B Academy of Molecular Imaging, 2009 Published Online: 28 March 2009
Mol Imaging Biol (2009) 11:473Y479 DOI: 10.1007/s11307-009-0203-6
RESEARCH ARTICLE
Prognostic Value of 18F-FDG PET/CT in Patients with Malignant Pleural Mesothelioma S. T. Lee,1,2,3 M. Ghanem,1 R. A. Herbertson,3,4 S. U. Berlangieri,1 A. J. Byrne,1 K. Tabone,1 P. Mitchell,2,4 S. R. Knight,5 M. Feigen,6 A. M. Scott1,2,3 1
Centre for PET, Austin Health, Heidelberg, Victoria, 3084, Australia Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia 3 Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Health, Heidelberg, Victoria, Australia 4 Ludwig Institute Oncology Unit, Austin Health, Heidelberg, Victoria, Australia 5 Department of Thoracic Surgery, Austin Health, Heidelberg, Victoria, Australia 6 Department of Radiation Oncology, Austin Health, Heidelberg, Victoria, Australia 2
Abstract Purpose: To evaluate prognostic value of integrated 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) and correlate histopathological subtype with maximum standardized uptake value (SUVmax) and survival in patients with malignant mesothelioma (MM). Procedures: Retrospective review of FDG-PET/CT scans, with derivation of SUVmax of FDGavid lesions, was performed in patients with biopsy-proven MM. Clinical follow-up and Kaplan– Meier survival analysis was performed. Results: Forty-six patients (37 M:9 F; mean age 61 years) with MM had a FDG-PET/CT scan in a 30-month period. Follow-up was available on 44/46 (96%) patients. Metastatic disease was detected in 9/46 (20%) patients on FDG-PET/CT, where 8/9 were previously undetected. Better survival was found in patients without metastases (p valueG0.05). Mean SUVmax of primary pleural lesions in patients with metastatic disease was significantly higher than in patients without metastatic disease (p valueG0.05). Progression-free survival was significantly better in the epithelioid histology group compared to the biphasic group (p value 0.015). Conclusions: Detection of extrathoracic metastases on FDG-PET/CT and nonepithelioid histopathology are poor prognostic indicators in patients with MM. Key words: FDG-PET/CT, Mesothelioma, Prognosis, PET
Introduction
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ustralia has the highest reported incidence of malignant pleural mesothelioma in the world, with 40 cases per million compared to 15 cases per million in the USA [1]. This has been attributed to Australia’s crocidolite asbestos mining and heavy industrial use of asbestos products. The incidence is projected to increase by 50% from 2001 to 2011, compared to a 2% increase in other cancers, given the long latency between asbestos exposure and diagnosis of mesothelioma [1]. Correspondence to: S. T. Lee; e-mail:
[email protected]
Despite modern advancements in diagnosis and treatment, patient survival remains poor, with a median survival of 12 months [1]. Intensive local therapy involving surgery and radiotherapy, with or without chemotherapy, may have an important impact on local disease. Recently, a new technique for postoperative radiotherapy, known as intensity-modulated radiation therapy, has shown great promise in reducing local recurrence following radical surgical resection, and the early detection of metastatic disease has become an important factor in patient selection for intensive approaches to treatment [2]. There have been various noninvasive imaging modalities used for staging in malig-
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nant mesothelioma, including computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). CT has a role in the detection of disease involving the pleura, and although it is commonly used to detect intrathoracic nodal disease, its sensitivity is suboptimal and biopsy is recommended for definitive diagnosis [3, 4]. MRI is used to complement CT, particularly in determining the extent of local invasion. MRI is superior to CT in the evaluation of local invasion of endothoracic fascia or single chest wall focus (accuracy 69% vs 46%) and the diaphragm (82% vs 55%) [5]. Determination of nodal disease is similar between both modalities at approximately 50% [5]. 18 F-2-fluoro-deoxy-glucose (18F-FDG) PET has been widely utilized to stage and diagnose cancer [6]. In mesothelioma, 18F-FDG PET has been evaluated predominantly in diagnosis [7] and preoperative staging [8–10]. 18 F-FDG PET has been shown to be able to detect metastatic disease in 11–25% of preoperative patients [8, 10] but was not reliable in the evaluation of locoregional nodal disease [11]. A previous study has shown that increased FDG uptake at initial diagnosis is associated with an unfavorable prognosis [7], but this has not been evaluated in the newer integrated PET/CT. Diffuse, infiltrative tumors such as malignant mesothelioma may have varying histology in different parts of the same tumor, and the most appropriate biopsy site is indeterminable based on CT alone. However, PET/CT may be able to identify areas of metabolic activity, which may guide the biopsy to areas of disease in order to yield a more accurate prognosis. There are three main histological types of malignant mesothelioma—epithelioid, biphasic/mixed, and sarcomatoid [12]. According to the Cancer and Leukaemia Group B and other prognostic scoring systems, the nonepithelioid histology has worse prognosis than the epithelioid pathology [13], with other poor prognostic factors, as listed in Table 1. Based on these factors, the median overall survival ranges from 3.9 months to 9.8 months, with 1-year survival figures of 14% to 50% [14]. Other factors shown to correlate with poor prognosis include intrathoracic lymph node disease, distant metastasis, and extensive pleural involvement [15].
