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Positron Emission Tomography in Staging of Esophageal CancerWestreenen, Henderik Leendert van

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POSITRON EMISSION TOMOGRAPHY IN STAGING OF ESOPHAGEAL CANCER

Henderik Leendert van Westreenen

HL van WestreenenPositron Emission Tomography in Staging of Esophageal CancerThesis University of GroningenISBN 90-367-2388-4

Printed byPrintPartners Ipskamp bv Enschede

Lay-out and design©snArf Productions

Cover IllustrationDrs Johan Lange Jr

The clinical studies were financially supported by a grant from ZonMw Health Care Efficiency Research (945-11-002).

Financial support for this thesis was kindly given by AstraZeneca bvBaxterBoston Scientific Benelux bvEurotecHitachi Medical Systems bvIntegraal Kankercentrum Noord-NederlandJanssen-Cilag bvNutricia Nederland bvNycomed Nederland bvPAES Nederland bv - OlympusPaul Hartmann bvSanofi-Synthelabo bvSiemens Nederland nvTyco Healthcare Nederland bv

© HL van Westreenen, The Netherlands, 2005. All rights reserved.

Rijksuniversiteit Groningen

Proefschrift

ter verkrijging van het doctoraat in deMedische Wetenschappen

aan de Rijksuniversiteit Groningenop gezag van de

Rector Magnificus, dr. F. Zwarts,in het openbaar te verdedigen op

woensdag 16 november 2005om 16.15 uur

door

Henderik Leendert van Westreenengeboren op 21 augustus 1977

te Echteld

POSITRON EMISSION TOMOGRAPHY IN STAGING OF ESOPHAGEAL CANCER

PromotoresProf. dr. T. WiggersProf. dr. J.J.B. van Lanschot

CopromotoresDr. J.Th.M. PlukkerDr. H.M. van DullemenDr. P.L. Jager

BeoordelingscommissieProf. dr. R.A.J.O. DierckxProf. dr. J.H. KleibeukerProf. dr. M. Oudkerk

ParanimfenDrs. A. van den Ham

Drs. G. van ‘t Hof

CONTENTSChapter 1Introduction

Chapter 2Systematic Review of the Staging Performance of FDG-PET in Esophageal Cancer

Chapter 3Esophageal Cancer: CT, EUS, and FDG-PET for Assessment of Response to Neoadjuvant Therapy - Systematic Review

Chapter 4Positron Emission Tomography with FDG in a Combined Staging Strategy of Esophageal Cancer Prevents Unnecessary Surgical Explorations

Chapter 5Additional Value of Positron Emission Tomography in Staging Esophageal Cancer - a Prospective Cohort Study and Cost Analysis

Chapter 6Synchronous Primary Neoplasms Detected on Positron Emission Tomography in Staging of Patients with Esophageal Cancer

Chapter 7Pitfalls of Positive Findings in Staging Esophageal Cancer with Positron Emission Tomography

Chapter 8Prognostic Value of the Standardized Uptake Value in Esophageal Cancer

Chapter 9Comparison of FLT-PET and FDG-PET in Esophageal Cancer

Chapter 10Summary and Future Perspectives

Chapter 11Samenvatting

Dankwoord

Publications

Curriculum Vitae

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1INTRODUCTION AND OUTLINE OF THE THESIS

10

CHAPTER 1

INCIDENCEThe incidence of esophageal carcinoma has been rising steadily over the 1980s and 1990s. This has been caused most to the increasing frequency of adenocarcinoma particularly in a preexisting Barrett’s esophagus.1 The reported overall incidence of esophageal cancer based on international data is currently 3.2 per 100,000 inhabitants leading to the 6th most frequent cancer type world-wide.2 In the Netherlands, there is an increasing incidence for males from 7.4 to 9.7 per 1,000,000 person-years and for females from 2.7 to 3.2 per 1,000,000 person-years during the period of 1989 to 1998 with a mortality/incidence ratio of 91%.3 Es-ophageal cancer has a high mortality, as reflected by a 5-year survival of 10% to 15%. More-over, more than 50% of patients with esophageal cancer have already inoperable disease at presentation.

TNM STAGINGThe American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) have established essentially identical staging classifications for esophageal cancer.4

Staging is based solely on the tumor-node-metastasis (TNM) classification system, which takes into account the characteristics of the primary tumor, regional nodal metastases, and distant metastases (Table 1).

‘T’ indicates the depth of primary tumor invasion. Esophageal cancer originate in the mucosa and invades progressively deeper layers of the gastrointestinal tract even into vital structures e.g. aorta (T4) (Figure 1). ‘N’ indicates the spread of cancer to specified regional lymph nodes. In esophageal cancer any regional lymph node is considered N1.

Table 1. TNM classification

Stage Tumor Node Metastasis

0 Tis N0 M0

I T1 N0 M0

IIA T2-3 N0 M0

IIB 1-2 N1 M0

III T3 N1 M0

T4 Any N M0

IVA Any T Any N M1a

IVB Any T Any N M1b

The primary tumor (T) is classified as follows: Tis, carcinoma in situ; T1, invasion of lamina propria or submucosa; T2, inva-sion of muscularis propia; T3, invasion of adventitia; and T4, invasion of adjacent structures. Regional lymph nodes (N) are classified as follows: N0, no regional lymph node me-tastases, and N1, regional lymph node metastases. Distant metastases (M) are classified as follows: M0, no distant me-tastases; M1a metastasis to cervical nodes in the case of cancer of the upper thoracic esophagus and metastasis to celiac nodes in the case of cancer of the lower thoracic esophagus; and M1b, other distant metastases.

11

Introduction and Outline of the Thesis

However, more distant lymph nodes represent distant metastases. For example, lymph node metastases at the celiac axis are considered to be not regional, but rather distant metas-tases. ’M’ indicates distant metastases to lymph nodes outside specified regional nodes, or to organs such as liver, lung and skeleton.

SURGERYSurgical resection is currently the only curative treatment in patients with localized esopha-geal cancer (stage I-III).5 Transhiatal resection seems to have lower morbidity rates in com-parison with transthoracic esophagectomy although, transthoracic approach tends to a better median survival and disease-free survival.6 Long-term survival after surgery with cura-tive intent of esophageal cancer is only 20%. Moreover, esophagectomy is associated with a substantial morbidity and mortality and may have a negative impact on quality of life over a period of several months.7 Therefore, conventional imaging techniques are employed to select only patients with resectable disease for esophagectomy.

CONVENTIONAL STAGING Currently, the most common conventional modality for locoregional staging of esophageal cancer is endoscopic ultrasonography (EUS) in combination with fine needle aspiration (FNA).8 The great advantage of EUS for staging is the ability to image distinct wall layers with histological correlates. EUS produces a five-layer image of the esophageal wall: the first layer corresponds to the superficial mucosa, the second layer to the mucosa, the third layer to the submucosa, the fourth layer to the muscularis propria, and the fifth layer to the adven-titia (Figure 2).9 The accuracy of EUS for staging depth of tumor invasion (T) is 85% and EUS is

FIGURE 1 Illustration shows stages of esophageal malignancy. T1 lesion involves mucosa (m) or submucosa (s), T2 lesion invades muscularis propria (mp), T3 lesion invades adventitia (a), and T4 lesion involves adjacent organ (A) (Iyer et al. Am J Roentgenol 2003).

12

CHAPTER 1

highly effective to distinguish stages T1 and T2 from stages T3 and T4.10,11 Furthermore, EUS is highly accurate in the assessment of regional and non-regional lymph nodes especially by the introduction of FNA. The reported accuracy of EUS for regional lymph node metastases (N) and distant lymph metastases (M) is 87% and 96%, respectively.12,13

Spiral computed tomography (CT) plays an important role in detecting distant me-tastases, especially hematogenous metastases (Figure 3).14 Furthermore, CT is complemen-tary to EUS findings regarding assessment of T stage especially in patients with stenotic tumors which are not to pass by EUS. The main limitation of CT is its insensitivity for the identification of

FIGURE 2 EUS image of a tumor (T) that invades the ad-ventitia (T3) with a locoregional lymph node (LN).

