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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Oncology
The role of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in resectable pancreatic cancer Stefano Crippa a , Matteo Salgarello b , Silvia Laiti c , Stefano Partelli a , Paola Castelli d , Antonello E. Spinelli e , Domenico Tamburrino c , Giuseppe Zamboni d , Massimo Falconi a,∗ a
Division of Pancreatic Surgery, Department of Surgery, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy Department of Nuclear Medicine, University of Verona, Negrar, Italy c Residency Programme in Surgery, University of Verona, Italy d Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar, Italy e Department of Medical Physics and Experimental Imaging, San Raffaele Scientific Institute, Milan, Italy b
a r t i c l e
i n f o
Article history: Received 31 December 2013 Accepted 16 March 2014 Available online xxx Keywords: Computed tomography Liver Lymph node Metastases Pancreatic cancer Positron emission tomography Staging
a b s t r a c t Background: The role of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in pancreatic ductal adenocarcinoma is debated. We retrospectively assessed the value of 18 fluorodeoxyglucose positron emission tomography/computed tomography in addition to conventional imaging as a staging modality in pancreatic cancer. Methods: 18 Fluoro-deoxyglucose positron emission tomography/computed tomography was performed in 72 patients with resectable pancreatic carcinoma after multi-detector computed tomography positron emission tomography was considered positive for a maximum standardized uptake value >3. Results: Overall, 21% of patients had a maximum standardized uptake value ≤3, and 60% of those had undergone neoadjuvant treatment (P = 0.0001). Furthermore, 11% of patients were spared unwarranted surgery since positron emission tomography/computed tomography detected metastatic disease. All liver metastases were subsequently identified with contrast-enhanced ultrasound. Sensitivity and specificity of positron emission tomography/computed tomography for distant metastases were 78% and 100%. The median CA19.9 concentration was 48.8 U/mL for the entire cohort and 292 U/mL for metastatic patients (P = 0.112). Conclusions: The widespread application of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in patients with resectable pancreatic carcinoma seems not justified. It should be considered in selected patients at higher risk of metastatic disease (i.e. CA19.9 > 200 U/mL) after undergoing other imaging tests. Neoadjuvant treatment is significantly associated with low metabolic activity, limiting the value of positron emission tomography in this setting. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Although the diagnosis and management of pancreatic ductal adenocarcinoma (PDAC) has improved in the last decades, its prognosis remains dismal. Surgical resection is the only treatment with curative intent with a 5-year survival rate of 20–25% [1,2]. Moreover, 20–30% of resected patients die of the disease within 12 months from resection because of early tumour recurrence, in the
∗ Corresponding author at: Department of Surgery, Division of Pancreatic Surgery, Università Politecnica delle Marche, Ospedali Riuniti, Via Conca 71, 60126 Ancona, Torrette, Italy. Tel.: +39 071 5965781; fax: +39 071 5964429. E-mail address: [email protected] (M. Falconi).
setting of unrecognized or rapidly progressive metastatic disease [3,4]. Therefore, accurate staging is of paramount importance when deciding if surgery should be performed for PDAC. Despite the significant advances in high-resolution imaging techniques, the appropriate assessment of resectability of PDAC is still challenging [5–7] and the diagnosis of small metastases can be problematic [8,9]. Whole body 2-(fluorine-18)fluoro-deoxy-d-glucose-positron emission tomography in combination with computed tomography (18 FDG-PET/CT) has demonstrated significant efficacy in the staging of different malignancies [10–12]. However, the role of 18 FDGPET/CT in patients with potentially resectable PDAC is still debated [13–17]. In fact, whether PET/CT is superior to multi-detector computed tomography (MDCT) for the identification of metastases is
http://dx.doi.org/10.1016/j.dld.2014.03.011 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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still a controversial issue. Moreover, several authors showed that PET/CT has a limited value for the detection of loco-regional lymph node metastases, with low sensitivity and specificity for nodal (N) status [13–17]. The primary aim of the present study was to assess the role of 18 FDG-PET/CT for the detection of metastatic disease in patients with resectable PDAC after conventional imaging. As secondary endpoint we evaluated the 18 FDG-PET/CT capability of identifying lymph node metastases.
injection of 0.08 mC/kg (2.96 MBq/kg) FDG. PET scanning was performed with a 16 cm bed for about 7/8 bed per patient. CT and PET scan data were co-registered. The standardized uptake value (SUV) was acquired using the attenuation-corrected images, the amount of injected FDG, the body weight of the patient, and the cross-calibration factors between PET and dose calibrator. The maximum SUV (SUVmax ) was evaluated 60 min after FDG injection, with a value of SUVmax of more than 3 being indicative of malignancy [16,18].
2. Methods
2.4. Treatment strategy based on 18 FDG-PET/CT data
Data from all consecutive patients with potentially resectable PDAC who underwent 18 FDG-PET/CT at the Sacro Cuore Hospital Don Calabria, Negrar (Italy), between May 2011 and July 2012 were retrospectively analyzed. Patients with pancreatic tumours other than ductal adenocarcinoma (i.e. intraductal papillary mucinous neoplasms) and patients with poor general conditions/severe comorbidities that precluded them from undergoing surgery were excluded from this study.
Surgical resection was initially planned for all the patients included in the present study after conventional staging. If 18 FDGPET/CT did not show distant metastases, the patient underwent laparotomy. When 18 FDG-PET/CT showed the presence of suspected distant metastases, patients underwent biopsy of the lesion (i.e. contrast-enhanced ultrasound with fine-needle aspiration for liver metastases [19]) in order to histologically confirm the diagnosis. For suspected peritoneal lesions, a laparoscopy was eventually planned. If distant metastases were confirmed, no laparotomy was performed. If 18 FDG-PET/CT showed the presence of suspected loco-regional lymph node metastases, considering the low sensitivity/specificity of PET/CT for N status and the high rate of lymph node metastases in resected PDAC [13–17], patients underwent laparotomy.