Table 1. Poor prognostic factors in malignant mesothelioma (Adapted from Cancer and Leukaemia Group B) [14] Poor performance status (Eastern Cooperative Oncology Group92) Age975 years Presence of chest pain Presence of pleural involvement Breathlessness as a major symptom Significant weight loss High white cell count Low hemoglobin level High serum lactate dehydrogenase (9500 IU/L) High platelet count (9400,000/μL)
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F-FDG PET/CT in Pleural Mesothelioma
The primary objective of our study was to evaluate the progression-free survival in patients with malignant pleural mesothelioma who had an integrated 18F-FDG PET/CT and correlate survival with FDG uptake measured using a semiquantitative measurement known as maximum standardized uptake value (SUVmax), which has not been previously studied in a group of patients at different stages of treatment. A secondary objective was to correlate the histology subtype with SUVmax and survival.
Materials and Methods Clinical Data All patients with biopsy-proven malignant mesothelioma who underwent integrated 18F-FDG PET/CT scan at the Centre for PET, Austin Health were identified from our institutional database. Histological information and follow-up data were collected from the patient’s history and referring doctors. Patients were classified into scan indications and histopathology subgroups. 18
F-FDG PET/CT Scan Acquisition
Patients were fasted for 6 h prior to intravenous injection of approximately 5 MBq/kg of 18F-FDG. Following a 60-min uptake period, PET scans from the base of the skull to the upper thighs were performed on a Philips Gemini PET/CT system (Philips Medical Systems, Cleveland, OH, USA), which included a lowdose 30-mA/slice two-slice CT for purposes of attenuation correction and anatomical localization. The CT was obtained in 5mm slices. A Cs-137 transmission source was used also for attenuation correction. The 18F-FDG PET emission scan duration was for 3 min per bed position, and the patients were scanned with their arms raised above their heads. The scans were processed with a Row Action Maximum Likelihood Algorithm-3D iterative reconstruction. 18
F-FDG PET/CT Scan Interpretation
The 18F-FDG PET/CT scans were interpreted by a nuclear medicine physician with access to clinical information, but not results of pre-PET staging investigations. All scans were evaluated for local extent of disease and for extrathoracic metastasis, with the SUVmax determined for both the primary pleural lesions and the metastatic lesions. The SUV was calculated according to standard methods, based on FDG uptake corrected for injected dose, blood glucose level at injection, and patient’s body weight [16]. The images were thresholded electronically to demonstrate the maximum voxel on the transaxial, coronal, and sagittal slices of the reconstructed images, with the SUVmax recorded for that region of interest.
Statistical Analysis Progression-free survival was defined as time from PET/CT scan until time of disease progression (radiologic on CT or clinical) or death in all patients with follow-`up. Patients with no evidence of disease progression were censored at the date of the last follow-up. The SPSS statistical software package was used to analyze the data
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Table 2. Scan indications and SUVmax findings Scan indication Staging (n=4) Postop staging (n=22) Restaging (n=18)
Mean SUVmax 6.0 5.4 4.5
SUVmax range 3.4–8.0 2.1–9.5 2.0–8.9
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Analysis of Surgical Procedures and Survival Median survival 4 months 5 months 9 months
and produce Kaplan–Meier survival curves and for basic statistical analysis of SUVmax values. The survival distribution in each group was compared using the log-rank test. A p value of G0.05 was considered statistically significant.