FIGURE 3 Patient with liver metastases (M1b) and involved ce-liac axis lymph nodes on CT.

13

Introduction and Outline of the Thesis

metastatic disease in normal-sized lymph nodes.15,16 In addition to EUS and CT, sonography of the neck, barium swallow, bronchoscopy, bone scintigraphy and diagnostic laparoscopy with or without laparoscopic ultrasonography are occasionally employed. Despite these efforts, metastatic spread (stage IV) or irresectable tumors (T4) are encountered during surgical exploration in up to 30% of patients.17-20 As a result, accurate preoperative staging is essential to select those patients who will benefit from surgery and to avoid unnecessary operations in patients with distant metastases.

POSITRON EMISSION TOMOGRAPHYSince the 1990s, positron emission tomography (PET) is a rapidly developing noninvasive method for staging of various types of cancer.21 PET uses positron-emitting radionuclides, which are incorporated into compounds that take part in physiological processes (trac-ers). The most frequently used PET tracer in oncology is 18F-fluorodeoxyglucose (FDG) and measures glucose utilization.22 FDG is a glucose analogue, which enters the cells via the same membrane transporters as glucose. Glucose as well as FDG are phosphorylated by the enzyme hexokinase. In contrast to glucose-6-phosphate, FDG-6-phosphate is not a substrate for further metabolism in the glycolytic pathway. Therefore FDG-6-phosphate is trapped in the cells, in proportion to their glycolytic activity. FDG-PET has been gaining acceptance as a noninvasive method for the staging of esophageal cancer especially for the detection of distant metastases (Figure 4). A sensitivity ranging from 70% to 74% is reported leading to a change in patient management ranging from 3% to 20%.23-27

FIGURE 4 Patient with mediastinal, celiac trunk, and para-aortal metastases on FDG-PET.

14

CHAPTER 1

OUTLINE OF THE THESISThe aim of this thesis it to assess the value of FDG-PET in management of patients with esophageal cancer. Since FDG-PET has additional value compared with conventional staging methods, the rate of unnecessary surgery might be reduced by the preoperative use of FDG-PET. Furthermore, the cost-effectiveness of preoperative staging with FDG-PET was assessed. For the development of proper guidelines for the use of FDG-PET in esophageal cancer, we must be aware of pitfalls of FDG-PET because FDG is not a tumor specific tracer, and FDG-PET may visualize unexpected neoplasms. In order to fulfill these objectives the following studies have been carried out:In chapter 2 and 3, the literature concerning FDG-PET in staging of esophageal cancer and in the response assessment to neoadjuvant therapy is systematically reviewed.In chapter 4, the impact of preoperative staging combined with FDG-PET on the rate of unnecessary surgical explorations is investigated.In chapter 5, we study the additional value of FDG-PET in detecting distant metastases in patients with cancer of the esophagus or gastro-esophageal junction who are suitable for potentially curative surgery based upon a state-of-the-art conventional preoperative staging. In addition, the number of prevented unnecessary surgical explorations are examined to assess the cost-effectiveness of introducing FDG-PET after a conventional preoperative work-up.In chapter 6, the rate and clinical importance of unexpected second primary neoplasms seen of FDG-PET scan obtained for the preoperative evaluation of patients with esophageal cancer is determined. In chapter 7, the possible pitfalls of false-positive findings on FDG-PET in staging of esophageal cancer are described and discussed.In chapter 8, the prognostic value of the standardized uptake value for esophageal cancer is evaluated.In chapter 9, the new tracer 18F-fluoro-3’deoxy-3’-L-fluorothymidine (FLT) is compared with FDG for detection and staging of esophageal cancer in a feasibility study.

15

Introduction and Outline of the Thesis

REFERENCES1.

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Pera M, Pera M. Recent changes in the epidemiology of esophageal cancer. Surg Oncol 2001;10:81-90.Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 1999;83:18-29.Siesling S, van Dijck JA, Visser O, Coebergh JW. Trends in incidence of and mortality from cancer in The Netherlands in the period 1989-1998. Eur J Cancer 2003;39:2521-30.Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edition. New York: John Wiley&Sons, 2003.Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003;349:2241-52.Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, Stalmeier PF, ten Kate FJ, van Dekken H, Obertop H, Tilanus HW, van Lanschot JJ. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347:1662-9.Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ. Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 2001;72:306-13.Rice TW. Clinical staging of esophageal carcinoma. CT, EUS, and PET. Chest Surg Clin N Am 2000;10:471-85.Lightdale CJ. Esophageal cancer. American College of Gastroenterology. Am J Gastroenterol 1999;94:20-9.Rosch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am 1995;5:537-47.Kelly S, Harris KM, Berry E, Hutton J, Roderick P, Cullingworth J, Gathercole L, Smith MA. A systematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma. Gut 2001;49:534-9.Catalano MF, Alcocer E, Chak A, Nguyen CC, Raijman I, Geenen JE, Lahoti S, Sivak MV, Jr. Evalu-ation of metastatic celiac axis lymph nodes in patients with esophageal carcinoma: accuracy of EUS. Gastrointest Endosc 1999;50:352-6.Vazquez-Sequeiros E, Wiersema MJ, Clain JE, Norton ID, Levy MJ, Romero Y, Salomao D, Dierkhising R, Zinsmeister AR. Impact of lymph node staging on therapy of esophageal carcinoma. Gastroen-terology 2003;125:1626-35.Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Sundaresan SR, Patterson GA, Cooper JD. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography. Am J Roentgenol 1997;168:417-24.Romagnuolo J, Scott J, Hawes RH, Hoffman BJ, Reed CE, Aithal GP, Breslin NP, Chen RY, Gumustop B, Hennessey W, Van Velse A, Wallace MB. Helical CT versus EUS with fine needle aspiration for ce-liac nodal assessment in patients with esophageal cancer. Gastrointest Endosc 2002;55:648-54.Thompson WM, Halvorsen RA, Jr. Staging esophageal carcinoma II: CT and MRI. Semin Oncol 1994;21:447-52.Ellis FH, Jr., Heatley GJ, Krasna MJ, Williamson WA, Balogh K. Esophagogastrectomy for carcino-ma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria. J Thorac Cardiovasc Surg 1997;113:836-46.Parshad R, Singh RK, Kumar A, Gupta SD, Chattopadhyay TK. Adenocarcinoma of distal esophagus and gastroesophageal junction: long- term results of surgical treatment in a North Indian Center. World J Surg 1999;23:277-83.Sariego J, Mosher S, Byrd M, Matsumoto T, Kerstein M. Prediction of outcome in “resectable” es-ophageal carcinoma. J Surg Oncol 1993;54:223-5.Shao LF, Gao ZG, Yang NP, Wei GQ, Wang YD, Cheng CP. Results of surgical treatment in 6,123 cases of carcinoma of the esophagus and gastric cardia. J Surg Oncol 1989;42:170-4.Czernin J, Phelps ME. Positron emission tomography scanning: current and future applications. Annu Rev Med 2002;53:89-112.Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. J Nucl Med 2001;42:1S-93S.

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Block MI, Patterson GA, Sundaresan RS, Bailey MS, Flanagan FL, Dehdashti F, Siegel BA, Cooper JD. Improvement in staging of esophageal cancer with the addition of positron emission tomography. Ann Thorac Surg 1997;64:770-6.Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, de Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18:3202-10.Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesopha-geal and gastroesophageal malignancy. Br J Cancer 1998;78:521-7.Meltzer CC, Luketich JD, Friedman D, Charron M, Strollo D, Meehan M, Urso GK, Dachille MA, Townsend DW. Whole-body FDG positron emission tomographic imaging for staging esophageal cancer comparison with computed tomography. Clin Nucl Med 2000;25:882-7.Wren SM, Stijns P, Srinivas S. Positron emission tomography in the initial staging of esophageal can-cer. Arch Surg 2002;137:1001-6.

23.

24.

25.

26.

27.

