Role of fluorodeoxyglucose positron emission tomography (FDG PET)-computed tomography (CT) in the staging of bladder cancer

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1 Role of fluorodeoxyglucose positron emission tomography (FDG PET)-computed tomography (CT) in the staging of bladder cancer Henry Goodfellow, Zaid Viney*, Paul Hughes*, Sheila Rankin*, Giles Rottenberg*, Simon Hughes*, Felicity Evison**, Prokar Dasgupta, Timothy O'Brien* and Muhammad Shamim Khan* Guy's, King's and St Thomas' Medical School, Kings College London, *Urology Centre, Guy's Hospital, Guy's and St Thomas' NHS Trust, **University Hospitals Birmingham NHS Foundation Trust, and Medical Research Council (MRC) Centre for Transplantation & National, Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, King's College London, King's Health Partners, Guy's Hospital, London, UK Objective To determine whether to use 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) scans in the preoperative staging of bladder cancer (BC). Patients and Methods In all, 233 patients with muscle-invasive BC (MIBC) or high-risk non-mibc being considered for radical cystectomy (RC) between 2005 and 2011 had FDG-PET and computed tomography (CT) of the chest, abdomen and pelvis to assess for pelvic lymph node (LN) involvement or distant metastases. Sensitivity and specificity for detecting pelvic LN involvement was determined by comparing the results of the scans to the histopathology reports in patients undergoing RC. These parameters for distant metastases were determined from biopsy results or follow-up imaging. In patients who did not undergo RC, follow-up imaging was used to evaluate the sensitivity and specificity. Patients were excluded from analysis if they either had neoadjuvant chemotherapy or had <10 LNs removed at lymphadenectomy. Results The PET scan was able to detect metastatic disease outside of the pelvis with a sensitivity of 54% compared with 41% for the staging CT (N = 207). Both scans had similar specificities of 97% and 98%. There were 13 PET avid lesions not visualised on the corresponding staging CT scans. These proved to be metastatic BC (six patients), a synchronous primary colonic cancer (one), colonic adenomas (one), basal cell tumour of the parotid gland (one) and inflammatory lesions (four). The sensitivity and specificity of the CT scans for pelvic LN involvement was 45% and 98%, respectively (N = 93). Using a combination of the PET and CT scan, the sensitivity for detecting metastatic disease in LNs increased to 69% with a 3% reduction in specificity to 95%. Conclusions PET when used in conjunction with a standard CT scan provides a small improvement in preoperative staging of BC. However, this advantage is not significant enough to justify the additional cost. Hence we recommend use of dual imaging only in highly selected patients. Keywords bladder cancer, cystectomy, FDG PET/CT, positron emission tomography, preoperative staging Introduction Bladder cancer (BC) is the seventh most prevalent cancer in the UK and fourth most common in males [1]. Non-muscle-invasive BC (NMIBC) accounts for 70 80% of cases at presentation while MIBC disease accounts for the rest. A further 10 20% of NMIBC may progress to MIBC [2]. This staging distinction is important as MIBC carries a poorer prognosis with a 5-year disease-specific survival of 50% [1]. Currently radical cystectomy (RC), including pelvic lymph node (LN) dissection and urinary diversion with or without neoadjuvant chemotherapy is the standard of care for MIBC and high-risk NMIBC [3 7]. Accurate preoperative staging is of primary importance in identifying patients with metastatic disease to prevent unnecessary RC. Secondly, detection of limited pelvic LN involvement would make a stronger case for neoadjuvant chemotherapy and an extended pelvic lymphadenectomy to enhance chance of cure in selected patients [7,8]. BJU International 2013 BJU International doi: /bju BJU Int 2014; 114: Published by John Wiley & Sons Ltd. wileyonlinelibrary.com

2 Goodfellow et al. The current recommended investigations for preoperative staging of BC include CT covering the chest, abdomen and pelvis (staging CT scan) and a pelvic MRI [6]. These radiological investigations assess the local stage of the primary tumour and may show pelvic LN involvement or metastatic disease outside of the pelvis. Both imaging investigations have a relatively low sensitivity and specificity, which accounts for under-staging in about a third of patients and over-staging in a quarter [9,10]. Both CT and a MRI have modest sensitivity (50 85%) for the detection of pelvic LN involvement, as these are limited by their inability to detect tumours in normal sized LNs [11]. Positron emission tomography (PET) although not recommended in the European Union guidelines due to lack of evidence can also