2.1. Conventional staging work-up Patients’ demographics, clinical presentation, and serum carbohydrate antigen (CA19.9) levels were collected for all patients. Preoperative staging and surgical resectability were based on abdominal contrast-enhanced MDCT and chest X-ray. All patient information and radiology images were reviewed and discussed at a multidisciplinary conference with pancreatic surgeons, gastroenterologists, medical oncologists, nuclear medicine physicians and at least one radiologist with more than 10 years of clinical experience and a specific interest in thoracic and abdominal CT. The diagnosis of potentially resectable PDAC was based on the following criteria: (1) absence of abutment/encasement of portal vein, superior mesenteric vein, hepatic artery, superior mesenteric artery, celiac trunk; (2) absence of infiltration of peripancreatic organs, with the exception of common bile duct and duodenum; (3) absence of distant metastases. In particular, the diagnosis of liver metastases was based on the presence of hepatic lesions that were hypovascular and hypoattenuating on portal phase scan. 2.2. Neoadjuvant treatment Patients with an initial diagnosis of “borderline-resectable” or locally advanced PDAC who underwent neoadjuvant treatment and who showed tumour-downstaging to potentially resectable disease were included in the study. Neoadjuvant chemotherapy/chemoradiation was administered either at our institution or under the care of the patients’ referring oncologist, according to the institution’s protocol. 2.3.
18 F-FDG
PET/CT protocol
All patients underwent 18 FDG-PET/CT within a week before the day of surgery. Patients were asked to fast for at least 6 h before the examination. For each patient blood glucose level was determined before the examination. Patients with diabetes mellitus underwent examination only when their blood glucose level was less than 140 mg/dL. All examinations were carried out by a single, highly experienced, nuclear medicine physician (MS). All the tests were performed using a hybrid PET/CT scanner (Siemens mCT Biograph, Germany). The whole-body CT scanning was performed using a continuous spiral technique on a 64-slice helical CT, while the PET scanner had 3 detector rings. No contrast medium was administered during CT scanning. After the CT scan, an emission scan was performed from the head to the thigh following intravenous
2.5. Surgical treatment and pathology Operative and postoperative data, complications, and pathology data were prospectively gathered. Formal pancreatic resections were carried out as already described [20]. Lymphadenectomy included the removal of anterior and posterior pancreatoduodenal, pyloric, and biliary duct, superior and inferior pancreatic head and/or body, common hepatic artery and celiac trunk lymph nodes, as well as lymph nodes along the right side of the superior mesenteric artery during pancreaticoduodenectomy and total pancreatectomy. Lymph node sampling between the aorta and vena cava was not routinely performed. Classification and grading of pancreatic ductal adenocarcinoma was based on the WHO 2010 criteria [21]. Tumour (T), nodal status (N) and grade (G) were determined using the standard TNM classification according to the AJCC classification [22]. Intraoperative evaluation of the resection margins was performed routinely. 2.6. Statistical analysis Distributions of continuous variables are reported as median and minimum/maximum range. Categorical variables are presented as numbers and percentages. The comparison between subgroups was performed with Student’s t-test or Mann–Whitney U test for continuous variables. Qualitative data were compared by the 2 test or Fisher’s exact test as appropriate. Cut-off points were calculated around the median for continuous variables. Statistical analyses were performed with the SPSS 16.0 software for Windows (SPSS Inc., Chicago, IL). P values were considered significant when ≤0.05. 3. Results Seventy-two consecutive patients were included in the study (50% males, median age 65 years, range 39–81 years). The median time interval between MDCT and 18 FDG-PET/CT was 28 days (range 5–51). The median time interval between 18 FDG-PET/CT and planned surgery was 2 days (range 1–7). The main patient characteristics are reported in Table 1. A SUVmax ≤ 3 was found in
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Table 1 Patient characteristics and neoadjuvant treatment details.
Table 2 Operative procedures, postoperative complications and pathology data.
N (%) Male gender Median age, years (range) Symptomatic patients Presence of diabetes Symptoms Jaundice Weight loss Pain Bowel obstruction Pancreatitis Tumoral markers CEA, ng/ml, median (range) CA19.9, U/ml, median (range) Neoadjuvant treatment Chemotherapy Gemcitabin and oxaliplatin FOLFIRINOXa Chemoradiation Gemcitabine and capecitabine + 45 Gy Gemcitabine and oxaliplatin + 45 Gy a
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36(50) 65 (39–81) 64 (89) 15 (21) 47 (65) 32 (44.5) 30 (41.5) 4 (5.5) 1 (1.5) 1.80 (0.5–19.9) 64.4 (0.8–3547) 14 (19) 7 (9.5) 3 (4) 4 (5.5) 7 (9.5) 3 (4) 4 (5.5)
5-Fuorouracil, oxaliplatin, irinotecan and leucovorin.
15 patients (21%) while the remaining 79% had a SUVmax > 3, thus defining 18 FDG-PET/CT “positive” for malignancy. 3.1. Neoadjuvant therapy Fourteen patients (19%) underwent neoadjuvant treatment because of locally advanced or borderline resectable pancreatic cancer (Table 1). In all these patients, re-staging after neoadjuvant therapy showed the presence of a potentially resectable disease. Overall, 60% of the patients (n = 9) with SUVmax ≤ 3 had undergone neoadjuvant treatment compared to 9% of those with SUVmax > 3 (n = 5, P = 0.0001).