2SYSTEMATIC REVIEW OF THE STAGING PERFORMANCE OF

18F-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY IN ESOPHAGEAL CANCER

HL van Westreenen1

M Westerterp2

PMM Bossuyt3

J Pruim4

GW Sloof5

JJB van Lanschot2

H Groen6

JThM Plukker1

Departments of Surgery1, Nuclear Medicine/PET center4,Office for Medical Technology Assessment6

University Hospital Groningen, The NetherlandsDepartments of Surgery2, Clinical Epidemiology and Biostatistics3,

Nuclear Medicine5

Academic Medical Center, Amsterdam, The Netherlands

Journal of Clinical Oncology 2004;22:3805-12

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CHAPTER 2

ABSTRACTIntroduction: Despite the increasing number of publications concerning 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for staging of esophageal cancer and the increasing availability of this novel diagnostic modality, its exact role in preoperative staging of these tumors is still unknown. The aim of this study was to systematically review the literature regarding the diagnostic performance of FDG-PET in preoperative staging of patients with esophageal cancer and to calculate summary estimates of its sensitivity and specificity.Materials and Methods: The databases of PubMed, Embase and Cochrane were searched for relevant studies. Two reviewers independently assessed the methodological quality of each study. A meta-analysis of the reported sensitivity and specificity of each study was performed.Results: Twelve studies met the inclusion criteria. The studies had several design deficiencies. Pooled sensitivity and specificity for the detection of locoregional metastases were 0.51 (95% CI, 0.34-0.69) and 0.84 (95% CI, 0.76-0.91) respectively. For distant metastases, pooled sensitivity and specificity were 0.67 (95% CI, 0.58-0.76) and 0.97 (95% CI, 0.90-1.0), respectively. Conclusion: FDG-PET showed moderate sensitivity and specificity for the detection of locoregional metastases, and reasonable sensitivity and specificity in detection of distant lymphatic and hematogenous metastases.

19

Systematic Review of FDG-PET in Esophageal Cancer

INTRODUCTIONThe incidence of esophageal carcinoma (EC) has been rising steadily over the 1980s and 1990s. This has been attributed most to the increasing frequency of adenocarcinoma particularly in a preexisting Barrett’s esophagus.1 Surgical resection is currently the best curative treatment in patients without distant metastases and locally advanced tumor growth. However, esophagectomy is associated with a substantial morbidity and mortality and may have a negative impact on quality of life over a period of several months.2 Therefore, conventional imaging techniques are employed to select only patients with resectable disease for esophagectomy. Despite these efforts, metastatic spread is encountered during operation in up to 60% of patients.3-6 As a result, accurate preoperative staging is essential to select those patients who will benefit from surgery and to avoid unnecessary operations in patients with distant metastases. Currently, the most common conventional modalities for staging of EC are endoscopic ultrasonography (EUS) with or without fine needle aspiration (FNA), computed tomography (CT) of the chest, and abdomen and ultrasonography of the neck and abdomen. Occasionally, barium swallow, bronchoscopy, bone scintigraphy and diagnostic laparoscopy with or without laparoscopic ultrasonography are employed. EUS is highly effective to distinguish stages T1 and T2 from stages T3 and T4.7 The accuracy of EUS has increased in combination with FNA to assess nodal involvement, especially of lymph nodes in the celiac trunk region.8 CT plays an important role in detecting distant metastases and in assessing the extent of invasion of surrounding structures by the primary tumor. The main limitations of CT are its insensitivity to the identification of irresectability (T4) and its inability to identify metastatic disease in normal-sized lymph nodes.9,10 Positron emission tomography (PET) is a rapidly developing noninvasive method for staging of various types of cancer.11 The increased glucose metabolism of malignant cells is the rationale behind the common use of FDG as a radiotracer in oncological PET studies.11-14 The use of whole body FDG-PET as a staging method in EC was first described by Yasuda et al.15 This case report was followed by several studies investigating the accuracy, sensitivity and specificity of FDG-PET in staging esophageal carcinoma. These studies have demonstrated that FDG-PET is a promising noninvasive method of detecting both distant nodal and hematogenous metastases, and might thus prevent futile esophagectomies. Despite the increasing number of publications concerning FDG-PET in staging of esophageal cancer, its exact role is still unknown. The aim of this study was to systematically review the available literature regarding the diagnostic performance of FDG-PET in preoperative staging of patients with EC, which might contribute to the development of guidelines for the effective use of PET.

MATERIALS AND METHODSThe systematic review and meta-analysis were conducted according to recently presented guidelines for diagnostic reviews.16-18 After conducting a comprehensive literature search, the methodological quality of all retrieved reports was assessed in terms of the potential for bias and lack of generalizibility of the identified studies.

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CHAPTER 2

A computer-aided search of the databases PubMed/Medline, Embase and Cochrane was conducted in June 2003. We used the search terms ‘positron emission tomography’ and ‘esophageal cancer’ without any language restrictions. All searches were performed using text word or medical subject heading (MeSH). We looked for clinical studies evaluating the diagnostic accuracy of FDG-PET in patients with histologically proven cancer of the esophagus or gastroesophageal junction and studies using pathology or surgery as reference standard. We augmented our computerized literature search by manually reviewing the reference lists of identified studies and relevant reviews. Unpublished data and conference proceedings were not included. Criteria for exclusion were insufficient information to construct 2x2 contingency tables, and duplicate studies on the same patients. Two reviewers (HLvW, MW) independently selected studies for possible inclusion in the review by checking titles and abstracts. The final decision regarding inclusion was based on the full article. Disagreement was resolved in a consensus meeting. Both reviewers independently assessed the methodological quality of the selected studies. The criteria list recommended by the Cochrane Methods Working Group on Systematic Review of Screening and Diagnostic Tests was used.19 Some items on the list were modified for this specific review. The complete criteria list used is shown in Table 1. Internal validity criteria (IV) were scored as ‘positive’ (adequate methods), ‘negative’ (inadequate methods, potential bias), or ‘unclear’ if insufficient information had been provided on a specific item. External validity criteria (EV) were assessed to evaluate generalizibility. Standard performance of FDG-PET was scored ‘positive’ when the type of PET camera, the dose of FDG, the time between injection and scanning and the method of reconstruction were described. The criteria for external validity scored positive if sufficient information was provided to judge generalizibility of findings. After the consensus meeting we decided to score unclear scores as negative. Agreement between both reviewers was quantified by Cohen’s kappa.20 Quality scores were expressed as a percentage of the maximum score. Subtotals were calculated for internal (maximum 6) and external validity (maximum 6) separately. Data on sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FDG-PET in the detection of both locoregional and distant metastases were calculated from the original numbers given in the publications to avoid rounding-off effects. For some articles, which did not present their data according to the TNM classification, the reviewers restaged patients according to the TNM classification if data were presented in a sufficiently detailed manner.21 Numbers of patients with locoregional metastases and distant metastases were placed in a 2x2 table independently by the two reviewers. If data were available for only a subset of patients, those data were included. Meta-analysis was performed using a bivariate random effects approach to pool the sensitivity and specificity for locoregional lymph nodes and distant metastases.22 This model assumes a bivariate normal distribution for the logit-transformed sensitivity and specificity values across studies, allowing for additional heterogeneity between studies due to differences in study characteristics. With this model estimates of the mean logit-transformed sensitivity and specificity were obtained. PPV and NPV were not subjected to

21

Systematic Review of FDG-PET in Esophageal Cancer

this analysis because these values depend on prevalence, which is rarely constant across studies included in a systematic review.23 Summary estimates of sensitivity and specificity with 95% confidence intervals (CI) were calculated after anti-logarithm transformation of these logit estimates. Statistical analyses were executed with the statistical software package SAS version 8.02 (SAS institute Inc., Cary, NC, USA).

