J Cancer Res Clin Oncol (2010) 136:1929–1935 DOI 10.1007/s00432-010-0852-5

ORIGINAL PAPER

High FDG uptake in PET/CT predicts worse prognosis in patients with metastatic gastric adenocarcinoma Hyun Woo Chung · Eun Jeong Lee · Yo-Han Cho · So Young Yoon · Young So · Sung-Yong Kim · Mark Hong Lee · Jeong Hwan Kim · Sun-Young Lee · In-Kyung Sung · Hyung-Seok Park · Moon-Won Yoo · Kyung-Yung Lee

Received: 1 October 2009 / Accepted: 17 February 2010 / Published online: 20 March 2010 © Springer-Verlag 2010

Abstract Purpose We evaluated the role of FDG-PET/CT in patients with metastatic gastric adenocarcinoma before palliative chemotherapy to predict prognosis and chemotherapeutic response.

J. H. Kim · S.-Y. Lee · I.-K. Sung · H.-S. Park Department of Internal Medicine, Division of Gastroenterology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea

Methods The study included 35 consecutive newly diagnosed patients with metastatic gastric adenocarcinoma who underwent FDG-PET/CT before palliative chemotherapy. Maximum standardized uptake value (SUVmax) of the primary tumor was assessed to evaluate survival and chemotherapeutic response. Survival analysis was performed for time to progression and overall survival using the Kaplan–Meier method. Cox proportional hazard models were used to determine independent prognostic factors. Results All primary tumors were visualized using FDGPET/CT (mean SUVmax = 8.1 § 4.5, range 2.5–22.1). Sensitivity, speciWcity, and accuracy of FDG-PET/CT in detection of solid organ metastasis were 95.2% (20/21), 100% (14/14), and 97.1% (34/35), respectively. No signiWcant diVerence of primary tumor SUVmax was found among the chemotherapeutic response groups. Univariate survival analysis demonstrated ECOG performance status (¸2), presence of solid organ metastasis, number of organs involved in distant metastasis (¸2), and SUVmax of the primary tumor (>8) as signiWcant predictors for poor overall survival. Multivariate survival analysis showed SUVmax of the primary tumor (P = 0.048), presence of solid organ metastasis (P = 0.015), and ECOG performance status (P = 0.002) as signiWcant independent prognostic predictors for overall survival. Conclusions High FDG uptake of the primary tumor in patients with metastatic gastric adenocarcinoma is associated with poor overall survival. Assessment of tumor FDG uptake has limited value for prediction of chemotherapeutic response, but provides useful information regarding prognosis.

M.-W. Yoo · K.-Y. Lee Department of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea

Keywords Metastatic gastric adenocarcinoma · FDG · PET/CT · Prognosis

Presented in part at the 56th Annual Meeting of the Society of Nuclear Medicine, Toronto, Canada, June 13–17, 2009. The authors H. W. Chung and E. J. Lee equally contributed to this work. H. W. Chung · Y. So Department of Nuclear Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, 4-12 Hwayang-dong, Kwangjin-gu, Seoul, Korea e-mail: [email protected] E. J. Lee Department of Nuclear Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108, Pyoung-dong, Jongro-gu, Seoul, Korea e-mail: [email protected] Y.-H. Cho (&) · S. Y. Yoon · S.-Y. Kim · M. H. Lee Department of Internal Medicine, Division of Hematology-Oncology, Konkuk University Medical Center, Konkuk University School of Medicine, 4-12 Hwayang-dong, Kwangjin-gu, Seoul, Korea e-mail: [email protected]