Results Patient Demographics There were 46 patients (37 M:9 F) with biopsy-proven malignant pleural mesothelioma who had an integrated 18 F-FDG PET/CT scan between October 2003 and February 2006. The mean age was 61 years (range 43–82 years). Follow-up was available on 44/46 (96%) patients, with two patients lost to follow-up. Where survival analysis was performed, this was based on the 44 patients with follow-up available. For analysis of SUVmax, all 46 patients were taken into account.
Analysis of Scan Indication, SUVmax, and Survival In the group of 44 patients with follow-up available, there were four patients who presented for staging purposes (without previous intervention), 18 patients for restaging posttreatment, and 22 patients for postoperative staging prior to adjuvant radiotherapy or chemotherapy. This last group included patients who had any surgical intervention in the 3 months preceding the 18F-FDG PET/CT. The surgical interventions included video-assisted thorascopy with pleurodesis (n=14) and pleurectomy (n=8). The group classified as having the 18 F-FDG PET/CT for restaging included patients undergoing studies for suspected clinical recurrence or for surveillance of previously treated disease. The SUVmax was similar in patients who were presenting for different indications as seen in Table 2. There was no statistically significant treatment between the groups, with a p value of 0.9. This is summarized in Table 2. Evaluation of progression-free survival by Kaplan– Meier analysis in the three groups of patients was not statistically significant, with a mean progression-free survival of 6 months for patients presenting for staging of disease, 9 months for patients for restaging of disease, and 5 months for patients who presented within 3 months postoperatively. Comparison of survival distribution using long-rank method also did not show any statistically significant difference in progression-free survival (p value 0.5).
Subanalysis of the surgical interventions and the survival showed that there was no difference in SUVmax or overall survival in patients who had different surgical procedures performed, as shown in Table 3.
Presence of Metastatic Disease Metastatic disease on 18F-FDG PET/CT was detected in 9/44 (20%) patients, of whom two patients were investigated for staging purposes as shown in Fig. 1. One patient for restaging, and six patients for postoperative staging. Five patients had epithelioid type and four patients had nonepithelioid histology. Eight patients had previously undetected metastatic disease. In one patient with known adrenal metastasis, a further metastatic lesion was detected in the soft tissue overlying the scapula, which was not previously known. In the eight patients with previously unknown metastases, 10 lesions were identified. There was one retroperitoneal deposit, three intra-abdominal lymph nodes, one inguinal lymph node, two axillary lymph nodes (Fig. 2), two soft tissue lesions, and one contralateral hemithorax involvement. There were also two incidental FDG-avid lesions identified—in the pancreas and thyroid, respectively—which were proven as pancreatic carcinoma and thyroid adenoma, respectively, but were not considered as metastatic disease. These lesions were correlated to anatomical lesions on concurrent low-dose CT but were not previously identified on pre-PET-staging CT scans.
Analysis of Metastatic Disease and Progression-free Survival Progression-free survival was better in the group of patients without metastasis (n=35) compared to the patients with metastasis (n=9), as shown in Fig. 3. The cumulative survival estimate by the Kaplan–Meier survival analysis was a median progression-free survival of 4 months for patients with metastatic disease and 8 months for patients without metastatic disease. By comparing the survival distribution using log-rank method, the group of patients with metastatic disease showed significantly shorter progression-free survival times compared to those without metastatic disease (p valueG0.05). The metabolic activity in the primary pleural lesions measured by SUVmax was correlated with the presence of metastatic disease. The mean SUVmax of the primary pleural lesion in patients with metastatic disease (n=9) was 7.1 (SD±1.8; range 4.8–9.5) and 4.7 (SD±1.7; range 2.0–8.9) in patients without metastatic disease (n=37). This was a Table 3. Surgical procedures and SUVmax findings Procedure
Mean SUVmax
SUVmax range
Median Survival
Pleurodesis (n=17) Pleurectomy (n=7
4.9 6.6
2.1–9.0 4.4–9.5
5 months 4 months
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Fig. 1. Primary mesothelioma and extrathoracic metastasis on 18F-FDG PET/CT. The FDG-avid lesion on A coronal PET (black arrow) and C transaxial PET is localized to the right adrenal gland on B transaxial CT, also seen on D transaxial fusion PET/CT image. No other extrathoracic metastasis is noted. The primary lesion(s) is (are) indicated with the white arrows in A coronal PET image, and some FDG in the left renal pelvis, distal ureters, and bladder is also seen.