RESULTSLiterature searchA total of 119 studies about initial staging of esophageal cancer with FDG-PET were identified. After reviewing the title and the abstract 98 studies had to be excluded. These studies included reviews, case reports, studies reporting on the use of FDG-PET for response evaluation to neoadjuvant therapy or studies comprising other carcinomas besides EC. Of the remaining 21 studies, 9 were excluded after reviewing the full article. Four of these 9 studies were excluded because of reporting data on the same patients.24-27 The other five studies were excluded because of insufficient information to construct a 2x2 table, and because the data of some of these studies were based on number of identified lesions and not on number of identified patients.28-32

Twelve studies met the inclusion criteria. The characteristics of the included studies are shown in Table 2. The total number of patients in a study ranged from 18 to 81 (median, 33 patients). Reported age ranged from 22 to 90 years, and the proportion of male patients ranged from 83% to 100%. Most studies comprised both squamous cell carcinoma and adenocarcinoma. Reference tests consisted of histopathology of resected specimens or

Table 1. Criteria List Used to Assess the Methodological Quality of the Studies

Criteria of Validity Positive score

Internal Validity (IV) 1. Valid reference test Histology, cytology, surgery

2. Blind measurement of FDG-PET without knowledge of reference test Mentioned in publication

3. Blind measurement of reference test without knowledge of FDG-PET Mentioned in publication

4. Avoidance of verification bias Assessment by reference test independent of FDG-PET results

5. FDG-PET interpreted independently of all clinical information Mentioned in publication

6. Prospective study Mentioned in publication

External Validity (EV) 1. Spectrum of disease All stages of disease

2. Demographic information Age and gender information given

3. Inclusion criteria Mentioned in publication

4. Exclusion criteria Mentioned in publication

5. Avoidance of selection bias Consecutive series of patients

6. Standard execution of FDG-PET Type of camera, dose FDG, time interval, reconstruction

FDG: 18F-fluorodeoxyglucose; PET: positron emission tomography

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CHAPTER 2

biopsies obtained during surgical procedures or radiographic follow up.

Methodological quality assessmentMethodological quality was assessed by 12 items for each of the 12 selected studies. There was disagreement in 40 of 144 scores with a Cohen’s kappa of 0.70. Main disagreement was in the questions IV3 and IV5. Disagreements were caused by reading errors and differences in interpretation. The scores for internal and external validity of the 12 selected studies are presented in Table 3. All studies had a valid reference test, but most studies (92%) did not describe whether the reference test was interpreted without knowledge of the FDG-PET findings. In 9 of the 12 studies (75%) verification bias was avoided because patients were

CT: computed tomography; BS: barium swallow; PA: pathology; EUS: endoscopic ultrasound; US: ultrasound (external); FU: follow-up (radiographic); SD: standard deviation

IV1-IV6: six criteria for internal validity (IV; see Table 1); EV1-EV6: six criteria for external validity (EV; see Table 1)

Table 2. Characteristics of the 12 Included Studies

Study Year No. of

Patients Sex

(male/female) Age Histology

(adeno/squamous/other) Preoperative Work-Up No. of Excluded

Patients Reference

Test

Block et al 1997 58 42/16 Range, 44-84 34/22/2 CT, Chest X-ray, BS, endoscopy, 1 PA

Kole et al 1998 26 22/4 Range, 41-76 21/4/1 CT, EUS PA

Rankin et al 1998 19 - - 13/6/- CT 6 PA

Kobori et al 1999 33 28/5 Range, 50-81 - endoscopy PA

Choi et al 2000 48 45/3 Range, 46-77 -/48/-

CT, EUS, bone scintigraphy,

bronchoscopy, US of neck 13 PA

Flamen et al 2000 74 - - 53/21/-

CT, EUS, BS, bronchoscopy,

US of neck PA/FU

Meltzer et al 2000 47 39/8 Mean ± SD, 63�10 37/10/- CT 20 PA/surgery

Jager et al 2001 18 15/3 Range, 22-75 11/4/3 - PA

Junginger et al 2002 30 25/5 Median, 63 16/14/- CT PA

Kato et al 2002 32 29/3 Range, 42-76 -/32/- CT, EUS, BS, bone scintigraphy PA

Wren et al 2002 24 24/- Mean ± SD, 66�11 15/7/2 - 30 PA/FU

Yoon et al 2003 81 78/3 Range, 31-90 -/81/- CT 55 PA

Table 3. Quality Assessment of the 12 Diagnostic Studies Included in the Present Review

Internal Validity External Validity Total IV Total EV % of Maximum

Study Year IV1 IV2 IV3 IV4 IV5 IV6 EV1 EV2 EV3 EV4 EV5 EV6 Score Score Score

Block et al 1997 + + + - + - + + - - + + 4 4 67%

Kole et al 1998 + + - + + + + + + - + + 5 5 83%

Rankin et al 1998 + + - + + + - - + - - + 5 2 58%

Kobori et al 1999 + + - - + + + + - - - + 4 3 58%

Choi et al 2000 + + - - + + - + - - + + 4 3 58%

Flamen et al 2000 + + - + + + + - + + - + 5 4 75%

Meltzer et al 2000 + + - + + - + + - + + + 4 5 75%

Jager et al 2001 + + - + + + + + - - + + 5 4 75%

Junginger et al 2002 + + - + - + + + - - - + 4 3 58%

Kato et al 2002 + - - + - - - + + - - + 2 3 42%

Wren et al 2002 + - - + - - + + - - - - 2 2 33%

Yoon et al 2003 + + - + + + - + - + + + 5 4 75%

23

Systematic Review of FDG-PET in Esophageal Cancer

selected for assessment by the reference test independently of the FDG-PET results (IV4). Eight studies were prospective (67%) and in six studies (50%) the patients entered the study consecutively. In a majority of the selected studies (67%), all stages of disease were included. Only in a minority of studies were the inclusion (33%) and exclusion (25%) criteria described. The total score for the combined internal and external validity, expressed as a fraction of the maximum score, ranged from 33% to 83% with a median of 63%. Ten of the 12 studies had a total score above 50%.

AnalysisFor all studies, a 2x2 table was constructed regarding the detection of locoregional lymph node metastases (N stage) and distant hematogenous and/or distant lymph node metastases (M stage). Supraclavicular, celiac, retroperitoneal and nonadjacent lymph nodes as defined in the study of Block et al were classified as distant lymph nodes (M1).33 The celiac nodes reported by Kole et al were considered N1 disease because of insufficient details. However, the supraclavicular nodal involvement was sufficiently described and considered as distant metastases.34 Rankin et al provided detailed information about periesophageal and left gastric lymph nodes only. Therefore, this study was entered in the analysis only concerning the N stage of disease.35 For both Kobori et al and Kato et al, the involvement of cervical and abdominal lymph nodes was classified as M1 disease, all other nodes were considered N1 disease.36,37 Common hepatic, celiac and para-aortic lymph nodes were classified M1 disease in the study presented by Choi et al. The remaining nodes were staged as N1 disease.38 N and M stage were presented according to the revised TNM classification in the studies of Junginger et al and Wren et al.39,40 Meltzer et al did not describe in detail the N and M stage. Therefore, the nodal staging was scored as N disease and distant metastases as M disease.41 The description in the studies of Flamen et al, Jager et al and Yoon et al enabled restaging of patients to the revised classification.42-44 The studies of Kobori et al, Choi et al, Kato et al and Yoon et al only described locoregional and distant lymph nodes. Distant hematogenous metastases had not been detected in their series. The data of each study and the results of the statistical pooling are shown in Tables 4 and 5 for N stage and M stage, respectively. The total number of patients included for analysis concerning N stage was 421 and the ranges of sensitivity, specificity, PPV and NPV were 0.08 to 0.92, 0.67 to 1.00, 0.70 to 1.00, and 0.64 to 1.00, respectively. The overall pooled sensitivity was 0.51 (95% CI, 0.34 to 0.69), and pooled specificity 0.84 (95% CI, 0.76 to 0.91) for staging locoregional lymph node involvement. The median prevalence of locoregional lymph node metastasis was 0.55, with PPV and NPV of 0.60 and 0.46, respectively. Sensitivity and specificity for distant metastases (M stage) were determined in 452 patients in 11 studies. Sensitivity, specificity, PPV and NPV ranged from 0.33 to 1.00, 0.90 to 1.00, 0.60 to 1.00, and from 0.24 to 0.88, respectively. The overall pooled sensitivity and specificity for M stage were 0.67 (95% CI, 0.58 to 0.76), and 0.97 (95% CI, 0.90 to 1.0), respectively. The median prevalence of distant lymph node and organ metastasis was 0.36, with PPV and NPV of 0.92 and 0.83, respectively.

