Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(2):338-345; doi:10.1093/annonc/mdl374
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© 2006 European Society for Medical Oncology
lung cancer |
A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis
1 Department of Nuclear Medicine and PET
2 Department of Oncology
3 Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark
* Correspondence to: Dr B. M. Fischer, Research Fellow, Department of Nuclear Medicine and PET, Copenhagen University Hospital, 4012 Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel: +45-39563550; Fax: +45-35453898; E-mail: malene.fischer{at}rh.dk
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Abstract |
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Background: Small-cell lung cancer (SCLC) accounts for 15%–20% of all lung cancer cases. Accurate and fast staging is mandatory when choosing treatment, but current staging procedures are time consuming and lack sensitivity.
Patients and methods: A prospective study was designed to examine the role of combined positron emission tomography/computed tomography (PET/CT) compared with standard staging (CT, bone scintigraphy and immunocytochemical assessment of bone marrow biopsy) of patients with SCLC. Thirty-four consecutive patients were included. Twenty-nine patients received initial PET/CT.
Results: PET/CT caused change of stage in 5/29 (17%). Excluding patients with unconfirmed findings or pleural effusion, the sensitivity for accurate staging of patients with extensive disease was the following: for standard staging 79%, PET 93% and PET/CT 93%. Specificity was 100%, 83% and 100%, respectively.
Conclusion: The results from this first study on PET/CT in SCLC indicates that PET/CT can simplify and perhaps even improve the accuracy of the current staging procedure in SCLC. A larger clinical trial, preferably with consequent histological confirmation in case of discordance, however, is warranted.
Key words: bone marrow, bone scintigraphy, diagnostic accuracy, PET/CT, small-cell lung cancer, staging
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introduction |
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Small-cell lung cancer (SCLC), accounting for 15%–20% of all new cases of lung cancer [1], is an aggressive disease, often disseminated at the time of diagnosis [2]. Patients with limited disease (LD, disease confined to one hemithorax) are offered chemotherapy combined with radiotherapy, whereas chemotherapy alone is standard treatment in patients with extensive disease (ED, disease outside one hemithorax). Thus, accurate staging is important, in order to reserve the combined modality treatment to those patients who actually might benefit from it. In patients with SCLC the initial response rate to chemotherapy is high (70%–80%), but the majority of these patients relapse shortly after termination of treatment, indicating that the current therapy is not effective enough but also that the current staging procedure and therapy evaluation are not sufficiently sensitive.
2-[Fluorine-18]fluoro-2-deoxy-D-glucose–positron emission tomography (FDG-PET) is known to have a high diagnostic yield in patients with solitary pulmonary nodules and in staging of non-small-cell lung cancer (NSCLC) [3]. Studies have indicated that positron emission tomography/computed tomography (PET/CT) probably is even more useful in this setting [4]. Recently, a large study has shown that FDG-PET might improve and simplify the current staging of patients with SCLC [5]. Previously, this has only been indicated by small, mainly retrospective studies [6–14]. Until now, no studies have assessed the value of PET/CT in staging SCLC.
Bone marrow biopsy or bone scintigraphy is a part of standard staging procedures for SCLC. Metastases to the bones and bone marrow are frequent in SCLC [15] and autopsy data have demonstrated bone or bone marrow metastasis in 45% of the patients initially diagnosed as having LD [16]. Even so, it is unsettled which diagnostic modality is the most efficient. The vast majority of bone metastasis often starts as intra-medullar lesions [17]. Thus, it should be possible to detect bone marrow metastasis also in patients without demonstrable bone metastasis. FDG-PET may detect both metastases to both the bone marrow and bone. Three retrospective studies have suggested that FDG-PET can replace bone scintigraphy in staging patients with NSCLC [18–20]. Bone scintigraphy has a high sensitivity but relatively low specificity—the opposite being the case for bone marrow biopsy [21]. Studies have suggested that the diagnostic value of bone marrow biopsy can be improved by performing immunocytochemical assessment of the bone marrow aspirates [22, 23].
In this study, we examined the role of combined PET/CT and PET compared with CT, bone scintigraphy and immunocytochemical assessment of bone marrow biopsy in the staging of patients with SCLC.