statistically significant difference with a p value of 0.003 [95% confidence interval (CI) 1.15, 3.73]. The mean SUVmax of the metastatic lesions was 4.5 (SD±1.8), ranging from 2.2 to 9.1.
Analysis of Histopathology and Progression-free Survival Of the 46 patients, the predominant histological subtype was epithelioid in 22/46 (48%), with biphasic histology in 15/46 (33%) patients. There were 2/46 (4%) patients with sarcomatoid disease and 7/46 (15%) patients with atypical histopathology that could not be classified. The mean SUVmax in each histological subtype is shown in Table 4. A two-sample T test analysis of the difference in SUVmax between the epithelioid and biphasic subtypes demonstrates Table 4. Histological subtype and SUVmax of primary lung lesions Histopathology
Mean SUVmax
Range of SUVmax
Epithelioid (n=22) Biphasic (n=15) Sarcomatoid (n=2) Atypical (n=7)
5.0 5.4 4.5 5.2
2.4–7.8 3.5–8.9 3.2–5.8 3.0–8.9
no statistically significant difference with a p value of 0.5 (95% CI −1.8, 0.95). Progression-free survival analysis could only be performed on patients with epithelioid and biphasic histology, as the other cohorts were too small to analyze. There was one patient in each group lost to follow-up. The cumulative survival estimate by the Kaplan–Meier survival analysis was a median progression-free survival of 4 months for patients with biphasic disease and 7 months for patients with epithelioid disease, as seen in survival curves in Fig. 2. By comparing the survival distribution using log-rank method, the group of patients with biphasic disease showed significantly shorter progression-free survival times compared to those with epithelioid disease (p value 0.015) (Fig. 4).
Discussion Accurate staging in patients with malignant mesothelioma is mandatory for informed treatment decisions, with all of the potential therapeutic modalities capable of producing major side effects, which can be life-threatening. Any patient with metastases outside the involved hemithorax is typically not suitable for surgery and should be offered palliative therapy [15]. Malignant mesothelioma is an aggressive tumor with poor median survival despite advancements in diagnosis
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Fig. 2. 18F-FDG PET/CT localization of extrathoracic metastasis. A single 18F-FDG avid lesion adjacent to the pleura on A coronal PET and C transaxial PET images, and localizes to a soft tissue axillary lesion on B transaxial CT and D fusion PET/CT image (white arrows). The primary pleural-based lesions are indicated with black arrows on the images (A–D).
with modern imaging modalities. In our study, we found metastatic disease in 9/44 (20%) of patients, of which only one patient had previously known metastatic disease but was found to have additional metastasis on PET. We also found that the patients with 18F-FDG PET/CT scans that were
positive for metastatic disease had a significantly poorer progression-free survival, despite treatment with a combination of surgery, radiotherapy, and/or chemotherapy. These two findings are in keeping with a recent study looking at integrated 18F-FDG PET/CT in patients being assessed for
Fig. 3. Kaplan–Meier curve of progression-free survival in the presence of metastatic disease (pG0.05).
