumologie 2001; 55:367–377.
Verhagen AFT, Bootsma GP, Tjan-Heijnen VCG, van der Wilt GJ, Cox AL, Brouwer MHJ, Corstens FHM, Oyen WJG. FDG-PET in staging lung cancer. How does it change the algorithm Lung Cancer 2004; 44:175–181.
Kimura H, Iwai N, Ando S, Kakizawa K, Yamamoto N, Hoshino H, Anayama T. A prospective study of indications for mediastinoscopy in lung cancer with CT findings, tumor size, and tumor markers. Ann Thorac Surg 2003; 75:1734–1739.
Poncelet AJ, Lonneux M, Coche E, Weynand B, Noirhomme Ph. PET-FDG scan enhances but does not replace surgical staging in non-small cell lung carcinoma. Eur J Cardio-thorac Surg 2001; 20:468–475.
Kernstine KH. Positron emission tomography with 2-[18F] Fluoro-2-deoxy-D-glucose: can it be used to accurately stage the mediastinum in non-small cell lung cancer as an alternative to mediastinoscopy J Thorac Cardiovasc Surg 2003; 126:1700–1703.
Nomori H, Watanabe K, Ohtsuka T, Naruke T, Suemasu K, Kobayashi T, Uno K. Fluorine 18-tagged fluorodeoxyglucose positron emission tomographic scanning to predict lymph node metastasis, invasiveness, or both, in clinical T1 N0 M0 lung adenocarcinoma. J Thorac Cardiovasc Surg 2004; 128:396–401.
van Tinteren H, Hoekstra OS, Smit EF, van den Bergh J, Schreurs Ad, Stallaert R, van Velthoven P, Comans E, Diepenhorst FW, Verboom P, van Mourik J, Postmus P, Boers M, Teule G. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002; 359:1388–1392.(Christoph Schimmer, Konra)
Abstract
We report about a MEDLINE research from 2000 to 2005 with the key words ‘positron emission tomography AND/OR mediastinoscopy’. The search identified 448 potential studies. Out of the published data sensitivity, specificity, positive and negative predictive value, and accuracy for mediastinal lymph node staging by FDG-PET ranged from 58%–94%, 76%–96%, 43%–95%, 56%–98% to 74%–91%, respectively. With corresponding values of 80%–96%, 100%, 100%, 92%–97%, and 94%, respectively, for mediastinoscopy. FDG-PET improved the rate of detection of local and distant metastases in 12% to 62% and changed the management of treatment in 8% to 60% of patients with NSCLC. Our study shows that in the diagnostic strategy of patients with NSCLC, additional FDG-PET can prevent non-therapeutic thoracotomy in a significant number of cases. If FDG-PET imaging and CT scan is negative for mediastinal lymph node involvement routinely mediastinoscopy can be omitted and thoracotomy can immediately be performed. In patients with negative FDG-PET scan, but positive CT scan, histologic verification by invasive methods can individually be considered. Patients with positive FDG-PET scan mediastinoscopy still remain a reliable standard for exact lymph node staging. By incorporating FDG-PET in clinical staging unnecessary exploratory thoracotomies, and mediastinoscopy, can be omitted.
Key Words: Non-small cell lung cancer; [18F]Fluoro-2-deoxy-D-glucose positron emission tomography; Mediastinoscopy; Staging
1. Introduction
Pathologic staging in patients with newly diagnosed non-small cell lung cancer (NSCLC) is of substantial importance determining the best possible therapeutic option, clarifying operability, detecting prognosis, and is essential in clinical trials comparing different management strategies, and enables universal communication regarding the efficacy of different treatments in specific patient groups. The likelihood of the surgical cure of primary NSCLC is strongly dependent on the local extent of the cancer, particularly whether or not the mediastinal lymph nodes are involved with cancer or whether extrathoracic metastases are present [1]. Mediastinal lymph node involvement is reported to be present in 28% to 38% of NSCLC at the time of diagnosis, and if present has an important bearing on the treatment plan [2]. Complete pathologic staging as derived from complete mediastinal lymph node dissection is the accurate way of providing definitive staging information. Additional FDG-PET diagnostics leads to avoid ineffective therapies, particularly unnecessary thoracotomy.