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Introduction

Materials and methods

Over a period of several decades, incidence of gastric carcinoma has shown a worldwide decline; however, the rate of this disease continues to occur at a high rate in East Asia, Eastern Europe, and parts of Central and South America countries. Despite the reduced incidence, gastric carcinoma is in fourth place behind malignancies of the lung, breast, and colon and rectum. Overall survival for gastric carcinoma has also improved, possibly due to an increased rate of early diagnosis. However, survival of patients with advanced gastric carcinoma has not improved. Therefore, gastric carcinoma is still the second most frequent cause of death from malignancy in the world (Bertuccio et al. 2009; Parkin et al. 2005; Alberts et al. 2003). A method for selection of patients with a better prognosis could inXuence treatment decisions and potentially reduce therapeutic toxicity, with the ultimate goal of improving survival. Fluorine-18 Xuorodeoxyglucose positron emission tomography (FDG-PET) is a functional imaging method for measurement of tumor glucose utility. FDG-PET combined with computed tomography (FDG-PET/CT) was recently introduced and is expected to provide more precise anatomical data along with metabolic information. The earliest application of FDG-PET in oncology has been in clinical staging, suggesting that FDG-PET could identify potential sites of disease that were not detected by standard imaging studies (Bomanji et al. 2001; Reed et al. 2003; van Westreenen et al. 2004). In addition, a number of studies have suggested that probing of the glycolytic characteristics of tumors with FDG-PET allows assessment of therapeutic response and prediction of prognosis (Downey et al. 2004; Cerfolio and Bryant 2006; de Geus-Oei et al. 2009; Hicks 2009). Despite the high frequency of gastric carcinoma, a relatively small number of studies using FDG-PET or PET/ CT imaging of this tumor type have been published (Ott et al. 2008; Kim et al. 2006; Chen et al. 2005; Dassen et al. 2009; Stahl et al. 2003; Yoshioka et al. 2003; Han et al. 2009). Most of these have consisted of locally advanced gastric carcinoma only. Furthermore, the role of initial FDG-PET imaging in gastric carcinoma is still under debate due to its relatively low sensitivity for detection of primary tumors and regional lymph node metastasis, particularly in early gastric carcinoma and non-intestinal type (Dassen et al. 2009; Stahl et al. 2003). Therefore, in this study, we evaluated FDG-PET/CT imaging of patients with metastatic gastric adenocarcinoma for prediction of the chemotherapeutic response according to FDG uptake before palliative chemotherapy, and further investigated its prognostic value.

Patients

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From April 2006 to December 2008, 157 consecutive newly diagnosed patients with gastric carcinoma underwent FDG-PET/CT as a part of the staging procedure at Konkuk University Medical Center. Primary gastric carcinoma was conWrmed by endoscopic biopsy. Following diagnosis of gastric carcinoma, distant metastasis was validated by histologic conWrmation or by contrast-enhanced CT and serial follow-up. Additional bone scintigraphy or magnetic resonance imaging was performed for evaluation of bone metastasis. Inclusion criteria for this study were as follows: First, the patient was required to show distant metastasis. No patient underwent palliative gastrectomy. Second, FDG-PET/CT should be performed prior to Wrst-line palliative chemotherapy, within 1 month. Third, only patients with gastric adenocarcinoma were included. Mucuscontaining tumors, such as signet ring cell carcinoma, were excluded, because this type of tumors showed low FDG uptake (Stahl et al. 2003). A total of 35 patients were eligible for this study (Fig. 1). This study was approved by the institutional review board. Chemotherapy and clinical follow-up All patients underwent palliative chemotherapy after diagnosis. Palliative chemotherapy regimens used in this study included FOLFOX (oxaliplatin, 5-Xuorouracil, and leucovorin, 29 pt), taxane and cisplatin (4 pt), and TS-1 based chemotherapy (2 pt). Chemotherapy regimen was selected by physician’s discretion and was not related to the degree of disease. Six patients with chemotherapy regimen other than FOLFOX wanted to receive outpatient chemotherapy. Evaluation of chemotherapeutic response was performed by contrast-enhanced CT after the third or fourth cycle of chemotherapy, according to Response Evaluation Criteria in Solid Tumors (RECIST) (Therasse et al. 2000). Patients without tumor progression underwent further therapy with the same regimen. Patients with progressive disease underwent second-line chemotherapy or supportive care. Followup monitoring for recurrence or metastasis was performed every 2–3 months. Follow-up evaluation included a complete physical examination, biochemical screening, and contrast-enhanced CT of the chest and abdomen. Gastroduodenoscopy, ultrasonography, and bone scintigraphy were performed whenever clinically indicated. FDG-PET/CT imaging and analysis All patients fasted for at least 6 h and blood glucose concentration was checked before PET studies (<120 mg/dl

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Fig. 1 Flowchart shows patient selection in study

for nondiabetic patients and <200 mg/dl for diabetic patients). Subjects in the resting state were intravenously injected with FDG (4.8 MBq/kg of body weight); PET/CT images were acquired 60 min later using a GEMINI PET/CT scanner (Philips Medical Systems, Cleveland, USA). Axes of both PET and CT systems were mechanically aligned. CT from the skull base to the mid-thigh (without i.v. contrast) was performed for attenuation correction and anatomic localization using a standardized protocol of 120 kV, 50 mA, a tube-rotation time of 0.75 s per rotation, a pitch of 1.5, and a section thickness of 5 mm. Immediately after CT, PET images were acquired for 2.5 min per frame using a conventional three-dimensional protocol. FDG-PET/CT images were assessed by two experienced nuclear medicine physicians. Maximum standardized uptake value (SUVmax) was used quantitatively to determine FDG-PET/CT activity. SUVmax was deWned as maximum tumor concentration of FDG divided by the injected dose, corrected for the body weight of the patient. To obtain the SUVmax, a transaxial image representing the highest tumor uptake was carefully selected, and a circular region of interest was placed in the FDG-accumulating area.

tested with log rank tests. Multivariate survival analysis for independent prognostic factors was performed using a Cox proportional hazards model that included signiWcant univariate variables. Statistical analyses were performed using SPSS version 12.0.1 for windows (SPSS, Chicago, IL). P < 0.05 was considered statistically signiWcant.