N (%) Pancreatic resection Pancreaticoduodenectomy Left pancreatectomy and splenectomy Total pancreatectomy Vascular resection Postoperative mortality Overall morbidity Pancreatic fistula Abdominal collection Sepsis Delayed gastric emptying Bleeding Chilous fistola Median tumour size (mm), range Grading G1 G2 G3 Presence of microvascular invasion Presence of perineural invasion R status R0 R1 R2 T stage T1 T2 T3 N status N0 N1
49 (80) 7 (12) 5 (8) 14 (23) 1 (1.5) 28 (46) 11 (18) 10 (16) 7 (11.5) 6 (10) 5 (8) 4 (6.5) 25 (8–50) 0 31 (51) 30 (49) 57 (93) 55 (90) 52 (85) 9 (15) 0 1 (1.5) 1 (1.5) 59 (97) 14 (23) 47 (77)
posterior mediastinum. The first patient underwent colonoscopy with biopsy that confirmed the presence of a colonic carcinoma. The second patient, who had a normal chest X-ray, underwent thoracoscopy with resection of a mediastinal neurinoma. Both patients subsequently underwent pancreaticoduodenectomy, also associated with left colectomy in the first one.
3.2. Detection of metastatic disease at PET/CT 3.4. Surgical treatment and pathology Fig. 1 shows the results of 18 FDG-PET/CT on patient management. Eight out of 72 patients (11%) were spared surgical exploration due to 18 FDG-PET/CT findings. In 7 patients liver metastases were found and pathologically confirmed in all cases after contrast-medium ultrasound (CEUS) with fine-needle aspiration. In these 7 patients, the median time interval between MDCT and PET/CT was 37 days. Metastatic lesions were located deep in the liver parenchyma with a size ranging between 0.8 cm and 1.8 cm (in 3 cases the largest lesions had a diameter ≥1.5 cm). In retrospect, no metastatic lesions could be clearly identified at CT. In the remaining patient, who had a normal chest X-ray, 18 FDG-PET/CT showed the presence of a synchronous lung adenocarcinoma with mediastinal lymph node metastases. PET/CT did not show peritoneal metastases in any patient. Sensitivity and specificity of 18 FDG-PET/CT for the detection of metastatic disease in the entire cohort of 72 patients were 78% and 100%, respectively. Excluding the 14 patients who underwent neoadjuvant treatment – characterized by a low metabolic activity in two thirds of the cases – sensitivity and specificity were 87.5% and 100%, respectively. 3.3. Detection of extrapancreatic synchronous tumours at PET/CT Exploratory laparotomy was planned in 64 patients (89%). In 2 of them, 18 FDG PET/CT confirmed the presence of a pancreatic head cancer and showed the presence of an associated extrapancreatic synchronous tumour, one in the left colon and the other in the
A pancreatic resection was carried out in 61/64 patients (95%) who underwent laparotomy. The remaining 3 patients (Fig. 1) did not undergo pancreatectomy because of unresectable locally advanced (n = 1) or metastatic disease (n = 2). These 2 latter patients had a SUVmax ≤ 3 and peritoneal carcinomatosis. Table 2 shows operative procedures, postoperative complications, and pathology data. 3.5. Detection of lymph node metastases at PET/CT 18 FDG-PET/CT showed an increased FDG uptake in the abdominal lymph nodes in 11/61 patients (18%) who underwent surgical resection. Sensitivity and specificity of 18 FDG-PET/CT for detecting lymph node metastases were 21% and 93%, respectively. 18 FDG-PET/CT confirmed the presence of suspected nodal metastases in lymph nodes along the celiac trunk or along the superior mesenteric artery and its aortic origin in 8/11 patients (73%). In this subgroup of patients, a wider lymphadenectomy was carried out, including also para-aortic stations. The median number of resected nodes was 41 in these 8 patients compared to 32 in the remaining patients (P = 0.235). Final histological examination showed the presence of lymph node metastases along the celiac trunk or superior mesenteric artery in 7/8 patients (87.5%), of whom 2 also had para-aortic lymph node metastases. In these latter 7 patients, the median size of metastatic nodes was 8 mm (range 4–15 mm).
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Fig. 1. Clinical management and therapeutic decisions following 2-(fluorine-18)fluoro-deoxy-d-glucose-positron emission tomography in combination with computed tomography in 72 patients with resectable pancreatic cancer after conventional staging with high-resolution imaging techniques.