24

CHAPTER 2

DISCUSSIONThis systematic review and meta-analysis included 12 studies concerning the value of FDG-PET in the staging performance for both locoregional and distant metastases in patients with newly diagnosed cancer of the esophagus or gastroesophageal junction. The included studies had a moderate methodological quality score, with a median of 63% for combined internal and external validity. Pooled sensitivity and specificity for the detection of locoregional metastases were 0.51 and 0.84, respectively. For the detection of distant metastases, pooled sensitivity and specificity were 0.67 and 0.97, respectively.

Table 4. Parameters of Diagnostic Accuracy of FDG-PET for the Detection of Locoregional Lymph Node Metastases (N stage)

Sensitivity Specificity Positive Predictive Value Negative Predictive Value

Study Year Value 95% CI Value 95% CI Value 95% CI Value 95% CI Prevalence

Block etal 1997 0.58 0.39-0.78 0.87 0.73-1.01 0.82 0.64-1.01 0.67 0.44-0.89 0.51

Kole et al 1998 0.92 0.78-1.01 0.88 0.65-1.10 0.92 0.78-1.07 0.88 0.70-1.06 0.62

Rankin et al 1998 0.38 0.12-0.65 0.67 0.29-1.04 0.71 0.38-1.05 0.33 -0.02-0.68 0.68

Kobori et al 1999 0.35 0.13-0.58 0.88 0.71-1.04 0.75 0.45-1.05 0.56 0.22-0.90 0.52

Choi et al 2000 0.82 0.68-0.96 0.85 0.69-1.01 0.89 0.76-1.01 0.77 0.61-0.93 0.58

Flamen et al 2000 0.19 0.00-0.38 0.85 0.65-1.04 0.60 0.17-1.03 0.46 0.02-0.90 0.55

Meltzer et al 2000 0.43 0.27-0.59 0.83 0.62-1.04 0.88 0.73-1.04 0.33 0.11-0.56 0.74

Jager et al 2001 0.08 -0.07-0.24 1.00 - 1.00 - 0.35 -0.58-1.29 0.67

Junginger et al 2002 0.38 0.17-0.59 1.00 - 1.00 - 0.24 -0.06-0.53 0.84

Kato et al 2002 0.67 0.43-0.91 0.88 0.73-1.04 0.83 0.62-1.04 0.75 0.51-1.00 0.47

Wren et al 2002 0.71 0.38-1.05 0.86 0.67-1.04 0.71 0.38-1.05 0.86 0.60-1.12 0.33

Yoon et al 2003 0.64 0.49-0.79 0.69 0.55-0.83 0.66 0.51-0.81 0.67 0.53-0.82 0.48

Pooled estimate 0.51 0.34-0.69 0.84 0.76-0.91 - - - - -

Table 5. Parameters of Diagnostic Accuracy of FDG-PET for the detection of Distant Lymph Node and Organ Metastases (M stage)

Sensitivity Specificity Positive Predictive Value Negative Predictive Value

Study Year Value 95% CI Value 95% CI Value 95% CI Value 95% CI Prevalence

Block et al 1997 0.65 0.42-0.87 0.97 0.90-1.03 0.92 0.76-1.07 0.83 0.62-1.04 0.36

Kole et al 1998 1.00 - 0.95 0.85-1.05 0.78 0.33-1.17 1.00 - 0.13

Rankin et al 1998 - - - - - - - - -

Kobori et al 1999 0.87 0.70-1.04 0.94 0.84-1.05 0.93 0.79-1.06 0.90 0.73-1.05 0.45

Choi et al 2000 0.56 0.32-0.81 1.00 - 1.00 - 0.82 0.73-1.05 0.33

Flamen et al 2000 0.74 0.59-0.88 0.90 0.81-0.99 0.86 0.74-0.99 0.80 0.65-0.95 0.46

Meltzer et al 2000 0.70 0.42-0.98 0.92 0.83-1.01 0.70 0.42-0.98 0.92 0.75-1.09 0.22

Jager et al 2001 0.80 0.45-1.51 1.00 - 1.00 - 0.93 0.68-1.18 0.28

Junginger et al 2002 0.33 0.07-0.60 1.00 - 1.00 - 0.64 0.17-1.11 0.46

Kato et al 2002 0.71 0.48-0.95 1.00 - 1.00 - 0.82 0.58-1.06 0.44

Wren et al 2002 0.67 0.40-0.93 0.92 0.76-1.07 0.89 0.68-1.09 0.73 0.44-1.02 0.50

Yoon et al 2003 0.43 0.06-0.80 0.99 0.96-1.01 0.75 0.33-1.17 0.95 0.73-1.17 0.09

Pooled estimate 0.67 0.58-0.76 0.97 0.90-1.0 - - - - -

25

Systematic Review of FDG-PET in Esophageal Cancer

The results of this systematic review should be interpreted with caution because of several limitations. First, the included studies have limited methodological quality. In these studies it was not clear whether the reference test was interpreted independently of the index test, which might lead to diagnostic bias. In general, this leads to overestimation of the diagnostic accuracy.45 The retrospective design in four studies as well as the interpretation of FDG-PET with other available clinical information available further decreased the methodological quality. In three studies there was verification bias, because the reference test was assessed on patients selected by the index test results, which can lead to overestimation of the sensitivity. While common in clinical practice, diagnostic studies should avoid this preferential ordering of a gold standard test.46 Another type of bias related to patient selection is spectrum bias, which occurs when the test performance in the research population differs from that seen in day-to-day customary care.47 This type op bias was present in three studies, which did not include all stages of disease. To improve the methodological quality in reporting of diagnostic studies, the new standards for reporting of diagnostic accuracy (STARD) checklist will be a useful and perhaps an obligatory resource.48 Unfortunately, most studies did not stage their patients according to the TNM classification. Many studies did not enable to stage all patients consistently as having locoregional or distant lymph node metastases. Celiac trunk metastases were considered as N disease in some studies, but M disease in others.33,34,36-38,40 Therefore, analysis was performed excluding the 4 studies34,36,37,41 that did not enable staging according to the UICC classification, yielding a pooled sensitivity and specificity for N stage of 0.47 (95% CI, 0.22 to 0.71) and 0.83 (95% CI, 0.71 to 0.95), respectively. Sensitivity and specificity regarding M stage were 0.61 (95% CI, 0.48 to 0.75) and 0.97 (95% CI, 0.84 to 1.0), respectively. This analysis showed a slightly lower sensitivity for detection of locoregional (N stage) and distant metastases (M stage). Studies reporting on the staging of esophageal cancer should therefore use the UICC classification to prevent confusion, especially about distant lymphatic disease.21

The pooled sensitivity and specificity of FDG-PET for the detection of locoregional metastases were low, 0.51 and 0.84, respectively. Reasons for this may be the inhomogenous tracer uptake in the primary tumor, masking of adjacent lymph nodes by tracer accumulation in the primary tumor and the occurrence of false-positive findings due to chronic inflammation.24,49,50 In both day-to-day clinical practice and in ongoing clinical trials, the presence or absence of lymph node metastases may have an impact on systemic treatment selection. Because of the moderate sensitivity for the detection of lymph node metastases, FDG-PET alone does not appear to be suitable for the allocation of neoadjuvant therapy in these patients. Currently, EUS combined with FNA is the first choice modality to assess locoregional lymph node involvement.42,51,52 The pooled sensitivity and specificity for the detection of distant lymph node metastases and hematogenous metastases was 0.67 and 0.97, respectively. The interpretation of these reasonable results is complicated by the heterogeneity of the M stage in this review, as mentioned earlier. Of the 11 included studies, 2 had conspicuously low sensitivity for the detection of distant metastases.39,44 Yoon et al attributed the low sensitivity in their study to the inclusion criteria. More cases of early-stage disease, and therefore more patients with only microscopic metastatic foci, might have been included in their study. Junginger et al argued that the uptake of FDG is low in smaller tumors and in tumors obtaining most of their energy from metabolic pathways other than glycolysis, which might explain the low