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materials and methods |
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design
This prospective study was approved by the local ethical committee and written informed consent was obtained from all participants.
Patients with histological or cytological proven SCLC were eligible. Patients with type-1 diabetes, known former or present malignant disease apart from SCLC, claustrophobia, pregnancy and age below 18 years were excluded. The protocolled staging work-up consisted of PET/CT, bone scintigraphy and immunocytochemical analysis of bone marrow. In addition, the patients underwent standard staging procedures including clinical examination, blood test, chest X-ray, bronchoscopy and bone marrow biopsy (bone scintigraphy is not a part of standard staging procedure at our institution). Standard CT of the thorax and upper abdomen was replaced by PET/CT. All examinations were performed within 1 week and before initiation of therapy. Since PET/CT has not been evaluated in patients with SCLC before this study, the clinicians only received the result from the CT scan part of the combined PET/CT. By blinding the PET/CT findings to the clinicians, it enabled us to assess the isolated effect of PET and PET/CT in assigning the correct stage of the patient. On the other hand, we were not able to obtain histological proof in case of discordant findings. In order to counter this and reduce bias, a number of evaluation criteria were prospectively defined to serve as ‘gold standard’[6]. These were based on: (i) histology if availabe, (ii) concordance between structural and metabolic imaging modalities, (iii) results of supplemental examinations (magnetic resonance imaging or ultra sound) and (iv) follow-up of the patient with emphasis on relevant foci. All information on discordant cases was presented to two independent experienced thoracic oncologists (SL and UL), who assigned the final stage.
study population
From February 2003 to December 2004, 34 patients were included. Four patients failed to receive initial PET/CT and one patient was lost to follow-up, leaving 29 patients for the final analysis on PET/CT (Figure 1). Thirty-one patients received bone scintigraphy and bone marrow analysis (in three of these patients immunohistochemical analysis failed). The patient demographics are described in detail in Table 1. Twenty-eight percentage of the patients (8/29) were staged as having LD. At the time of data analysis, 24 patients (71%) had died, the median survival time in this group being 9.0 months (range 1–25 months). One patient was lost to follow-up after 1.2 months. The remaining nine patients were followed for a median of 16.8 months (13–29 months).
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positron emission tomography/computed tomography
PET/CT scans were performed at the Department of Clinical Physiology, Nuclear Medicine and PET. After a fasting period of 6 h, 400 MBq 18-F-FDG was given i.v. and the patient rested for 1 h. The plasma glucose was measured by glucometer before scanning (mean 4.7 mmol/l). The patient was scanned from the head to the upper thigh on an integrated PET/CT system (GE Discovery LS; General Electric Medical Systems, Milwaukee, WI). A standardised CT protocol (80–120 mAs, 140 kV, tube rotation time of 0.5 s per rotation, pitch 6 and a slice thickness of 5 mm, shallow breathing) with i.v. contrast was applied followed by PET scan (3 or 5 min emission scan per table position, depending on whether the patient could keep the arms above the head during scanning or not). The effective dose equivalent was 11 mSv from the CT scan and 8 mSv from the FDG injection. The scan was reconstructed by filtered back projection and ordered subset expectation minimisation, and data from the CT scan were used for attenuation correction. Coronal, sagittal and transaxial images were reconstructed and viewed on a computer workstation. An experienced radiologist (AKB), blinded to the PET findings, interpreted the CT scan. PET scans were analysed visually and interpreted by an experienced nuclear medicine physician (AL), blinded to the CT findings; lesions were classified as malignant if there was focally increased tracer uptake that exceeded the background regional FDG accumulation in the relevant organ and if the lesion was located at typical metastatic site. Foci in the lung were considered malignant if FDG accumulation exceeded background accumulation in the mediastinum. Fused PET/CT images were evaluated in consensus afterwards. Pre-defined clinical report forms were used throughout. Patients with disease confined to one hemithorax (including metastasis to mediastinal and ipsilateral supraclavicular lymph nodes) were classified as having LD. Patients with tumour beyond these sites, including ipsilateral pleural effusion, were classified as having ED [15]. A TNM (tumour–node–metastasis)-stage according to Mountain classification [24] was assigned as well.