3.6. CA19.9 values in patients with advanced disease at PET/CT The median CA19.9 value was 64 U/mL for the entire cohort (range 0.8–3547 U/mL). In patients with liver metastases detected at PET/CT, the median CA19.9 value was 292 U/mL (range 47–3547 U/mL) compared to 48.8 U/mL (range 0.8–256 U/mL) in the remaining patients (P = 0.112). The median CA19.9 value was 218 U/mL (range 414–1126 U/mL) in patients with celiac/paraaortic nodes compared to 47.7 U/mL (range 0.8–1805 U/mL) in the remaining patients (P = 0.165). 4. Discussion Preoperative evaluation of the extent of PDAC is crucial in order to decide the most appropriate treatment options and to offer surgery to patients who are likely to benefit from it. Although the advances in high-resolution imaging techniques have improved the quality of preoperative tumour staging, in 10–15% of patients with PDAC deemed to be resectable after conventional imaging, advanced disease is found at laparotomy [5–8]. Moreover, 20% of resected patients will die within 12 months after surgery, because of early tumour recurrence due to metastatic disease [3]. Since 18 FDG-PET/CT proved to be accurate for the staging of different malignancies, it has been performed also in pancreatic cancer patients, but with uncertain results [10–17]. In this retrospective study, 18 FDG-PET/CT excluded from surgical exploration 11% of patients because of the presence of advanced disease. Sensitivity and specificity of PET/CT for the identification of metastases were 78% and 100%, respectively. In previous series,
the sensitivity of PET/CT for the diagnosis of metastatic disease ranged between 68% and 91%, while specificity between 64% and 97% [13–16,23–25]. Frohlich and colleagues showed that the sensitivity of 18 FDG-PET/CT in detecting liver metastases was 97% for lesions greater than 1 cm in size but it was only 43% for those less than 1 cm [25]. In this series, the size of liver metastases detected at PET/CT ranged between 0.8 and 1.8 cm at CEUS, but no metastatic lesions were identified after retrospective re-evaluation of MDCT. Some limitations of our study must be considered to explain these results. Firstly, this is a retrospective study and most patients underwent MDCT outside our hospital with different protocols. The lack of a single MDCT protocol, as well as the interval of about 1 month between MDCT and PET/CT, represents a limitation for the interpretation of the differences between these 2 imaging techniques. Secondly, our preoperative staging was based only on MDCT, while other diagnostic modalities, including CEUS or diagnostic laparoscopy, were not routinely performed. Of note, CEUS identified liver metastases in all 7 patients after PET/CT. CEUS has emerged in recent years as a safe and low-cost diagnostic tool for the diagnosis and staging of PDAC [26–28], with a high accuracy for the differential diagnosis of subcentrimetric hepatic lesions, including liver metastases [27]. It is likely that CEUS should be considered as a complementary imaging method after MDCT and before other diagnostic tools including PET/CT. Thirdly, preoperative staging included chest X-ray instead of chest CT scan, since this latter procedure is not strictly recommended in resectable PDAC [6]. Two extra-pancreatic tumours were found at 18 FDG-PET/CT in the chest, but we acknowledge that a chest CT scan associated with
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abdominal CT could easily detect these neoplasms without adding significant costs. Overall, 19% of the 72 patients underwent neoadjuvant chemotherapy/chemoradiation for a locally advanced or borderline resectable PDAC. Our results show that neoadjuvant treatment is significantly associated with the lack of an increased FDG uptake at PET/CT (SUVmax ≤ 3). In keeping with this observation, a significant decrease of the median SUVmax , comparing pre and post-chemoradiation values, as well as a possible correlation between PET/CT findings and clinicopathological response have been reported [29,30]. Therefore, in patients with PDAC scheduled for neoadjuvant therapy, PET/CT should be performed at baseline and after completion of their treatment to properly evaluate a metabolic response. In keeping with the current literature [13–16,23,25], our results showed that 18 FDG-PET/CT was poorly sensitive for the detection of lymph node metastases (sensitivity 21%). Different causes can explain these results. Pancreatic cancer is commonly associated with a high rate of lymph node metastases, and most metastatic nodes are small in size and close to the primary tumour. Therefore, the metabolic activity of the primary neoplasm may “hide” that of the nodes, resulting in a poor sensitivity for PET/CT in distinguishing primary pancreatic cancer from metastatic nodes. An interesting finding from our study is the capability of 18 FDGPET/CT to detect “distant” lymph node metastases. In fact, in 8 of the 61 resected patients (13%), PET/CT identified possible metastases along the celiac trunk, the origin of the superior mesenteric artery, and para-aortic nodes. These patients underwent pancreatic resection and, although a wider lymphadenectomy was carried out in order to verify PET/CT findings, the median number of resected nodes did not significantly differ between these patients and the remaining ones (41 versus 32, P = 0.235). Nodal metastases were found at histological examination in 7 of these 8 patients (87.5%). Para-aortic/celiac node metastases are associated with poor prognosis in PDAC, and they may be considered as systemic metastatic disease [31–33]. However, their accurate preoperative diagnosis with conventional imaging is very difficult [32]. Therefore our preliminary results, based on a retrospective analysis of few cases, without a systematic lymph node dissection of the same nodal stations in all the patients, should be considered with caution. Further studies are needed to confirm the accuracy of 18 FDG-PET/CT in the identification of this subgroup of patients who may represent the target of neoadjuvant treatment. PET/CT is an expensive diagnostic tool and the costs of PET/CT scans represent a major limitation of its widespread application. Considering the results of this study, the data from the literature, and the cost of PET/CT, the systematic application of 18 FDG-PET/CT to all patients with resectable PDAC seems not justified. It is likely that this imaging modality should be performed in subgroups of selected patients. In this light, perioperative CA19.9 levels >200 U/mL can correlate with tumour burden, tumour spread, and early recurrence after resection in PDAC [3,34]. In the present study we found that the median CA19.9 level was higher (>200 U/mL) in patients with both liver metastases and celiac/para-aortic nodal disease identified at PET/CT. The lack of a statistical significance is likely due to the low number of patients with advanced disease. Since the diagnostic yield of PET/CT scan for advanced disease increased in patients with CA19.9 > 200 U/mL, we propose that 18 FDG-PET/CT should be performed after MDCT and CEUS in this subgroup of patients that are at higher risk of metastatic disease. In conclusion, our data do not support the widespread application of 18 FDG-PET/CT in the preoperative staging of patients with resectable PDAC. 18 FDG-PET/CT should be considered in selected patients at higher risk of metastatic disease (i.e. patients with