26

CHAPTER 2

sensitivity they reported.36 Exclusion of both outliers from the present meta-analysis results in a pooled sensitivity of 0.72 and pooled specificity of 0.95. In contrast to the N stage of disease, M stage directly influences the clinical management of esophageal cancer. The presence of distant hematogenous metastases excludes a curative intended surgical, leading to a palliative nonsurgical treatment as the only treatment option.53 The optimal management of patients with positive celiac trunk nodes is still a matter of debate.54,55 For many years, CT has been the first-line method to detect distant metastases in EC with a sensitivity of 37% to 66%.34,51,56 Later on, EUS was introduced and became the most reliable method for determining T stage and identifying pathological involvement of regional lymph nodes. EUS combined with FNA enabled selective aspiration of echographically suspected nodes, including those at the celiac trunk.9 Sensitivity, specificity, positive predictive value and negative predictive value for the assessment of celiac lymph nodes are ranging from 53% to 98%, 77% to 100%, 79% to100%, and 82% to100%, respectively.9,57-60 Different studies have shown a high accuracy of FDG-PET. However, the hallmark for implementation in diagnostic work-up is the ability to change patient management due to more accurate staging. Of the included studies, the change in patient management ranged from 3% to 20% due to addition of FDG-PET to preoperative work-up.33,34,39-42 However, these studies involved only a limited number of patients. PET may be cost-effective in the prevention of noncurative surgery by detecting metastases not identified by conventional staging modalities.60 Recently, the spatial resolution of CT has increased by a multislice technique. Therefore, in future studies FDG-PET should preferably be compared to multislice CT after an obligate EUS-FNA examination. In this systematic review, FDG-PET was found to have moderate sensitivity and specificity in the detection of locoregional lymph node metastases, with considerable heterogeneity across the included studies. In the detection of distant nodal and hematogenous metastases, FDG-PET has reasonable sensitivity and specificity, with a lower degree of heterogeneity. As M stage determines patient management, we feel that the potential contribution of FDG-PET to staging should carry more weight than its role in N staging when deciding whether or not to implement FDG-PET in the standard preoperative work-up of patient with esophageal cancer. Larger prospective studies should quantify to what extent the routine use of FDG-PET leads to changes in management and better health care for these patients.

ACKNOWLEDGMENTThis study was supported by a ZonMw program for Health Care Efficiency Research.

27

Systematic Review of FDG-PET in Esophageal Cancer

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3ESOPHAGEAL CANCER: CT, EUS, AND FDG-PET FOR

ASSESSMENT OF RESPONSE TO NEOADJUVANT THERAPY - SYSTEMATIC REVIEW

M Westerterp1

HL van Westreenen2

JH Reitsma3

OS Hoekstra4

PL Jager5

J Stoker6

P Fockens7

BL van Eck-Smit8

JThM Plukker2

JJB van Lanschot1

GW Sloof8

Departments of Surgery1, Clinical Epidemiology and Biostatistics3,Radiology6, Gastroenterology7, Nuclear Medicine8

Academic Medical Center, Amsterdam, The NetherlandsDepartment of Nuclear Medicine4, VU Medical Center, Amsterdam,

The NetherlandsDepartments of Surgery1, Nuclear Medicine/PET center5

University Hospital Groningen, The Netherlands

Radiology 2005;236;841-851

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ABSTRACTIntroduction: To compare diagnostic accuracy of computed tomography (CT), endoscopic utrasonography (EUS), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for assessment of response to neoadjuvant therapy in patients with esophageal cancer by using a systematic review of the literature.Materials and Methods: Medline and Embase databases and Cochrane Database of Systematic Reviews were searched for relevant studies. Two reviewers independently assessed the methodological quality of each study. Summary receiver operating characteristic (ROC) analysis was used to summarize and compare the diagnostic accuracy of the three modalities.Results: Four studies with CT, 13 with EUS, and seven with FDG-PET met inclusion criteria. Percentages of maximum score in regard to methodological quality ranged from 15% to 100%. Summary ROC analysis could be performed for three studies with CT, four with EUS, and four with FDG-PET. The maximum joint values for sensitivity and specificity were 54% for CT, 86% for EUS, and 85% for FDG-PET. Accuracy of CT was significantly lower than that of FDG-PET (P < 0.006) and of EUS (P < 0.003). Accuracy of FDG-PET and that of EUS were similar (P = 0.839). In all patients, CT was always feasible, whereas EUS was not feasible in 6% of the patients, and FDG-PET was not feasable in less than 1% of the patients.Conclusion: CT has poor accuracy for assessment of response to neoadjuvant therapy in patients with esophageal cancer. EUS and FDG-PET have equivalent good accuracy, but EUS is not always feasible after chemotherapy and radiation therapy. FDG-PET seems to be a promising noninvasive tool for assessment of neoadjuvant therapy in patients with esophageal cancer.

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INTRODUCTIONEsophageal cancer (EC) has an unfavorable prognosis among digestive tract malignancies.1,2,3

The best option for curative treatment for patients with esophageal cancer is radical surgery4, with a long-term survival of only 25%.5,6 Therefore, various forms of neoadjuvant or adjuvant multimodality therapy have been evaluated in an effort to improve these survival results. Neoadjuvant therapy is aimed at the eradication of lymphatic and/or hematogenous micrometastases and metastases, with improvement of survival, and at shrinkage of the primary tumor, with an improved radical resectability rate. At many institutions, neoadjuvant chemotherapy and radiation therapy is applied to improve long-term outcome, especially after the recent publication of favorable long-term results of a randomized trial from the Medical Research Council Oesophageal Cancer Working Group, in which neoadjuvant chemotherapy followed by surgery was compared with surgery alone.7 In a large proportion of patients, however, an insufficient objective response is achieved. These patients do not benefit from neoadjuvant therapy but suffer from toxic side effects while appropriate surgical therapy is delayed. For this reason, a diagnostic test that can accurately predict tumor response early in the course of neoadjuvant therapy is of crucial importance. Currently, there is no universally accepted, reproducible, and reliable means of monitoring the response of esophageal cancer to chemotherapy.Response to therapy currently is evaluated by using morphological imaging, such as computed tomography (CT), and endoscopic ultrasonography (EUS).8-10 General restrictions of these methods are the difficulty in distinguishing viable tumor from necrotic or fibrotic tissue and the delay between cell kill and tumor shrinkage.6,11,12

With 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), alterations in tissue metabolism that generally precede anatomic change are reflected. FDG preferentially accumulates in cells with high rates of glucose utilization (e.g. the brain, the myocardium, and most solid malignancies). The accumulation of FDG in tumor cells can be measured noninvasively by using PET. There are various approaches for analytical methods ranging from visual assessment (qualitative) to semiquantitative indices (e.g. standardized uptake value (SUV)). FDG-PET has been shown to be sensitive in the imaging of several malignancies (e.g. lymphoma, lung cancer, colorectal cancer, and head and neck cancer) and has been shown to be promising for detection of the response to nonsurgical therapy in breast cancer.13 Thus, the purpose of our study was to compare the diagnostic accuracy of CT, EUS, and FDG-PET for the assessment of the response to neoadjuvant therapy in patients with esophageal cancer by using a systematic review of the literature.

MATERIALS AND METHODSSearch strategy and inclusion criteria Two authors (MW and HLvW) independently performed a formal computer-assisted search of the medical databases Medline (January 1980 to January 2004), Embase (January 1980 to January 2004), and for the Cochrane Database of Systematic Reviews (January 1980 to January 2004). The following keywords, including comparable synonyms, and medical subject heading were used: ‘positron emission tomography’, ‘computed tomography’,

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‘endosonography’, ‘esophageal cancer’ and ‘neoadjuvant therapy OR response’ without any language restrictions. A manual search with cross-reference of the eligible articles was performed to identify additional relevant articles. We did not include conference abstracts because of the limited data presented in them. The same two authors independently assessed articles for possible inclusion in the review by checking titles and abstracts. Included were clinical studies that fulfilled all the following inclusion criteria: evaluation of CT, EUS or FDG-PET in the assessment of the response to neoadjuvant therapy (before and after therapy); histologic proof of cancer of the esophagus, gastroesophageal junction or gastric cardia; use of a valid reference standard (i.e. pathologic findings); and a number of patients of 10 or greater. Duplicate studies involving the same patients were excluded. The final decision about inclusion was based on the full article. Disagreement was resolved in a consensus meeting.