bone scintigraphy
Whole-body scan with a dual-head gamma camera (GE or ADAC) with high-resolution low-energy collimator was performed 2–4 h after injection of 500–700 MBq 99mTc-oxydronate (TechneScan HDP; Mallinckrodt, Hazelwood, MO, USA). The scan lasts 
30 min, and if indicated, a subsequent tomography (single-photon emission computed tomography) was performed. An experienced nuclear medicine physician (JM) interpreted the bone scintigraphies and results were reported on pre-defined clinical report forms.
bone marrow examination
Bilateral bone marrow aspiration was performed from the posterior iliac crest. The bone marrow aspirates were immediately prepared for immunocytochemistry against cytokeratin, n-cam, CD56 and thyroid transcription factor-1 (TTF-1) [23, 25]. Mononuclear cells were isolated from the samples using a density gradient (Lymphoprep, spun at 400 g in 27 min at 20°C). The mononuclear cell layer was washed in phosphate-buffered saline, counted in Neuenbayer haemocytometer and resuspended at 100 x 106 cells/ml. A volume of 500 µl of the cell suspension was cytospun (Hettich cytocentrifuge, 190 g in 4 min). The cytospins (5 x 106 cells per slide, 10 slides) were dried at room temperature overnight and frozen at –20°C. Immunocytochemistry was performed using VECTASTAIN®Elite-ABC (DAKO Cytomation, Glostrup, Denmark) according to the prescription provided by the manufacturer. Samples were incubated for 60 min with CK-AE (DAKO), Synaptophysin (DAKO) and TTF-1 (DAKO) in 2% bovine serum albumin (Sigma A4503) in concentration 1 : 50 and washed for 5 min in phosphate-containing buffers and incubated with secondary antibody (Envision+; DAKO). Staining was developed using Vector®NovaRED (DAKO) and counterstained for 30 s with Mayers Haemalune. Samples from each patient were scored as positive (at least one positive tumour cell per cell group) or negative for either antibody by an experienced pathologist (BLP). The bone biopsy and remaining bone marrow aspirate was analysed by standard histological methods.
costs
Total costs from a hospital perspective were calculated based on 2006 Danish prices (in euros) [26]. Only direct medical costs associated with initial staging (chest X-ray, CT, bone scintigraphy or PET/CT), first-line therapy (i.e. chemo- and radiotherapy) outpatient visits and hospital admission were included. All costs included personnel, materials, depreciation and overheads. Costs of chemotherapy were based on a standard patient of height 180 cm, weight 80 kg and surface of 2.0 m2 receiving six cycles of etoposide, carboplatin and vincristine. Each cycle included 3 days of hospital admission and one outpatient visit. On the basis of current recommendations for standard staging [2, 27], we chose not to include costs for bone marrow biopsy in the total costs for standard staging.
data analysis
Diagnostic accuracy was calculated as sensitivity, specificity, positive and negative predictive values as well as likelihood ratio (LR) for standard staging, PET and PET/CT. Corresponding 95% confidence intervals were calculated.
In order to compare standard staging, PET and PET/CT McNemar's test for paired data were applied. Statistical analysis was performed using SPSS version 13.0.
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results |
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description of intra-thoracic findings
PET/CT and PET identified the primary tumour in all patients (results presented in detail in the Appendix). CT and PET assigned a different T-stage in eight patients and PET down-staged all tumours except one. PET/CT and CT assigned concordant stage in all patients except one. CT and PET/CT diagnosed pleural fluid in nine patients, PET in three patients. Metastases to the ipsilateral lung were diagnosed by CT in six patients, by PET in five and by PET/CT in four patients. Contralateral metastases were found by all three modalities in three patients and by PET alone in one patient (turned out to be tuberculosis). Mediastinal metastases were diagnosed by CT in 25 patients, by PET and PET/CT in 24 patients. CT and PET/CT assigned discordant N-stage in four patients, CT and PET in six patients.
description of extra-thoracic findings
Metastases to the liver were suspected by CT, PET or PET/CT in 14 patients (48%); nine patients had metastases to the liver diagnosed by all three modalities. One patient had liver metastasis diagnosed by CT and confirmed by follow-up, but missed by PET and PET/CT. PET suggested liver metastasis in one patient which was interpreted as a lymph node on PET/CT, but missed by CT. PET/CT diagnosed a further three patients with liver metastases, one of these missed by PET and two missed by CT.