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Fig. 4. Kaplan–Meier curve of progression-free survival and histopathology subtypes (pG0.05).
extrapleural pneumonectomy, which showed that approximately 25% of patients had extrathoracic metastases, of which more than half were not detected clinically or on another imaging modality prior to PET/CT scan [9]. Another more recent study also showed that patients with metastatic disease and higher SUVmax values had poorer survival [17]. However, these two studies concentrated on patients prior to surgical treatment, and not the broader population we had in our study, which included patients presenting within 3 months postsurgical treatment, which may result in higher SUVmax values due to postsurgical inflammation. We found that the group of patients with metastatic disease also had significantly higher SUVmax in the primary pleural lesions compared to the group of patients without metastatic disease, which, to our knowledge, has not been previously reported. This is an important observation, and it may provide an indication of the aggressiveness of primary disease and independent information on the prognosis of these patients. In our study, the histologic subtype of the tumor did not correlate with SUVmax on the 18F-FDG PET/CT, but the SUVmax may have been confounded by posttreatment inflammation. Both epithelioid and biphasic histology had similar mean SUVmax, with no statistical difference between the histological subtypes. SUVmax has been shown to have a better correlation with surgical staging than histological grade [4]. However, we did confirm that the progression-free survival of the epithelioid subtype was significantly better than the biphasic subtype, as previously described [13]. There were too few tumors of the sarcomatoid subtype to analyze. The presence of nodal disease is known to be associated with poor prognosis, and the presence of N2 or N3 disease can preclude curative resection [4]. There are large retrospective studies that have shown that up to 50% of patients who undergo extrapleural pneumonectomy for malignant
mesothelioma have intrathoracic nodal metastasis [18, 19]. While the use of PET may aid in the evaluation of nodal stations inaccessible by mediastinoscopy, the previous reported sensitivity of PET alone was only 11%. However, a more recent study evaluating the use of integrated PET/CT in detection of nodal (N2) disease in malignant mesothelioma showed a sensitivity of 38%, specificity of 78%, and accuracy of 59% [9]. Therefore, any management decision based on FDG PET findings of nodal disease should be confirmed by surgical evaluation [11], and final staging still requires surgery. Hence, the role of PET/CT would still lie in the detection and localization of distant metastatic disease, both in the staging and restaging of disease. In our study, the CT component of the PET/CT scan was useful for specific anatomical localization of FDG avid activity, to delineate soft tissue disease from bony disease, pleural disease from rib invasion, and localization of the incidental pancreatic and thyroid lesions. The use of PET is particularly important in the evaluation of malignant mesothelioma, as this disease has an unusual distribution of metastatic disease. One of the limitations of our study includes the fact that only a single calculation of SUVmax localising to the maximum voxel of FDG uptake was evaluated. This may not necessarily be an accurate measure of disease burden in such a diffuse disease. In a small study looking at the use of different PET parameters such as the total lesion glycolysis (TLG), which is defined as the SUVmax multiplied by tumor volume assessed on CT, it was reported that TLG correlated better to subsequent CT response [20]. The TLG has also been used in a chemotherapy setting and can be used as a measure of metabolic response to chemotherapy [21] and was superior to results from CT alone [22]. Also, we had a large cohort of patients who were referred for 18F-FDG PET/CT scans after surgical intervention, prior to receiving postoperative radiotherapy, which is a practice of the
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radiation oncology team at our hospital who use the 18 F-FDG PET/CT scans in treatment planning. This may influence the SUVmax obtained in this group of patients, as postoperative inflammation in the pleura and surgical site can cause an elevated SUVmax. The results of our study showed that the detection of metastatic disease and histopathology subtype is able to predict survival in malignant mesothelioma patients, including postsurgical patients. Unfortunately, our cohort of patients who presented for primary staging of disease was too small to establish a difference in survival between these patients and patients presenting for restaging purposes, although previous reports have found that preoperative staging with 18F-FDG PET may improve detection of extrathoracic metastatic disease [4, 11] and, hence, survival [17]. More recently, the use of staging PET alone has been the reported in predicting survival in patients with mesothelioma, with a combination of SUVmax, histology, and disease stage as the key predictors of survival [17]. Larger prospective studies looking at staging scans to evaluate the direct impact of integrated PET/CT on prognosis would be important, particularly to evaluate the impact on surgical management. PET/CT can also be used to assess the degree of metabolic response pre- and posttreatment with chemotherapy and/or radiotherapy, as an early reduction of FDG uptake measured as relative changes in SUVmax significantly correlated with patient outcome, and patients found as metabolic nonresponders showed subsequent disease progression on CT [23].
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