identify distant metastatic disease and pelvic LN involvement. The diagnostic capability of PET is not reliant on gland size, like MRI or CT scans, but increased metabolic activity of tissues. Recent publications examining the role of PET scans in preoperative LN assessment in MIBC have reported sensitivity in the range of 46% to 70% and specificity of 88 97% [12 16]. However, only one study has compared PET and CT scans in the detection of metastatic disease outside of the pelvic region or the use of PET scans combined with the staging CT scan to detect pelvic LN disease [14]. This was a relatively small study that included 55 patients of which only six had metastatic disease outside of the pelvis. The aim of the present study was to determine the role of a PET scan in the perioperative staging of BC. There are three potential ways PET scans could be used in this setting: scan all patients, a select group of patients or none of the patients. In our trust it was felt that if the PET scans showed a clear benefit by changing the management of >10% of the patients then you would recommend that PET scans be used routinely. If the PET scan only changed management in 5 10% of patients then PET scans should be used in selected patients. Finally, if <5% of patients had their management changed then PET scans should not be used. To determine the best rational use, we first examined the role of PET in detecting metastatic disease at sites not included in the staging CT. Secondly, we evaluated the sensitivity and specificity of PET and staging CT in combination to detect pelvic LN metastases. We hypothesised that using the scans in combination would increase the sensitivity and specificity due to the ability of PET to detect small positive metastases or LNs with high metabolic activity, while the staging CT scan would detect the larger metastases or LNs with low metabolic activity. Patients and Methods All patients who presented to our dedicated BC clinic and were considered potential candidates for RC for either MIBC or high-risk NMIBC (high risk defined as G3pT1 ± carcinoma in situ [CIS], extensive CIS or failed BCG therapy) between December 2005 and December 2011 underwent staging CT scan of the chest abdomen and pelvis and PET-CT scan. The main objective was to improve pre-treatment staging accuracy before recommendation of appropriate treatment. The PET and CT scan results for metastatic disease outside the pelvis were confirmed either by biopsy or additional scans at 12 months to re-evaluate the lesion [14]. In all, 26 patients were excluded as they were either followed up at another hospital or died from a cause other than metastatic BC within the year. Imaging All scans were performed at the PET Imaging Centre at St Thomas hospital, London, UK. Scans were performed on a GE Discovery ST (General Electric Medical Systems, Waukesha, WI, USA) BGO four slice PET/CT scanner and a Discovery VCT BGO 64 slice PET/CT scanner. Images were acquired in two dimensions and reconstructed using OSEM (ordered subset expectation maximization) 30 subsets, one iteration, 5.14 m post filter, 4.69 mm loop filter. All patients fasted for 6 h and the uptake time was 90 min, following 350 MBq fluorodeoxyglucose (FDG). Half-body imaging was acquired in five or six bed positions from skull base to thighs. A CT scan for attenuation correction and anatomical localisation was performed at 140 kvp and 80 mas. All scans were double reported by experienced nuclear medicine physicians and radiologists. To ensure that differences between PET and staging CT were not due to prolonged time lag (>30 days) between the scans, the CT component of the PET study was used instead of the staging CT to determine the preoperative staging in these patients. All the PET and staging CT scans were reviewed by the reporting radiologist at the time of the scan and re-reviewed by a second radiologist to confirm the findings. The average time between the PET scan and RC was 50 days. Assessment of Pelvic LNs RCs were performed by two uro-oncology surgeons. Pelvic lymphadenectomy was performed up to the bifurcation of the aorta. In patients where no positive LNs were detected on histopathology, a minimum of 10 dissected LNs were required to consider the patient negative for metastatic pelvic LN involvement [17]. The LNs were placed in two separate containers and labelled as right/left pelvic nodes for histopathological assessment. Peri-vesical LNs were identified by the histopathologists in the RC specimens. The results of histology were compared with staging CT and PET scans in this subgroup. All LNs that had increased FDG uptake were considered positive on PET scan. Pelvic LNs with a maximum short axis diameter of >8mmonCTwere considered positive according to the consensus of the radiologists at our institution. Using combined imaging, LN 390 BJU International 2013 BJU International