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Oncology
The role of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in resectable pancreatic cancer Stefano Crippa a , Matteo Salgarello b , Silvia Laiti c , Stefano Partelli a , Paola Castelli d , Antonello E. Spinelli e , Domenico Tamburrino c , Giuseppe Zamboni d , Massimo Falconi a,∗ a
Division of Pancreatic Surgery, Department of Surgery, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy Department of Nuclear Medicine, University of Verona, Negrar, Italy c Residency Programme in Surgery, University of Verona, Italy d Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar, Italy e Department of Medical Physics and Experimental Imaging, San Raffaele Scientific Institute, Milan, Italy b
a r t i c l e
i n f o
Article history: Received 31 December 2013 Accepted 16 March 2014 Available online xxx Keywords: Computed tomography Liver Lymph node Metastases Pancreatic cancer Positron emission tomography Staging
a b s t r a c t Background: The role of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in pancreatic ductal adenocarcinoma is debated. We retrospectively assessed the value of 18 fluorodeoxyglucose positron emission tomography/computed tomography in addition to conventional imaging as a staging modality in pancreatic cancer. Methods: 18 Fluoro-deoxyglucose positron emission tomography/computed tomography was performed in 72 patients with resectable pancreatic carcinoma after multi-detector computed tomography positron emission tomography was considered positive for a maximum standardized uptake value >3. Results: Overall, 21% of patients had a maximum standardized uptake value ≤3, and 60% of those had undergone neoadjuvant treatment (P = 0.0001). Furthermore, 11% of patients were spared unwarranted surgery since positron emission tomography/computed tomography detected metastatic disease. All liver metastases were subsequently identified with contrast-enhanced ultrasound. Sensitivity and specificity of positron emission tomography/computed tomography for distant metastases were 78% and 100%. The median CA19.9 concentration was 48.8 U/mL for the entire cohort and 292 U/mL for metastatic patients (P = 0.112). Conclusions: The widespread application of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in patients with resectable pancreatic carcinoma seems not justified. It should be considered in selected patients at higher risk of metastatic disease (i.e. CA19.9 > 200 U/mL) after undergoing other imaging tests. Neoadjuvant treatment is significantly associated with low metabolic activity, limiting the value of positron emission tomography in this setting. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Although the diagnosis and management of pancreatic ductal adenocarcinoma (PDAC) has improved in the last decades, its prognosis remains dismal. Surgical resection is the only treatment with curative intent with a 5-year survival rate of 20–25% [1,2]. Moreover, 20–30% of resected patients die of the disease within 12 months from resection because of early tumour recurrence, in the
∗ Corresponding author at: Department of Surgery, Division of Pancreatic Surgery, Università Politecnica delle Marche, Ospedali Riuniti, Via Conca 71, 60126 Ancona, Torrette, Italy. Tel.: +39 071 5965781; fax: +39 071 5964429. E-mail address: [email protected] (M. Falconi).
setting of unrecognized or rapidly progressive metastatic disease [3,4]. Therefore, accurate staging is of paramount importance when deciding if surgery should be performed for PDAC. Despite the significant advances in high-resolution imaging techniques, the appropriate assessment of resectability of PDAC is still challenging [5–7] and the diagnosis of small metastases can be problematic [8,9]. Whole body 2-(fluorine-18)fluoro-deoxy-d-glucose-positron emission tomography in combination with computed tomography (18 FDG-PET/CT) has demonstrated significant efficacy in the staging of different malignancies [10–12]. However, the role of 18 FDGPET/CT in patients with potentially resectable PDAC is still debated [13–17]. In fact, whether PET/CT is superior to multi-detector computed tomography (MDCT) for the identification of metastases is
http://dx.doi.org/10.1016/j.dld.2014.03.011 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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still a controversial issue. Moreover, several authors showed that PET/CT has a limited value for the detection of loco-regional lymph node metastases, with low sensitivity and specificity for nodal (N) status [13–17]. The primary aim of the present study was to assess the role of 18 FDG-PET/CT for the detection of metastatic disease in patients with resectable PDAC after conventional imaging. As secondary endpoint we evaluated the 18 FDG-PET/CT capability of identifying lymph node metastases.
injection of 0.08 mC/kg (2.96 MBq/kg) FDG. PET scanning was performed with a 16 cm bed for about 7/8 bed per patient. CT and PET scan data were co-registered. The standardized uptake value (SUV) was acquired using the attenuation-corrected images, the amount of injected FDG, the body weight of the patient, and the cross-calibration factors between PET and dose calibrator. The maximum SUV (SUVmax ) was evaluated 60 min after FDG injection, with a value of SUVmax of more than 3 being indicative of malignancy [16,18].
2. Methods
2.4. Treatment strategy based on 18 FDG-PET/CT data
Data from all consecutive patients with potentially resectable PDAC who underwent 18 FDG-PET/CT at the Sacro Cuore Hospital Don Calabria, Negrar (Italy), between May 2011 and July 2012 were retrospectively analyzed. Patients with pancreatic tumours other than ductal adenocarcinoma (i.e. intraductal papillary mucinous neoplasms) and patients with poor general conditions/severe comorbidities that precluded them from undergoing surgery were excluded from this study.
Surgical resection was initially planned for all the patients included in the present study after conventional staging. If 18 FDGPET/CT did not show distant metastases, the patient underwent laparotomy. When 18 FDG-PET/CT showed the presence of suspected distant metastases, patients underwent biopsy of the lesion (i.e. contrast-enhanced ultrasound with fine-needle aspiration for liver metastases [19]) in order to histologically confirm the diagnosis. For suspected peritoneal lesions, a laparoscopy was eventually planned. If distant metastases were confirmed, no laparotomy was performed. If 18 FDG-PET/CT showed the presence of suspected loco-regional lymph node metastases, considering the low sensitivity/specificity of PET/CT for N status and the high rate of lymph node metastases in resected PDAC [13–17], patients underwent laparotomy.