Results Patient characteristics and analysis of tumor FDG uptake Clinical characteristics of the 35 study subjects (11 women and 24 men; age 57 § 13) with metastatic gastric adenocarcinoma are summarized in Table 1. FDG-PET/CT visualized all primary tumor masses (mean SUVmax = 8.1 § 4.5, range 2.5 to 22.1). SUVmax of distant metastatic sites were Table 1 Clinical characteristics of patients with metastatic gastric adenocarcinoma Clinical characteristic

Value

Male/female

24/11

Mean age (range)

57 § 13 (31–82)

ECOG performance statusa

Statistical analysis

0/1/2/3

4/23/7/1

The signiWcance of diVerences of SUVmax for chemotherapeutic response among patient groups was compared with analysis of variance (ANOVA). Correlation between SUVmax of primary tumor and distant metastatic site was assessed with the Pearson test. Duration of disease free from tumor progression and overall survival was evaluated by survival analysis. Univariate analysis of prognostic factors was performed using the Kaplan–Meier method, and signiWcance of diVerence between survival curves was

Peritoneum/nonregional lymph node

16/25

Lung/liver/bone/adrenal gland

4/11/9/1

Distant metastatic siteb

Presence of distant solid organ metastasis Presence/absence

21/14

Total number of organs involved in distant metastasis 1/2/3 a b

11/18/6

ECOG: Eastern Cooperative Oncology Group Each distant metastatic site in a patient was counted as 1

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also evaluated (8.7 § 4.4, range 1.6 to 17.8). SUVmax of the primary tumor and distant metastatic sites showed signiWcant correlation to each other (r = 0.52, P = 0.001, Fig. 2). Distant metastases were classiWed as present or absent for each metastatic site. Solid organ metastasis (lung, liver, bone, or adrenal gland) was assessed as distinct from peritoneum or nonregional lymph node metastases. Solid organ metastasis with/without peritoneum or nonregional lymph node metastases was found in 21 of 35 patients. Compared with histologic conWrmation or conventional imaging methods, sensitivity, speciWcity, and accuracy of FDG-PET/CT for detection of solid organ metastasis in patients were 95.2% (20/21), 100% (14/14), and 97.1% (34/35), respectively. The one patient whose solid organ metastasis was not detected by FDG-PET/CT had liver metastasis. Among 11 patients with liver metastasis, FDG-PET/CT found liver metastasis in 10 patients. Distant metastasis of only non-solid organs (peritoneum or nonregional lymph node) was conWrmed in 34 of 35 patients. Sixteen patients showed peritoneum metastasis. Among these, peritoneum-only metastasis was found in 6 patients. Sensitivity, speciWcity, and accuracy of FDG-PET/ CT for detection of peritoneum-only metastasis in patients were 66.7% (4/6), 100% (19/19), and 92.0% (23/25), respectively. Chemotherapeutic response evaluation and survival analysis According to RECIST, chemotherapeutic response was assessable in 29 of 35 patients with measurable malignant sites. Among 29 patients, there were no complete responses, 20 partial responses, 4 stable diseases, and 5 progressive