3 FDG pet in the staging of bladder cancer status was regarded as negative if both imaging methods failed to show any abnormality. Conversely, a LN was regarded as positive if either the PET or CT scan or both showed an abnormality. To establish a difference in sensitivity and specificity between the two types of scan and the combined scan a receiver operating characteristic (ROC) curve analysis was completed. As data on the number of malignant LNs detected by the PET/CT scans was not recorded, but rather only the determination of malignancy, an expected number of LNs for each scan was calculated. This expected number was based on the probability of a scan missing malignant LNs and the numbers seen during biopsy. The sensitivity of the ROC curves to the specific probability calculated was then tested by varying the probability (±0.2). Results In all, 233 patients were studied in this cohort. Of these 175 (75%) were men and 58 (25%) were women. The mean (range) age was 69 (23 85) years (Table 1). Most (221 patients, 95%) had TCC and 12 (5%) had other histological types (Squamous, five; adenocarcinoma, four; small cell, one; paraganglioma, one; neuroendocrine, one) (Table 1). In all, 26 patients were excluded from the study as they were either followed up at another hospital or died from a cause other than metastatic BC within a year of presentation (Fig. 1). Staging for Distant Metastases The PET/CT (PET) scan and staging CT scan were compared to determine concordance for the detection of metastatic disease outside of the pelvis in 207 patients. Overall, the PET scan was more sensitive than the CT for detecting metastatic disease outside of the pelvis (54% vs 41%; Table 2). The specificity on the contrary was high in both PET (97%) and CT (98%). There was discordance in findings between the PET and CT scans in 16 patients (4.2%). The PET scan identified 13 patients with FDG avid lesions with no abnormality on the Table 1 Demographics of study. corresponding CT scan (Fig. 2). The CT scan showed three abnormalities not evident on the PET scan. Of the 13 patients with PET avid lesions, six were distant metastases (three skeletal, one pulmonary and two LN) (Table 3). The remaining seven patients with abnormal PET scans were found to have an adenocarcinoma of the colon (one), colonic adenoma (one), a parotid basal cell tumour (one) and inflammatory lesions (four) (Table 3). Fig. 1 Flow chart of study. In all, 233 patients were considered for RC and had a PET and CT scan for the preoperative staging of BC. The PET and CT scans were compared for metastatic disease outside of the pelvis in 207 patients. A RC was performed on 159 patients of whom 66 had neoadjuvant therapy or did not have an adequate lymphadenectomy. The histopathology report of the pelvic LNs could be compared with the original CT and PET scans in 93 patients. Total patients N = 233 PET and CT Scans N = 207 Radical Cystectomy N = 159 Histopathology compared to PET and CT scans N = 93 Excluded Follow up at another hospital Died from cause other than BC Excluded Did not have a radical cystectomy Excluded Inadequate lymphadectomy Neoadjuvant treatment Variable Value Number of patients in study 233 Mean (range) age, years 69 (23 85) N (%): Men 175 (75) Women 58 (25) Ta 17 (7) Tis 6 (3) T1 60 (26) T2 82 (35) T3 50 (21) T4 18 (8) TCC 221 (95) Other cell type 12 (5) Neoadjuvant treatment 41 (18) Metastatic lesions 56 Table 2 The detection of metastatic disease outside of the pelvis by the PET and staging CT scans. Metastatic disease PET CT Total False positives 4 3 False negative True positive True negative Sensitivity Specificity Positive predictive value Negative predictive value Accuracy BJU International 2013 BJU International 391

4 Goodfellow et al. Fig. 2 PET scan and CT component of the PET scan for two patients with metastatic disease. A, B and C is the PET, CT and coloured overlay for a patient who had a metastatic BC lesion in the right femur. A, B and C is the PET, CT and coloured overlay for a patient who had a metastatic pelvic LNs. Table 3 Lesions identified by the PET scan with no corresponding pathology on the CT scan. Table 4 Histopathological analysis of primary BC and the pelvic LNs dissected. Disease Location Pathology Confirmation* Variable Value Metastatic Femur TCC Biopsy Ilium TCC Biopsy Cervical LN TCC Biopsy Vertebrae TCC CT scan Lung TCC CT scan Para aortic LN TCC CT scan Primary cancer Colon Carcinoma Biopsy Benign Colon Adenoma Biopsy Colon inflammatory CT scan Parotid Basal cell Biopsy Aortocaval LN inflammatory CT scan Axilla LN inflammatory Biopsy Number of patients with RC and adequate lymphadenectomy 93 N (%): Ta 4 (4) Tis 3 (3) T1 25 (27) T2 21 (23) T3 29 (31) T4 11 (12) Mean (interquartile range) time between PET and RC 38 (26) Mean (range) number of