2.1. Conventional staging work-up Patients’ demographics, clinical presentation, and serum carbohydrate antigen (CA19.9) levels were collected for all patients. Preoperative staging and surgical resectability were based on abdominal contrast-enhanced MDCT and chest X-ray. All patient information and radiology images were reviewed and discussed at a multidisciplinary conference with pancreatic surgeons, gastroenterologists, medical oncologists, nuclear medicine physicians and at least one radiologist with more than 10 years of clinical experience and a specific interest in thoracic and abdominal CT. The diagnosis of potentially resectable PDAC was based on the following criteria: (1) absence of abutment/encasement of portal vein, superior mesenteric vein, hepatic artery, superior mesenteric artery, celiac trunk; (2) absence of infiltration of peripancreatic organs, with the exception of common bile duct and duodenum; (3) absence of distant metastases. In particular, the diagnosis of liver metastases was based on the presence of hepatic lesions that were hypovascular and hypoattenuating on portal phase scan. 2.2. Neoadjuvant treatment Patients with an initial diagnosis of “borderline-resectable” or locally advanced PDAC who underwent neoadjuvant treatment and who showed tumour-downstaging to potentially resectable disease were included in the study. Neoadjuvant chemotherapy/chemoradiation was administered either at our institution or under the care of the patients’ referring oncologist, according to the institution’s protocol. 2.3.
18 F-FDG
PET/CT protocol
All patients underwent 18 FDG-PET/CT within a week before the day of surgery. Patients were asked to fast for at least 6 h before the examination. For each patient blood glucose level was determined before the examination. Patients with diabetes mellitus underwent examination only when their blood glucose level was less than 140 mg/dL. All examinations were carried out by a single, highly experienced, nuclear medicine physician (MS). All the tests were performed using a hybrid PET/CT scanner (Siemens mCT Biograph, Germany). The whole-body CT scanning was performed using a continuous spiral technique on a 64-slice helical CT, while the PET scanner had 3 detector rings. No contrast medium was administered during CT scanning. After the CT scan, an emission scan was performed from the head to the thigh following intravenous
2.5. Surgical treatment and pathology Operative and postoperative data, complications, and pathology data were prospectively gathered. Formal pancreatic resections were carried out as already described [20]. Lymphadenectomy included the removal of anterior and posterior pancreatoduodenal, pyloric, and biliary duct, superior and inferior pancreatic head and/or body, common hepatic artery and celiac trunk lymph nodes, as well as lymph nodes along the right side of the superior mesenteric artery during pancreaticoduodenectomy and total pancreatectomy. Lymph node sampling between the aorta and vena cava was not routinely performed. Classification and grading of pancreatic ductal adenocarcinoma was based on the WHO 2010 criteria [21]. Tumour (T), nodal status (N) and grade (G) were determined using the standard TNM classification according to the AJCC classification [22]. Intraoperative evaluation of the resection margins was performed routinely. 2.6. Statistical analysis Distributions of continuous variables are reported as median and minimum/maximum range. Categorical variables are presented as numbers and percentages. The comparison between subgroups was performed with Student’s t-test or Mann–Whitney U test for continuous variables. Qualitative data were compared by the 2 test or Fisher’s exact test as appropriate. Cut-off points were calculated around the median for continuous variables. Statistical analyses were performed with the SPSS 16.0 software for Windows (SPSS Inc., Chicago, IL). P values were considered significant when ≤0.05. 3. Results Seventy-two consecutive patients were included in the study (50% males, median age 65 years, range 39–81 years). The median time interval between MDCT and 18 FDG-PET/CT was 28 days (range 5–51). The median time interval between 18 FDG-PET/CT and planned surgery was 2 days (range 1–7). The main patient characteristics are reported in Table 1. A SUVmax ≤ 3 was found in
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Table 1 Patient characteristics and neoadjuvant treatment details.
Table 2 Operative procedures, postoperative complications and pathology data.
N (%) Male gender Median age, years (range) Symptomatic patients Presence of diabetes Symptoms Jaundice Weight loss Pain Bowel obstruction Pancreatitis Tumoral markers CEA, ng/ml, median (range) CA19.9, U/ml, median (range) Neoadjuvant treatment Chemotherapy Gemcitabin and oxaliplatin FOLFIRINOXa Chemoradiation Gemcitabine and capecitabine + 45 Gy Gemcitabine and oxaliplatin + 45 Gy a
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36(50) 65 (39–81) 64 (89) 15 (21) 47 (65) 32 (44.5) 30 (41.5) 4 (5.5) 1 (1.5) 1.80 (0.5–19.9) 64.4 (0.8–3547) 14 (19) 7 (9.5) 3 (4) 4 (5.5) 7 (9.5) 3 (4) 4 (5.5)
5-Fuorouracil, oxaliplatin, irinotecan and leucovorin.
15 patients (21%) while the remaining 79% had a SUVmax > 3, thus defining 18 FDG-PET/CT “positive” for malignancy. 3.1. Neoadjuvant therapy Fourteen patients (19%) underwent neoadjuvant treatment because of locally advanced or borderline resectable pancreatic cancer (Table 1). In all these patients, re-staging after neoadjuvant therapy showed the presence of a potentially resectable disease. Overall, 60% of the patients (n = 9) with SUVmax ≤ 3 had undergone neoadjuvant treatment compared to 9% of those with SUVmax > 3 (n = 5, P = 0.0001).