The purpose of this review is to assess on the basis of published studies the value of FDG-PET and of mediastinoscopy in lymph node staging in patients with NSCLC as well as to question to what extent FDG-PET may bypass mediastinoscopy in some cases.
2. Methods
We performed a MEDLINE analysis restricted to the years 2000 to 2005 with the key words ‘positron emission tomography AND/OR mediastinoscopy’ (448 hits). The diagnostic value of FDG-PET, CT, and mediastinoscopy were defined by sensitivity, specificity, positive and negative predictive value, and accuracy, respectively.
3. Results
The MEDLINE search identified 448 potential studies. We selected 28 articles (3 meta-analyses, 17 prospective and 8 retrospective articles). All other studies were excluded after scanning their abstracts, including studies written in another language other than English or German, or because of insufficient data reported, respectively.
3.1. 2-[18F]Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)
Positron emission tomography, a non-invasive imaging modality with the metabolic tracer F-18-fluorodeoxyglucose allows for functional characterization of tissues. The amount of FDG taken up by the abnormal lesion can be represented by semiquantitative measures, such as the standard uptake value (SUV) or ratio (SUR), and made comparable between patients [3]. The use of FDG-PET must take into account the significance of false-positive (i.e. pneumonia, granuloma/sarcoidosis/tuberculosis/aspergillosis/histoplasmosis, pulmonary hamartoma, inflammation or inflammatory response such as bronchiectasis and atelectasis) and false-negative results (atypical carcinoid, NSCLC 1 cm in size or less, and bronchoalveolar carcinomas) (Table 1).
3.2. Cervical and anterior mediastinoscopy
In the work-up for a thoracotomy in patients with NSCLC mediastionoscopy is considered to be an accurate method, providing a high negative and positive predictive value, and a low morbidity and mortality rate. The only anatomic contraindication is the presence of a permanent tracheostomy. Anterior mediastinoscopy is performed when the primary lesion originates in the left upper lobe or left hilium, or when there is suspicious adenopathy in the anterior mediastinum or aortopulmonary window [4]. But mediastinosocopy can lead to false-negative results, because not all lymph node stations could easily be reached (i.e. subcarinal area, paraesophageal area, and pulmonary ligament). Furthermore, mediastinoscopy is associated with a low but present risk of serious complications (in 0.5% of the patients), including hemorrhage, mediastinitis, pneumothorax, or vocal cord paralysis (Table 2).
4. Discussion
Many authors propose that only patients with positive FDG-PET scan do require mediastinoscopy before exploration for resection and mediastinal lymph node dissection, others recommend performing mediastinoscopy on every patient with potentially operable NSCLC [5,6]. This advice is justified because of the fact that the use of FDG-PET can lead to false-positive and false-negative results. A positive FDG-PET scan result does not necessarily represent malignant disease, and histological confirmation is always warranted.
4.1. FDG-PET versus CT-scan
CT-scan is neither sufficiently sensitive nor specific in identifying lymph node metastases. FDG-PET provides information regarding the functional activity of a malignant lesion rather than strictly anatomic information as is provided by computed tomography (CT) [7]. Several studies have shown that FDG-PET is superior to CT scan in staging mediastinal lymph node involvement in patients with NSCLC (Table 3).