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diseases. Overall response rate was 69% (20/29). Mean SUVmax of the primary tumor before palliative chemotherapy for each response group was 9.1 § 5.4 in the partial response group, 6.5 § 0.9 in the stable disease group, and 8.7 § 2.1 in the progressive disease group. No signiWcant diVerence was found among response groups. Median survival for all patients was 9.7 mo (range 1.6 to 22.2 mo). At the time of the last follow-up, 8 patients had survived with a minimum of 7.4 mo of clinical follow-up (median, 11.5 mo) after treatment, and 1 patient was lost to follow-up after 9.2 mo. Overall survival between FOLFOX and other than FOLFOX groups was not signiWcantly diVerent (10.9 § 5.6 mo vs. 10.4 § 4.8 mo, respectively). For survival analysis, cutoV values for categorization of low and high SUVmax of the primary tumor and distant metastatic site were set at 8.0 and 9.0, respectively. Each cutoV value was constructed with regard to the mean value. For time to tumor progression, no signiWcant prognostic predictor was found in univariate survival analysis of the following factors: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, presence of solid organ metastasis, number of organs involved in distant metastasis, SUVmax of the primary tumor, and SUVmax of the distant metastatic site before palliative chemotherapy. However, for overall survival, univariate survival analysis determined that ECOG performance status (¸2), presence of solid organ metastasis, number of organs involved in distant metastasis (¸2), and SUVmax of the primary tumor (>8.0) before palliative chemotherapy were signiWcant prognostic predictors. However, SUVmax of distant metastatic sites was not a signiWcant prognostic predictor (Table 2). The Kaplan–Meier survival curve with regard to SUVmax of the primary tumor is shown in Fig. 3. After multivariate survival analysis, SUVmax of the primary tumor (P = 0.048), presence of solid organ metastasis (P = 0.015), and ECOG performance status (P = 0.002) before palliative chemotherapy were still independent prognostic predictors for overall survival (Table 3). Examples of patients with metastatic gastric adenocarcinoma with high and low FDG uptakes of the primary tumor are demonstrated in Fig. 4.

Discussion

Fig. 2 Correlation between SUVmax of primary tumors and distant metastatic sites

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The majority of patients with gastric carcinoma show an advanced stage of disease at presentation, and chances of survival 5 years after diagnosis of gastric carcinoma are still low (Dickson and Cunningham 2004; Hundahl et al. 1997). To the best of our knowledge, the value of FDG-PET/CT with regard to prediction of prognosis and chemotherapeutic response before palliative chemotherapy in patients with metastatic gastric adenocarcinoma has not been established. We hypothesized that initial FDG-PET/CT would represent

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Table 2 Univariate analysis of overall survival Variable

Table 3 Multivariate analysis of overall survival

Number of patients

Median survival time (months)

P value*

Variable

Relative risk (exp. B)

95% CI

P value

1.007 to 5.815

0.048

19

10.2

0.98

SUVmax of primary tumor >8.0

2.240

<57 ¸57

16

14.0

Presence of solid organ metastasis

3.307

1.258 to 8.695

0.015

Female

11

14.0

ECOG performance status 2/3

4.444

1.731 to 11.410

0.002

Male

24

9.7

Age

Sex 0.45

ECOG performance status 0/1

27

13.8

2/3

8

5.6

0.003

Solid organ metastasis Absence

14

21.1

Presence

21

9.7

0.007

Number of organs involved distant metastasis 1

11

21.1

¸2

24

9.7

0.02

SUVmax of the primary tumor ·8.0

22

11.7

>8.0

13

8.2

0.03

SUVmax of distant metastatic sites ·9.0

21

10.2

>9.0

14

11.7

0.09

* P value was obtained based on the log rank test

Fig. 3 Kaplan–Meier analysis of overall survival of patients with metastatic gastric adenocarcinoma according to SUVmax of the primary tumor

survival and chemotherapeutic response in patients with metastatic gastric adenocarcinoma. In this study, we investigated patients with newly diagnosed metastatic gastric adenocarcinoma and found active uptake of FDG in levels suYcient enough to allow visualization by PET/CT in 100% of the primary tumors. Also, FDG uptake levels in primary tumors showed close correlation with levels of FDG uptake in distant metastatic sites. FDG uptake of gastric carcinoma has been reported as

somewhat poor, and PET imaging is limited in its capacity for detection of gastric carcinoma (Dassen et al. 2009; Stahl et al. 2003; Han et al. 2009; Mochiki et al. 2004). However, this has occurred frequently in diVusely growing and mucus-containing tumor types. In addition, one study by Chen et al. (2005), which consisted of 79% of patients with stage III and IV disease, demonstrated 94% sensitivity of FDG-PET for primary tumor detection. Because the current study focused only on metastatic gastric adenocarcinoma, the patient population could explain the high detection rate of primary tumor by FDG-PET/CT in our results. In gastric carcinoma, the role of FDG-PET in providing prognostic information has been reported discordantly. While one report suggested that the survival of patients according to SUVmax of the primary tumor was not signiWcantly diVerent, the other demonstrated that the survival of patients with high SUVmax of the primary tumor was signiWcantly poorer than patients with low SUVmax (Stahl et al. 2003; Mochiki et al. 2004). FDG-PET imaging is used to probe the biological characteristics of malignancy based on the rate of glucose metabolism. Previous studies have suggested that FDG uptake of the primary tumor site may correlate with tumor aggressiveness in various types of malignancy (Garin et al. 2009; Are et al. 2007; Higashi et al. 2005; Kitagawa et al. 2003). FDG-PET is a promising modality that is complementary to prognostic information provided by conventional methods. We found results that support and extend the Wndings reported in these articles. The magnitude of primary tumor FDG uptake in patients with metastatic gastric carcinoma was revealed as an independent prognostic predictor of overall survival. Poor performance status of patients with advanced gastric carcinoma has been reported as a negative prognostic factor in prior studies (Trumper et al. 2006; Lee et al. 2007). Concordantly, the current study showed that poor ECOG performance status of a patient was an independent prognostic predictor of overall survival. In addition, the presence of solid organ metastasis was another independent prognostic predictor of overall survival. The role of FDGPET for detection of distant metastasis was demonstrated variably according to metastatic sites. Using FDG-PET, one study found a sensitivity and speciWcity of 85 and 74%