pelvic LNs dissected 17 (1 38) Number of patients with metastatic pelvic LNs 28 The CT scan detected lesions in three patients not shown on PET scan. One patient had enlarged para-aortic and iliac LNs not detected on the PET scan. The other two were small (<10 mm) indeterminate lung nodules, which on subsequent (follow-up) imaging remained stable and hence were assumed to be benign. Staging of Pelvic LN Disease In all, 159 (76.2%) patients underwent RC; 66 patients (42%) were excluded from the analysis; 42 due to inadequate LN yield from pelvic lymphadenectomy (<10 LNs on final histology) and another 24 due to previous neoadjuvant chemotherapy treatment (Fig. 1). This left a total of 93 patients with final pathological staging as follows: four (4%) had Ta disease, three (3%) had Tis disease, 25 (27%) T1 disease, 21 (23%) T2 disease, 29 (31%) T3 disease, and 11 (11%) T4 disease (Table 4). The mean (range) LN count was 17 (1 38) LNs (Table 4). Both PET and staging CT scans had a low sensitivity of 46% but a high specificity of 97% and 98%, respectively (Table 5). The low sensitivity was due to few true positives with both PET and CT detecting 13 out of a possible 28 patients with Table 5 The detection of pelvic LN disease by the PET, CT and combined PET-CT scans. RC patients PET CT PET and CT Total False positives False negative True positive True negative Sensitivity Specificity Positive predictive value Negative predictive value Accuracy metastatic LNs (Fig. 2). When the results of PET and staging CT were combined to assess pelvic LN involvement, six additional true-positive patients were detected, which increased the sensitivity of the combined imaging from 46% to 68% (Table 5). The ROC curve and area under the curve (AUC) indicate that the combined PET and CT scan results are more effective at detecting the true nature of the LNs than the CT or PET scan alone [AUC (combined) vs (PET), (CT); Fig. 3]. 392 BJU International 2013 BJU International

5 FDG pet in the staging of bladder cancer Discussion RC is a complex surgical procedure associated with high morbidity and significant mortality [18 20]. Most importantly RC has considerable impact on a patients quality of life because of the need for a urinary diversion and the high risk of sexual dysfunction. The latter is highly relevant in younger patients with normal sexual function before RC [18 20]. Hence accurate preoperative staging is essential to prevent unnecessary surgery in patients with metastatic disease in whom RC would be of little or no therapeutic benefit. Accurate and reliable staging of the local pelvic disease helps in rationalising the treatment of BC. Patients with LN-positive disease have a poor prognosis and it is important to consider the degree/extent of LN involvement while discussing therapeutic options. Systemic chemotherapy (neoadjuvant/ palliative) is the first-line treatment of choice in suitable patients. Those with low-volume LN involvement who achieve a complete response after neoadjuvant chemotherapy may benefit from surgery and an extended lymphadenectomy [21]. Fig. 3 The ROC curve and AUC for the combined PET and CT scan plus each scan individually. True positive rate PET scan CT scan PET & CT scan combined False positive rate However, bulky lymphadenopathy at presentation or a poor response to neoadjuvant chemotherapy portends a very poor prognosis [22] and radical surgery is not the standard of care in this clinical setting but radical radiotherapy (whole bladder ± pelvis) may be beneficial. In the present study, the PET scan was better at staging metastatic BC outside of the pelvis than the CT scan. Seven patients (or 3% of all the patients scanned) were found to have either metastatic disease or a synchronous primary cancer not detected by the staging CT scan (Table 3). These findings influenced subsequent management of the patients; as histological assessment of these lesions was required and surgery was deferred. Conversely, six patients had increased FDG uptake on PET scan, which proved to be benign (Table 3). Two of these patients had benign tumours; four had inflammatory lesions one of which was caused by diverticular disease in the colon (Table 3). Many of the false-positive PET scanswerecausedbyindividualfdgavidlnsoravidlesions in the colon. In such cases, the PET scan should be interpreted with caution in conjunction with CT scan and clinical judgment. The sensitivity and specificity for the detection of pelvic LN disease by the PET scan in the present study are comparable with the reported figures in other studies, with a high specificity (range %) and a lower sensitivity (range 46 70%) (Tables 5,6) [12 16]. However the sensitivity to detect pelvic LN disease improved from 46% to 68% when the PET and the CT were used in combination. This increase in sensitivity was due to the PET and CT