Cerfolio et al. [8] prospectively assessed the role of FDG-PET and CT scan in staging 400 patients with NSCLC. Suspicious N2 lymph nodes by either chest CT or by FDG-PET scan were biopsied. In this study, it could be demonstrated that FDG-PET had a higher sensitivity (71% vs. 43%, P<0.001), positive predictive value (44% vs. 31%, P<0.001), negative predictive value (91% vs. 84%, P=0.006), and accuracy (76% vs. 68%, P=0.037) than CT scan for N2 lymph nodes. Similarly, FDG-PET had a higher sensitivity (67% vs. 41%, P<0.001), but lower specificity (78% vs. 88%, P=0.009) than CT scan for N1 lymph nodes. Furthermore, the authors could show that FDG-PET was most commonly falsely negative in the subcarinal station and the aortopulmonary window lymph node stations [8]. Hellwig et al. investigated 20 studies for FDG-PET imaging (n=1292 patients) and found a sensitivity of 88%, specificity of 92%, and accuracy of 91%, respectively, versus 19 studies for CT-scan (n=1268 patients) with a sensitivity of 65%, specificity of 76%, and accuracy of 73%, respectively [9]. Birim et al. found 17 studies with 833 patients. Sensitivity and specificity were determined using the area under the receiver operating characteristic (ROC) curve. The point on the ROC with equal sensitivity and specificity for FDG-PET was 0.9. For CT it was 0.7. The difference was highly significant (P<0.0001) [1].
Several trials could prove a significant improvement of integrated PET-CT compared to FDG-PET alone (Table 4).
4.2. Mediastinoscopy
Mediastinoscopy, first described by Carlens and associates in 1959, is an invasive procedure with a low but present risk of serious complications. In many clinics mediastinoscopy is not a standard procedure for mediastinal lymph node staging. The utility of mediastinoscopy in the presence of normal-sized mediastinal lymph nodes is more controversial. Even patients with peripheral T1 tumors and no mediastinal adenopathy according to CT may be found to have positive mediastinal lymph nodes in up to 20% of cases. Because N2 disease is a strong marker for probable occult distant metastatic disease, many thoracic surgeons routinely perform mediastinoscopy, which provides the opportunity to consider induction therapy before thoracotomy [10]. Therefore, lymph node sampling or lymph node dissection by means of invasive procedures (cervical and/or anterior mediastinoscopy) provides the definitive possibility for pathologic staging. Daniels et al. investigated 76 patients with NSCLC and performed mediastinoscopy on every patient with potentially operable NSCLC (except for T1 squamous cell carcinoma). Ten percent of the patients were prevented from exploratory thoracotomy by the routine use of mediastinoscopy. The authors conclude that mediastinoscopy should be performed on every patient with possibly operable NSCLC, regardless of the outcome of CT, except for patients with T1 squamous cell carcinoma [6]. Because it is neither practical nor economical to recommend mediastinoscopy for all candidates for surgery, Kimura et al. have developed – in a prospective study with 121 patients – indication criteria for cervical mediastinoscopy. Patients with resectable NSCLC were chosen for mediastinoscopy when at least one of three clinical indicators was present: (1) computed tomographic evidence of mediastinal adenopathy, (2) elevated levels of serologic tumor markers, and (3) diameters of primary cancers 2 to 3 cm. Pathologic examinations after mediastinoscopy indicate that the diagnostic sensitivity and negative predictive value for the postulated indication criteria were 95.8% and 97.4%, respectively. Using three indicators for N2 prediction the authors avoided 37% unnecessary mediastinoscopies. FDG-PET was less effective than the three criteria, yielding 70% (diagnostic sensitivity), 86% (specificity), and 84% (accuracy), respectively [11].