CT found adrenals suspicious for metastases in five patients, PET in three and PET/CT in four patients. Metastases to extra-thoracic lymph nodes were found in eight patients; five on CT, five on PET and five on PET/CT.
metastases to bone and bone marrow
Metastases to bone or bone marrow were diagnosed in 13 of 34 patients (38%), findings were considered positive for metastases if they were confirmed by at least two modalities or follow-up. Sensitivity of PET and PET/CT was 80% (95% CI 49% to 94%). Sensitivity of CT was 30% (95% CI 11% to 60%). The sensitivity of conventional bone marrow analysis was 58% (95% CI 32% to 81%) compared with 82% (95% CI 52% to 95%) for immunocytochemical analysis. In two patients metastases to the bone marrow was diagnosed by immunocytochemical analysis only. The performance of bone scintigraphy was hampered by the frequent occurrence of equivocal findings affecting 10 of 31 procedures. Interpreting equivocal findings as most likely positive, the resulting sensitivity and specificity of bone scintigraphy was 75% and 58%, respectively (95% CI 47% to 91% and 36% to 77%). In three patients bone scintigraphy suggested bone metastasis which could not be confirmed by any of the other modalities or follow-up.
diagnostic accuracy and impact on management
With the present use of a dual staging system in the management of SCLC, only disagreement on the presence or absence of metastases outside one hemithorax or pleural effusion, indicating ED and excluding the patient from first-line radiotherapy, will have any significant impact on patient management. According to standard staging methods, 33% (95% CI 20% to 50%) of the patients had LD, after PET/CT and at final staging this number was decreased to 28% (95% CI 15% to 46%). PET/CT suggested a different stage compared with standard staging in 5 of 29 patients (17%), PET in 9 patients (31%) (Table 2), the stage suggested by PET and PET/CT turned out to be most likely correct in 3 patients and equivocal in 1. In one patient, PET and PET/CT overlooked a liver metastasis, but follow-up confirmed the finding by CT. In three patients, PET did not visualise pleural effusion, and in one patient a chronic infection was interpreted as a contralateral metastasis; all four were correctly diagnosed by PET/CT. In two patients metastases to the bone and bone marrow was diagnosed by PET and PET/CT only, and later confirmed by follow-up. Cross-tabulation and the diagnostic accuracy of standard staging, PET and PET/CT compared with the final stage are presented in Table 3 (excluding patient 9 with unconfirmed findings and all patients with pleural effusion). The diagnostic value of PET and standard staging was almost equal, and PET/CT appeared to be superior to the other modalities. McNemar's test was applied to test whether the possibility of a positive diagnosis (ED) was different between the three modalities; this difference was not significant.
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costs
The isolated costs of standard staging (chest X-ray, CT of thorax and upper abdomen and bone scintigraphy) was
1094 and 2250 for a PET/CT scan. The total costs (Table 4) of staging and therapy after the two strategies was 22 941 and 23 127 respectively, taking into account the hospital admission in connection with staging (5 days for standard staging and 4 with PET/CT) and the costs associated with therapy (all patients received chemotherapy and radiotherapy offered to 0.33 and 0.28 patient after standard and PET/CT staging, respectively. No significant difference in total cost between the two strategies was found.