Quality assessmentThe same two reviewers who performed the search and assessed publications for inclusion independently assessed the methodological quality of the included studies. They used the list of criteria recommended by the Cochrane Methods Working Group on Systematic Review of Screening and Diagnostic Tests, with some modifications.14 The complete list of criteria is shown in Table 1. Internal validity criteria were assigned a score of positive (adequate methods), negative (inadequate methods, potential for bias), or unclear (if insufficient information had

Table 1. Criteria List Used to Assess the Methodological Quality of the Studies

Criteria of Validity Positive score

Internal Validity (IV) 1. Valid reference test Responders and nonresponders defined on histopathology

2. Definition of index test Responders and nonresponders defined

3. Blind measurement of technique without knowledge of reference test Mentioned in publication

4. Blind measurement of reference test without of technique Mentioned in publication

5. Avoidance of verification bias Assessment by reference test independent of CT, EUS or FDG-PET results

6. Technique interpreted independently of all clinical information Mentioned in publication

7. Prospective study Mentioned in publication

External Validity (IV)1. Spectrum of disease Stages of disease eligible for curative surgery

2. Demographic information Age and gender information given

3. Inclusion criteria Mentioned in publication

4. Exclusion criteria Mentioned in publication

5. Avoidance of selection bias Consecutive series of patients

6. Description of index test Sufficient details to permit replication of the test

CT: computed tomographyEUS: endoscopic ultrasonographyFDG: 18F-fluorodeoxyglucosePET: positron emission tomography

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been provided about a specific item). External validity criteria were assessed to evaluate generalizibility. The criteria for external validity were assigned a positive score if sufficient information was provided to judge generalizibility of findings. Description of the index test was assigned a positive score when sufficient details were described to permit replication of the test. After the consensus meeting, it was decided to change unclear scores to negative scores. Quality scores were expressed as a percentage of the maximum score. Subtotals were calculated for internal validity (maximum score, seven) and external validity (maximum score, six) criteria separately.

Data and statistical analysis For all included studies, an attempt was made to extract the 2x2 table that was created with cross-classification of the patients based on the results of CT, EUS, and FDG-PET and the final outcome that was confirmed with the reference standard (histologic findings). From these tables, we calculated sensitivity and specificity, together with exact 95% confidence intervals, on the basis of the binomial distribution for each study. Forrest plots were used to present data. For each study, we plotted the pairs of sensitivity and specificity in receiver operating characteristic (ROC) space and used the approach of Moses et al, Littenberg and Moses, and Irwig et al to summarize the data by fitting the summary ROC curve.15,16 This method models test accuracy, defined by the log diagnostic odds ratio (D), as a linear function of the test threshold (S). S represents the (implicit) threshold for a positive test result for each study. The model D = a + bS was used to capture the variation in diagnostic odds ratio caused by differences in test threshold between studies. This model was fitted using equally weighted least squares regression because this produces results that are more consistent with a random-effects approach and allows additional variance in accuracy beyond the test threshold and sampling error.17 We transformed the regression line back to the original ROC space to obtain the summary ROC curve. Because the log odds ratio is difficult to interpret clinically, we expressed the results in terms of the maximum joint sensitivity and specificity, also known as the Q-point. This is the point on the summary ROC curve closest to the optimal upper left corner of the ROC plot. It is also the point where sensitivity equals specificity. We used the Q-point to test for a difference in accuracy between techniques. This test was directly derived from the model by comparing the diagnostic odds ratio at S=0 among the three modalities. For clinical purposes, however, a high negative predictive value of a modality is necessary to avoid erroneous discontinuation of neoadjuvant therapy. Therefore, the predicted value of specificity at a high value of sensitivity of 90% was calculated from the summary ROC regression line. A difference with a two-sided P value less than 0.05 was considered significant. To avoid division by zero in the calculation of the diagnostic odds ratio, the standard correction of adding 0.5 to all four cells of the 2x2 table was applied when one of the four cells contained a zero. Statistical analyses were performed by using a statistical software system (SAS Institute Inc., version 8.02, Cary, NC, USA).

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N: number of patients included; ‡ number of excluded patients; M/F: male/female; AC/SCC: adenocarcinoma/squamous cell carcinoma; PA: pathology; CT: chemotherapy; CRT: chemoradiotherapy; MCSA: maximal cross-sectional area; ECOG: Eastern Cooperative Oncology Group solid tumor response criteria; WHO: World Health Organisation criteria; JSED: Japanese Society for Esophageal Diseases; SUV: standardized uptake value; delta-TUR: tumor to liver uptake ratio; SKM: simplified kinetic method; NLR: non linear regression; #: median; § mean

Table 2. Characteristics of the Included Studies

Modality N Excluded‡ M/FAge

(range) Histology

(AC/SCC/other) Therapy Stage of disease

Modality response

PA response

Prevalence responders

CT

Walker 1991 38 - 32/6 45-73 19/15/4 CT I-III Miller et al Other

ROC analysis

Griffith 1999 45 - - - 45/-/- CRT I-IV MCSA Mandard 24%

Jones 1999 50 - 34/16 43-81 12/38/- CRT I-IIB ECOG Other 42%

Kroep 2003 13 2 12/1 50-69 11/1/1 CT III WHO Mandard 36%

EUS

Rice 1992 13 2 13 50-69 13/-/- CT IIA-IV Restaging Not defined

Hordijk 1993 11 1 7/4 55-75 -/11/- CT I-III Restaging Not defined

Dittler 1994 18 - - - -/-/- CT III Restaging Not defined

Isenberg 1998 31 8 22/9 62§ 19/12/- CRT II-III Restaging MCSA Not defined

Bowrey 1999 17 - 10/7 47-72 10/7/- CRT IIB-III Restaging Not defined

Laterza 1999 87 25 - - -/87/- CRT I-III Restaging Not defined

Zuccaro 1999 59 - - 30-77 41/18/- CRT I-III Restaging Not defined

Beseth 2000 26 6 24/2 38-74 24/2/- CRT I-III Restaging Not defined

Chak 2000 59 - 44/15 61# 36/23/- CRT II-III MCSA Not defined

ROC analysis

Hirata 1997 34 7 28/6 51-75 -/34/- CRT II-III MCSA JSED 48%

Giovannini 1997 32 6 28/4 38-70 7/25/- CRT II-III Restaging Other 38%

Willis 2002 41 - 32/9 29-76 28/12/1 CRT II-III MCSA Mandard 56%

Kroep 2003 13 2 12/1 50-69 11/1/1 CT III Restaging Mandard 42%

PET

Arslan 2002 24 - 24/0 36-82 22/2/- CRT I-III SUV Other

Kato 2002 10 - 8/2 36-77 -/10/- CRT III SUV JSED

Downey 2003 39 22 34/5 36-76 26/13/- CRT I-III SUV Not defined

ROC analysis

Brucher 2001 27 3 23/4 38-61 -/27/- CRT II-III SUV Mandard 54%

Weber 2001 40 3 37/3 44-66 40/-/- CT III SUV Mandard 24%

Flamen 2002 36 - 28/8 60# 29/7/- CRT III Delta TUR Other 39%

Kroep 2003 13 3 12/1 50-69 11/1/1 CT III SUV/SKM/NLR Mandard 40%

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Table 3. Quality Assessment of the Diagnostic Studies