4.3. Comparison of FDG-PET to mediastinoscopy
Several reports tried to answer the question whether FDG-PET can reduce the need for mediastionoscopy in patients who are potentially eligible for a curative resection and to what extent FDG-PET is able to affect management of treatment. Actually, only prospective studies that compare FDG-PET scanning to detect lymph node metastases versus other methods do provide a truly definitive answer. In the year 2001, Poncelet et al. tried to assess – in a prospective study with 64 patients – the effectiveness of FDG-PET in mediastinal lymph node staging for NSCLC and compared it to conventional clinical and surgical staging. This study showed that FDG-PET imaging strength lies in its very high negative predictive value and increased sensitivity. Combinded with chest CT-scan preoperatively, it may alleviate the need for surgical staging when FDG-PET studies of the mediastinum are negative. However, with a positive FDG-PET scan result, further diagnostic procedures should be pursued in order to avoid overstaging and allow better surgical patient selection [12]. On the other hand, Gonzalez-Stawinski et al. compared prospectively the efficacy of FDG-PET to mediastinoscopy in 202 patients with known NSCLC. Of the 65/202 patients (32.2%) with positive results of FDG-PET, only 29 patients had positive results of mediastinoscopy in the corresponding nodal station. Of the 137 patients with negative results of FDG-PET, 16 patients (11.7%) were demonstrated to have N2 or N3 disease. Therefore, the authors concluded that FDG-PET neither confirms nor excludes involvement of the mediastinum in patients with NSCLC and cervical mediastinoscopy with lymph node biopsy remains the criterion standard for mediastinal staging. In this study the false-positive results (55.4%) of mediastinal FDG-PET included granulomatous inflammation, sinus histiocytosis, and silicosis [5]. Also Kernstine [13] could demonstrate results with 237 patients (sensitivity of FDG-PET of 68%, specificity of 82%, positive predictive value of 54%, and negative predictive value of 89%). On the basis of these results, the author concluded, that relative to mediastinoscopy FDG-PET alone is not sufficient to accurately stage the mediastinum and that mediastinoscopy should continue to be performed in potentially operable cases. The author summarized the impact of FDG-PET in the clinical management: (1) it is useful in diagnosis and staging, though it neither diagnoses nor excludes the presence of malignancy; (2) it can discriminate less suitable candidates for surgical resection, estimated to be 20% to 25% of potential surgical patients; and (3) it may provide helpful prognostic information in additional to the staging information. Even Verhagen et al. assessed prospectively the impact of adding FDG-PET to full conventional clinical staging. The authors concluded that by incorporating FDG-PET in clinical staging, 15% of patients with NSCLC are upstaged due to unexpected extrathoracic metastases. In case of a negative mediastinal FDG-PET scan, mediastinoscopy can only be omitted in the presence of a non-centrally located primary tumor and without FDG-PET positive N1 nodes [10]. The PLUS (PET in LUng cancer Staging; multicenter trial with 188 patients) study was designed to work with routine clinical workup of patients with suspected NSCLC. The authors compared the current strategy of conventional diagnostic methods with a strategy in which FDG-PET was added to non-invasive diagnostic techniques. The results showed that addition of FDG-PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected NSCLC [15]. Also, the American College of Surgeons Oncology Group undertook a trial to ascertain whether FDG-PET could detect lesions that would preclude pulmonary resection in a group of patients with documented or suspected NSCLC. They found that in patients with suspected or proven NSCLC considered respectable by standard staging procedures, FDG-PET can prevent non-therapeutic thoracotomy in a significant number of cases. By correctly identifying advanced disease (stages IIIA, IIIB, and IV) or benign lesions, FDG-PET potentially avoided unnecessary thoracotomy in 1 of 5 patients [7]. Furthermore, several studies pointed out that by adding FDG-PET to conventional staging the management of treatment is changed in 8% to 60% of patients and prevents unnecessary invasive exploratory thoracotomy, and mediastinoscopy in 12% to 62% (Table 5).
5. Conclusions
In conclusion, the results of these studies indicate that in patients with NSCLC incorporating FDG-PET in clinical staging can prevent unnecessary invasive procedures in a significant number of cases. If FDG-PET imaging and CT scan is negative for mediastinal lymph node involvement routinely mediastinoscopy can be omitted and thoracotomy can immediately be performed. In patients with negative FDG-PET scan, but positive CT scan, histological verification by invasive methods can individually be considered. In patients with positive FDG-PET scan mediastinoscopy still remains the definitive method for exact lymph node staging.
References
Birim , Kappetein AP, Stijnen T, Bogers JJC. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann Thorac Surg 2005; 79:375–381.
Fritscher-Ravens A, Bohuslavizki KH, Brandt L, Bobrowski C, Lund C, Knfel WT, Pforte A. Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 2003; 123:442–451.
Dhital K, Saunders CAB, Seed PT, O'Doherty MJ, Dussek J. [18F] Fluorodeoxyglucose positron emission tomography and its prognostic value in lung cancer. Eur J Cardio-thorac Surg 2000; 18:425–428.
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