N (%) Pancreatic resection Pancreaticoduodenectomy Left pancreatectomy and splenectomy Total pancreatectomy Vascular resection Postoperative mortality Overall morbidity Pancreatic fistula Abdominal collection Sepsis Delayed gastric emptying Bleeding Chilous fistola Median tumour size (mm), range Grading G1 G2 G3 Presence of microvascular invasion Presence of perineural invasion R status R0 R1 R2 T stage T1 T2 T3 N status N0 N1
49 (80) 7 (12) 5 (8) 14 (23) 1 (1.5) 28 (46) 11 (18) 10 (16) 7 (11.5) 6 (10) 5 (8) 4 (6.5) 25 (8–50) 0 31 (51) 30 (49) 57 (93) 55 (90) 52 (85) 9 (15) 0 1 (1.5) 1 (1.5) 59 (97) 14 (23) 47 (77)
posterior mediastinum. The first patient underwent colonoscopy with biopsy that confirmed the presence of a colonic carcinoma. The second patient, who had a normal chest X-ray, underwent thoracoscopy with resection of a mediastinal neurinoma. Both patients subsequently underwent pancreaticoduodenectomy, also associated with left colectomy in the first one.
3.2. Detection of metastatic disease at PET/CT 3.4. Surgical treatment and pathology Fig. 1 shows the results of 18 FDG-PET/CT on patient management. Eight out of 72 patients (11%) were spared surgical exploration due to 18 FDG-PET/CT findings. In 7 patients liver metastases were found and pathologically confirmed in all cases after contrast-medium ultrasound (CEUS) with fine-needle aspiration. In these 7 patients, the median time interval between MDCT and PET/CT was 37 days. Metastatic lesions were located deep in the liver parenchyma with a size ranging between 0.8 cm and 1.8 cm (in 3 cases the largest lesions had a diameter ≥1.5 cm). In retrospect, no metastatic lesions could be clearly identified at CT. In the remaining patient, who had a normal chest X-ray, 18 FDG-PET/CT showed the presence of a synchronous lung adenocarcinoma with mediastinal lymph node metastases. PET/CT did not show peritoneal metastases in any patient. Sensitivity and specificity of 18 FDG-PET/CT for the detection of metastatic disease in the entire cohort of 72 patients were 78% and 100%, respectively. Excluding the 14 patients who underwent neoadjuvant treatment – characterized by a low metabolic activity in two thirds of the cases – sensitivity and specificity were 87.5% and 100%, respectively. 3.3. Detection of extrapancreatic synchronous tumours at PET/CT Exploratory laparotomy was planned in 64 patients (89%). In 2 of them, 18 FDG PET/CT confirmed the presence of a pancreatic head cancer and showed the presence of an associated extrapancreatic synchronous tumour, one in the left colon and the other in the
A pancreatic resection was carried out in 61/64 patients (95%) who underwent laparotomy. The remaining 3 patients (Fig. 1) did not undergo pancreatectomy because of unresectable locally advanced (n = 1) or metastatic disease (n = 2). These 2 latter patients had a SUVmax ≤ 3 and peritoneal carcinomatosis. Table 2 shows operative procedures, postoperative complications, and pathology data. 3.5. Detection of lymph node metastases at PET/CT 18 FDG-PET/CT showed an increased FDG uptake in the abdominal lymph nodes in 11/61 patients (18%) who underwent surgical resection. Sensitivity and specificity of 18 FDG-PET/CT for detecting lymph node metastases were 21% and 93%, respectively. 18 FDG-PET/CT confirmed the presence of suspected nodal metastases in lymph nodes along the celiac trunk or along the superior mesenteric artery and its aortic origin in 8/11 patients (73%). In this subgroup of patients, a wider lymphadenectomy was carried out, including also para-aortic stations. The median number of resected nodes was 41 in these 8 patients compared to 32 in the remaining patients (P = 0.235). Final histological examination showed the presence of lymph node metastases along the celiac trunk or superior mesenteric artery in 7/8 patients (87.5%), of whom 2 also had para-aortic lymph node metastases. In these latter 7 patients, the median size of metastatic nodes was 8 mm (range 4–15 mm).
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Fig. 1. Clinical management and therapeutic decisions following 2-(fluorine-18)fluoro-deoxy-d-glucose-positron emission tomography in combination with computed tomography in 72 patients with resectable pancreatic cancer after conventional staging with high-resolution imaging techniques.