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J Cancer Res Clin Oncol (2010) 136:1929–1935

Fig. 4 FDG-PET/CT and contrast-enhanced CT of patients with metastatic gastric adenocarcinoma. a 55-year-old man with high SUVmax of the primary tumor (18.2, arrow). Overall survival was 8.4 mo. b 67-year-old man with low SUVmax of the primary tumor (4.5, arrow). Overall survival was 21.9 mo

for the detection of liver metastasis; 67 and 88% for lung metastasis; 24 and 76% for ascites; 4 and 100% for pleural carcinomatosis; and 30 and 82% for bone metastasis, respectively (Yoshioka et al. 2003). FDG-PET was not useful for detection of bone metastases and peritoneal and pleural metastases. However, in the current study, sensitivity and speciWcity of FDG-PET/CT to detect solid organ metastasis in patients were high (95.2 and 100%, respectively). FDG-PET/CT did not detect solid organ metastasis in only 1 of 21 patients with solid organ metastasis. This Wnding may suggest a potential additional role for FDG-PET/CT in providing prognostic information in patients with metastatic gastric adenocarcinoma. Furthermore, peritoneum metastasis was detected by FDG-PET/ CT with relatively high sensitivity and speciWcity (66.7 and 100%, respectively). Better visualization of ascites and peritoneal nodular lesions by PET/CT rather than by PET might improve sensitivity for detection of peritoneum metastasis. Although chemotherapeutic response in advanced gastric carcinoma was improved, approximately half of patients who received chemotherapy still failed to achieve a response (Rosati et al. 2009). In order to avoid unnecessary therapy with its associated side eVects and costs, discrimination between patients who do not respond to chemotherapy early in the course of treatment or prior to treatment is important. A small number of studies have reported on the usefulness of FDG-PET for evaluation of chemotherapeutic response in gastric carcinoma (Ott et al. 2008; Di Fabio et al. 2007). These studies demonstrated that assessment of metabolic response was possible by FDG-PET following the Wrst cycle of chemotherapy. In the current study, we compared mean SUVmax of primary tumors before palliative chemotherapy according to chemotherapeutic response groups. We observed no signiWcant diVerence of SUVmax among chemotherapeutic response groups. However, the stable disease group showed a tendency toward relatively low SUVmax of the primary tumor before palliative chemotherapy.

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There are several limitations in the current study. First, not all of the distant metastatic sites were conWrmed by histologic diagnosis. Validation of distant metastasis by conventional imaging methods and serial follow-up may cause imprecise estimation of distant metastasis. Second, our small study population weakened statistical power and may be associated with inherent biases. Third, follow-up duration was limited in some patients. However, because the majority of patients with metastatic gastric adenocarcinoma survive less than 1 year, it is unlikely that the conclusions of the current study will change signiWcantly with further follow-up. Therefore, these reported results should be considered as a preliminary experience, and further prospective studies enrolling large populations will be needed to establish the role of FDG-PET/CT in metastatic gastric adenocarcinoma. In conclusion, FDG-PET/CT images of metastatic gastric adenocarcinoma can visualize primary tumors and can also identify distant metastasis of solid organs with a high detection rate. Furthermore, high FDG uptake of primary tumors is associated with poor overall survival as an independent prognostic factor. However, the role in prediction of chemotherapeutic response is limited. Thus, in newly diagnosed patients with metastatic gastric adenocarcinoma, assessment of tumor FDG uptake provides potentially useful information with regard to patient prognosis. Acknowledgments University in 2008.

This work was supported in part by Konkuk

ConXict of interest statement of interest.

We declare that we have no conXict

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