scans detecting metastatic LNs in six different patients (Fig. 2). Using combined imaging resulted in a small reduction of 3% in the specificity (Table 5). In our trust these six patients would now be considered for neoadjuvant therapy before having a RC with an extended lymphadenectomy. There is only a single published study in which both PET and CT scan combination was used to determine LN status, showing an increase in sensitivity of only 5%. However, the number of patients with pelvic LN disease in that study was small (12) compared with 28 in our present study [14]. The present study has several limitations. The CT component of the PET scans was used in 43 (17%) patients due to a Table 6 Comparison of present study PET results with other studies. Reference N Sensitivity, % Specificity, % PPV, % NPV, % ACC, % Recommendation Drieskens et al. (2005) [14] PET advocated Kibel et al. (2009) [13] PET advocated Swinnen et al. (2009) [12] PET not advocated Lodde et al. (2010) [15] PET advocated Jensen et al. (2011) [16] 18 N/A 93 N/A 87.5 N/A Not given Present study (2013) PET not advocated PPV, positive predictive value; NPV, negative predictive value; ACC, accuracy. BJU International 2013 BJU International 393

6 Goodfellow et al. prolonged lag time (>30 days) between the PET and staging CT scans. A full-dose diagnostic staging CT with i.v. contrast medium might have given a better LN and metastatic assessment than the CT component of the PET scan. However, the CT component was felt to be sufficient to identify enlarged LNs in all the patients analysed. Peri-vesical LNs were often missed by both imaging techniques, as they are either too small to be detected on the staging CT or obscured by FDG-tracer in the bladder on PET scan [23,24]. It is possible to use diuretics during the PET scan to improve local regional accuracy but this was not done for any of the patients in the present trial [24]. The average time between the PET scan and RC was 38 days and this might have allowed time for disease progression (Table 4). There are several other imaging methods that have the potential to improve preoperative staging of BC. MRI can be used in the staging of local disease in BC due to its high contrast resolution [6]. Further improvements in the local staging have been shown with the use of functional MRI such as diffusion-weighted and dynamic contrast-enhanced MRI [1]. The results for the functional MRI techniques are promising but have mainly been assessed in the research setting [25]. There has only been limited research on the use of MRI to stage LN disease using ferumoxtran-10. This is now banned in human studies [26]. Radiotracers other than 18 F-glucose have also been looked at, the most notable of which is 11 C-choline. This has the advantage of being minimally excreted in the bladder making local staging easier but results from a few trials have shown little difference in the accuracy of staging metastatic spread compared with 18 F-glucose [23]. A full cost-benefit analysis is required to accurately access the financial burden of performing PET scans on all patients with BC who are being considered for RC. A cheaper alternative to a PET scan is a bone scintigraphy, the gold standard imaging method for detecting bone metastases. Of the six patients with metastatic disease detected by PET, three had bony metastases which might have been detected by bone scintigraphy [15]. In summary, the addition of a PET scan in the preoperative staging of BC can improve the detection of both distant metastases and pelvic LN spread compared with using CT scans alone. PET identified an additional 13 patients (5.6%) with new metastatic disease inside or outside of the pelvis. However, for the seven patients in whom PET detected metastases outside pelvis there were six patients with false-positive lesions. Three of the metastatic lesions were in the bones and could potentially have been detected by a bone scintigraphy, which is a cheaper alternative. In conclusion, due to small additional diagnostic yield (5.6%) and the high financial burden, we recommend that PET scans should not be used routinely in the preoperative staging of BC. A PET scan may be useful in select patients with; (a) enlarged pelvic LNs and a small primary bladder tumour, (b) suspected metastases in LNs outside of the pelvic lymphadenectomy window and (c) patients with indeterminate metastases. Acknowledgements None. Conflict of Interest None declared. References 1 Bouchelouche K, Turkbey B, Choyke PL. PET/CT and MRI in bladder cancer. JCancerSciTher2012; S14: pii: Rozanski TA, Grossman HB. Recent developments in the pathophysiology of bladder cancer. AJR Am J Roentgenol 1994; 163: Bischoff CJ, Clark PE. Bladder cancer. Curr Opin Oncol 2009; 21: Schumacher MC, Jonsson MN, Wiklund NP. 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