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discussion |
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This prospective study investigated the value of PET/CT in staging of 29 patients with newly diagnosed SCLC. PET/CT correctly changed the stage in three of 29 patients (10%). PET alone caused change of stage in nine patients, but PET erroneously down-staged three patients with pleural effusion and up-staged one patient with a chronic infection. A very low negative LR(= –0.07) of PET/CT was found; thus, if the pre-test probability of ED is 65%, then the post-test probability of ED after a PET/CT indicating LD is reduced to 10% [28]. After standard staging (LR = –0.21) the post-test probability in a similar setting would be 30%. In a recent study, Brink et al. [5] found that FDG-PET alone was significantly better than standard staging in detecting extra-thoracic lymph node involvement and distant metastases. Furthermore, PET caused change of stage in 14 (12%) of 120 patients. Apparently, none of the included patients had pleural effusion and excluding patients with pleural effusion from our dataset gives similar results. It is broadly accepted that PET is inferior to CT in detecting pleural effusion; however, studies have shown that PET might be useful in discriminating between malignant and benign pleural effusion diagnosed by CT [29, 30]. This is supported by recent data indicating that even a monolayer or a solution with as few as 106 malignant cells can be visualised by FDG-PET [31]. The role of pleural effusion in the management of patients with SCLC is ambiguous. It has been reported that patients with an isolated pleural effusion survive as long as other patients with LD, but other series indicate that survival with an isolated pleural effusion is comparable to patients with a single metastatic site [15]. Most randomised clinical trials evaluating combined modality treatment in patients with limited-stage SCLC exclude patients with pleural effusion (benign or malignant). Given these ambiguities, we chose to exclude patients with pleural effusion from the analysis on diagnostic accuracy. Including all patients with pleural effusion (except patient 9 with unconfirmed findings) would result in a sensitivity of standard staging, PET and PET/CT of 86%, 81% and 95%, respectively. Similarly, the specificity would be 100%, 83% and 100%, respectively, reflecting the well-known superiority of CT in detecting pleural effusion.
A common problem in SCLC is detection of metastases to the bones and bone marrow, affecting up to 40% the patients [15]. We addressed this problem offering bone scintigraphy and bone marrow biopsy (analysed by means of conventional histology and immunocytochemistry) to the patients included. Similar to previous studies on NSCLC [19, 20], we found PET and PET/CT to be just as sensitive as bone scintigraphy and bone marrow biopsy. Immunocytochemical analysis of bone marrow aspirates appear superior to conventional analysis detecting two patients with bone marrow metastasis not found by histology.
On the basis of our findings and the direct medical costs associated with staging and primary therapy we compared the total costs of the standard staging and PET/CT strategy. Given that the PET/CT strategy will diagnose more patients with ED and shorten the length of hospital admission in connection with staging with 1–2 days, no significant difference in the costs of each strategy was found.
A drawback in the present study, and all other studies on PET in SCLC [6–9, 11–14], is the lack of consequent histological verification of discordant findings, reflecting that patients with SCLC are often in a relatively poor performance status, and immediate initiation of therapy is mandatory. Thus, it is difficult and ethically questionable to obtain biopsies from all affected sites. In order to counteract this limitation, we prospectively designed a number of evaluation criteria, inspired by Blum et al. [6] and these were applied by two experienced thoracic oncologists. In one patient (number 9) it was not possible to obtain sufficient proof to assign a final stage and this patient was excluded from the analysis on diagnostic accuracy.
No patients presented with brain metastases. Thus, it was not possible to estimate the value of PET/CT in this setting, but previous studies have shown that PET alone is not suited for the diagnosis of brain metastasis [5, 11].
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conclusion |
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Is there a role for PET/CT in the staging of SCLC? Taking all the reservations necessary when concluding on a small material, the answer is: most likely. By including whole-body PET/CT in staging patients with SCLC, it is possible that conventional CT of thorax and upper abdomen, bone scintigraphy and bone marrow biopsy can be omitted saving precious time and making rapid initiation of therapy possible. Whether PET/CT can significantly improve the accuracy of SCLC staging and positively influence patient management remains to be settled. Thus, a larger clinical trial, preferably with histological confirmation in case of discordance, is warranted before final conclusions can be draw.
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appendix |
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Table A1. Intra-thoracic findings by CT, PET and PET/CT in each patient (n = 29)
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An empty space equals negative findings.
aMetastasis to the ipsilateral lung.
bMetastasis to the contralateral lung.
CT, computed tomography; PET, positron emission tomography.
Table A2. Extra-thoracic findings by CT, PET and PET/CT in each patient (n = 29)
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An empty space equals negative finding.
CT, computed tomography; PET, positron emission tomography.
Table A3. Metastases to bone and bone marrow (n = 32)
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An empty space equal negative finding.
PET, positron emission tomography; CT, computed tomography; NA, not applicable since the analysis was not performed in this patient.
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Acknowledgements |
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The authors wish to thank technologists Susanne Svalling, Camilla Qvist and registered nurse Anne-Lise Andersen for their invaluable assistance.
Received for publication April 28, 2006. Revision received August 22, 2006. Accepted for publication August 30, 2006.
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