3.6. CA19.9 values in patients with advanced disease at PET/CT The median CA19.9 value was 64 U/mL for the entire cohort (range 0.8–3547 U/mL). In patients with liver metastases detected at PET/CT, the median CA19.9 value was 292 U/mL (range 47–3547 U/mL) compared to 48.8 U/mL (range 0.8–256 U/mL) in the remaining patients (P = 0.112). The median CA19.9 value was 218 U/mL (range 414–1126 U/mL) in patients with celiac/paraaortic nodes compared to 47.7 U/mL (range 0.8–1805 U/mL) in the remaining patients (P = 0.165). 4. Discussion Preoperative evaluation of the extent of PDAC is crucial in order to decide the most appropriate treatment options and to offer surgery to patients who are likely to benefit from it. Although the advances in high-resolution imaging techniques have improved the quality of preoperative tumour staging, in 10–15% of patients with PDAC deemed to be resectable after conventional imaging, advanced disease is found at laparotomy [5–8]. Moreover, 20% of resected patients will die within 12 months after surgery, because of early tumour recurrence due to metastatic disease [3]. Since 18 FDG-PET/CT proved to be accurate for the staging of different malignancies, it has been performed also in pancreatic cancer patients, but with uncertain results [10–17]. In this retrospective study, 18 FDG-PET/CT excluded from surgical exploration 11% of patients because of the presence of advanced disease. Sensitivity and specificity of PET/CT for the identification of metastases were 78% and 100%, respectively. In previous series,
the sensitivity of PET/CT for the diagnosis of metastatic disease ranged between 68% and 91%, while specificity between 64% and 97% [13–16,23–25]. Frohlich and colleagues showed that the sensitivity of 18 FDG-PET/CT in detecting liver metastases was 97% for lesions greater than 1 cm in size but it was only 43% for those less than 1 cm [25]. In this series, the size of liver metastases detected at PET/CT ranged between 0.8 and 1.8 cm at CEUS, but no metastatic lesions were identified after retrospective re-evaluation of MDCT. Some limitations of our study must be considered to explain these results. Firstly, this is a retrospective study and most patients underwent MDCT outside our hospital with different protocols. The lack of a single MDCT protocol, as well as the interval of about 1 month between MDCT and PET/CT, represents a limitation for the interpretation of the differences between these 2 imaging techniques. Secondly, our preoperative staging was based only on MDCT, while other diagnostic modalities, including CEUS or diagnostic laparoscopy, were not routinely performed. Of note, CEUS identified liver metastases in all 7 patients after PET/CT. CEUS has emerged in recent years as a safe and low-cost diagnostic tool for the diagnosis and staging of PDAC [26–28], with a high accuracy for the differential diagnosis of subcentrimetric hepatic lesions, including liver metastases [27]. It is likely that CEUS should be considered as a complementary imaging method after MDCT and before other diagnostic tools including PET/CT. Thirdly, preoperative staging included chest X-ray instead of chest CT scan, since this latter procedure is not strictly recommended in resectable PDAC [6]. Two extra-pancreatic tumours were found at 18 FDG-PET/CT in the chest, but we acknowledge that a chest CT scan associated with
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abdominal CT could easily detect these neoplasms without adding significant costs. Overall, 19% of the 72 patients underwent neoadjuvant chemotherapy/chemoradiation for a locally advanced or borderline resectable PDAC. Our results show that neoadjuvant treatment is significantly associated with the lack of an increased FDG uptake at PET/CT (SUVmax ≤ 3). In keeping with this observation, a significant decrease of the median SUVmax , comparing pre and post-chemoradiation values, as well as a possible correlation between PET/CT findings and clinicopathological response have been reported [29,30]. Therefore, in patients with PDAC scheduled for neoadjuvant therapy, PET/CT should be performed at baseline and after completion of their treatment to properly evaluate a metabolic response. In keeping with the current literature [13–16,23,25], our results showed that 18 FDG-PET/CT was poorly sensitive for the detection of lymph node metastases (sensitivity 21%). Different causes can explain these results. Pancreatic cancer is commonly associated with a high rate of lymph node metastases, and most metastatic nodes are small in size and close to the primary tumour. Therefore, the metabolic activity of the primary neoplasm may “hide” that of the nodes, resulting in a poor sensitivity for PET/CT in distinguishing primary pancreatic cancer from metastatic nodes. An interesting finding from our study is the capability of 18 FDGPET/CT to detect “distant” lymph node metastases. In fact, in 8 of the 61 resected patients (13%), PET/CT identified possible metastases along the celiac trunk, the origin of the superior mesenteric artery, and para-aortic nodes. These patients underwent pancreatic resection and, although a wider lymphadenectomy was carried out in order to verify PET/CT findings, the median number of resected nodes did not significantly differ between these patients and the remaining ones (41 versus 32, P = 0.235). Nodal metastases were found at histological examination in 7 of these 8 patients (87.5%). Para-aortic/celiac node metastases are associated with poor prognosis in PDAC, and they may be considered as systemic metastatic disease [31–33]. However, their accurate preoperative diagnosis with conventional imaging is very difficult [32]. Therefore our preliminary results, based on a retrospective analysis of few cases, without a systematic lymph node dissection of the same nodal stations in all the patients, should be considered with caution. Further studies are needed to confirm the accuracy of 18 FDG-PET/CT in the identification of this subgroup of patients who may represent the target of neoadjuvant treatment. PET/CT is an expensive diagnostic tool and the costs of PET/CT scans represent a major limitation of its widespread application. Considering the results of this study, the data from the literature, and the cost of PET/CT, the systematic application of 18 FDG-PET/CT to all patients with resectable PDAC seems not justified. It is likely that this imaging modality should be performed in subgroups of selected patients. In this light, perioperative CA19.9 levels >200 U/mL can correlate with tumour burden, tumour spread, and early recurrence after resection in PDAC [3,34]. In the present study we found that the median CA19.9 level was higher (>200 U/mL) in patients with both liver metastases and celiac/para-aortic nodal disease identified at PET/CT. The lack of a statistical significance is likely due to the low number of patients with advanced disease. Since the diagnostic yield of PET/CT scan for advanced disease increased in patients with CA19.9 > 200 U/mL, we propose that 18 FDG-PET/CT should be performed after MDCT and CEUS in this subgroup of patients that are at higher risk of metastatic disease. In conclusion, our data do not support the widespread application of 18 FDG-PET/CT in the preoperative staging of patients with resectable PDAC. 18 FDG-PET/CT should be considered in selected patients at higher risk of metastatic disease (i.e. patients with
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Please cite this article in press as: Crippa S, et al. The role of 18 fluoro-deoxyglucose positron emission tomography/computed tomography in resectable pancreatic cancer. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.011