Internal Validity External Validity Total IV Total EV % of Max

Study Year IV1 IV2 IV3 IV4 IV5 IV6 IV7 EV1 EV2 EV3 EV4 EV5 EV6 score score score

CT

Walker 1991 + + - - + - + + + - - - - 4 2 46%

Griffith 1999 + + + - + - + - - - - - + 5 1 46%

Jones 1999 + + + + + + - + + + + + + 6 6 92%

Kroep 2003 + + - + + - + + + + + + - 5 5 77%

Median 62%

EUS

Rice 1992 - - + - + - + - + + + - + 3 4 54%

Hordijk 1993 - - + - + - + + + + + - + 3 5 62%

Dittler 1994 - - - - - - + + - - - - - 1 1 15%

Giovannini 1997 - + - - + - - + + + - - + 2 4 46%

Hirata 1997 + + + - + - - + + + - - + 4 4 62%

Isenberg 1998 - + + - + - - + + + - - + 3 4 54%

Bowrey 1999 - - + - + - - + + + + - + 2 5 54%

Laterza 1999 - - + - + - + + - + + - + 3 4 54%

Zuccaro 1999 - - + + + - + + + + + - + 4 5 69%

Beseth 2000 - - + - - - - + + - - - + 1 3 31%

Chak 2000 - + + - + - - + + + + - + 3 5 62%

Willis 2002 + + + + + - + + + + - + + 6 5 85%

Kroep 2003 + + - + + - + + + + + + - 5 5 77%

Median 54%

PET

Arslan 2002 + + - - + - + + + + - - + 4 4 62%

Kato 2002 + + - + + - - + + - - - + 4 3 54%

Downey 2003 - + + - + + + + + - - - - 5 2 54%

Brucher 2001 + + + + + - + + + + + - + 6 5 85%

Weber 2001 + + + - + + + + + + + + - 6 5 85%

Flamen 2002 + + + - + + + + + + + + + 6 6 92%

Kroep 2003 + + + + + + + + + + + + + 7 6 100%

Median 85%

IV1-IV7: 7 criteria for Internal Validity; EV1-EV6: 6 criteria for External Validity; Total IV: total score of Internal Validity;Total EV: total score of External ValidityThe + and – symbols indicate the presence or absence of the criteria for internal or external validity.

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RESULTS Literature searchWith our initial search, we identified 58 studies about CT, 26 studies about EUS, and 26 studies about FDG-PET. After reviewing the title and the abstract of these studies, some studies were excluded: 53 studies with CT, 12 studies with EUS, and 15 studies with FDG-PET. These studies included narrative reviews, case reports, studies in which researchers reported the use of these modalities for initial staging, and studies in which carcinomas other than esophageal cancer were included. Five studies were potentially relevant to the value of CT in the monitoring of a response. Of these remaining five studies, the study by Helmberger et al18 was excluded because of the absence of a valid reference standard. In that study, CT during neoadjuvant therapy was compared with endoscopy, although the value of endoscopy in the monitoring of the response to therapy is still debatable. Thus, only four studies with CT met the inclusion criteria.19-22

In the case of EUS, 14 studies were potentially relevant to the value of therapeutic response assessment. The study by Nousbaum et al23 was excluded because of the absence of a valid reference standard; the authors used recurrence instead of histologic findings as the reference standard. Thus, 13 studies with EUS met the inclusion criteria.21,24-35

For studies with FDG-PET, 11 were potentially relevant to the value of therapeutic response assessment. Of these 11 studies, four were excluded after a review of the full article. One study was excluded because of the absence of a baseline FDG-PET image.36 Couper et al compared FDG-PET during neoadjuvant therapy with CT and changes in weight and dysphagia scores.37 Since the value of CT in monitoring response is still under discussion, it is not suitable to be used as a reference standard. Another two studies were excluded because one comprised carcinomas other than esophageal cancer and one included fewer than 10 patients with esophageal cancer.38,39 Thus, seven studies met the inclusion criteria.21,40-45 The characteristics of the included studies are shown in Table 2.

Methodological quality assessment Thirteen methodological quality items were assessed for each of the 24 studies (Table 3). There was disagreement in 20 out of 312 items that were assigned a score. Disagreement was most frequent for internal validity criterion 4 and internal validity criterion 5, mainly because of reading errors and/or differences in interpretation. The percentage of maximum score for the combined internal and external validity ranged from 15% to 100%, with a median of 62% for studies with CT, 54% for those with EUS, and 85% for those with FDG-PET. Most studies were assigned a positive score for avoidance of verification bias (internal validity criterion 5 with positive score: 22 of 24 studies = 92%), inclusion of right spectrum of disease (external validity criterion 1 with positive score: 22 of 24 studies = 92%), and provision of sufficient demographic information (external validity criterion 2 with positive score: 21 of 24 studies = 88%). For most studies, performance was poor in regard to avoidance of selection bias because a consecutive series of eligible patients was not included (external validity criterion 5 with positive score: seven of 24 studies = 29%). Quality of studies with FDG-PET was high for definition of the reference test (internal validity criterion 1: six of seven = 86% versus three of four = 75% for studies with CT and only

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four of 13 = 31% for studies with EUS) and definition of the index test (internal validity criterion 2: seven of seven = 100% versus only six of 13 = 46% for studies with EUS). The latter item was also present in all studies with CT.

Studies with CTWalker et al evaluated 38 patients with esophageal cancer by using CT and a barium swallow study before and after completion of preoperative chemotherapy.22 Chemotherapy consisted of a combination of fluorouracil, doxorubicin hydrochloride, (Adriamycin), and mitomycin (n = 15 patients), also known as FAM; a combination of mitomycin, ifosfamide, and cisplatin (n = 19 patients), also known as MIC; or a combination of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, methotrexate, and etoposide (n = 4), also known as CAPOMET. Radiographic response was assessed according to the criteria of Miller et al.47 Pathologic response was defined as follows: complete microscopic response (no microscopic evidence of residual tumor); complete macroscopic response (no visible evidence of residual tumor); partial response (unequivocal signs of healing); no response (no substantial signs of healing). A response to therapy, either partial or complete, was found in 94% (n = 36) of the patients, and 48% (n = 18) of all patients showed a response at CT. Griffith et al assessed the therapeutic response by using spiral CT after completion of two courses of fluorouracil and cisplatin in 45 patients with squamous cell carcinoma.19 Response to therapy was defined as a volume reduction of more than 50%. The pathologic response was assessed according to the criteria of Mandard et al.47 According to these criteria, 24% (n = 11) of patients were responders. Griffith et al did not find a correlation between tumor volume reduction at serial CT and quantitative pathologic tumor assessment, nor did they find a correlation between tumor volume reduction and survival. Jones et al assessed the value of CT for tumor response assessment in 50 patients with esophageal cancer who were treated with fluorouracil and cisplatin, whereas in 12 patients, paclitaxel was added to the regimen. Radiographic response was determined by using the response criteria for solid tumors of the Eastern Cooperative Oncology Group. Pathologic response was defined as follows: no tumor (42% for responders) and tumor present (58% for nonresponders). CT had a sensitivity of 33% and a specificity of 66% in accurate evaluation of the pathologic response of the tumor to chemoradiation therapy. Kroep et al evaluated 13 patients with esophageal cancer who were treated with neoadjuvant cisplatin and gemcitabine plus granulocyte macrophage colony-stimulating growth factor.21 CT assessment of the therapeutic response was determined, according to World Health Organization criteria.46 A pathologic response was observed in 36% of the patients, as assessed according to criteria of Mandard et al.47 Both early (after two cycles of neoadjuvant therapy) and late (after completion of neoadjuvant therapy) response evaluation showed a specificity of 50% and a sensitivity of 71%.

Studies with EUSIn nine studies with EUS that were included, restaging, which was indicated by a change in tumor stage, was used as a parameter for assessment of neoadjuvant therapeutic response. In three EUS studies, change in volume measurements of the maximum tumor cross-sectional dimensions was used as a parameter for assessment.21,24-35 Researchers in one study evaluated both restaging and volume measurements.31 These are different parameters and, thus,

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evaluation of the results was interpreted separately.

RestagingIn seven of nine studies, a test definition was not described in regard to restaging with EUS after neoadjuvant therapy.24,25,27,30-33,35 Before and after therapy, staging with the TNM classification was described properly, but the definition of responders or nonresponders was not described. Therefore, the value of EUS for the monitoring of a response in these studies could not be determined. Accuracy in regard to tumor staging after completion of therapy, however, can be determined and ranged from 27% to 82%, with a median of only 48%. Giovannini et al described a test definition.28 Thirty-two patients were included in that study. Complete EUS was not performed in six of the 32 patients before therapy because of esophageal stenosis. After therapy, complete EUS was performed in all patients. Thus, findings at EUS in 26 patients with T3 and T4 esophageal carcinomas who were treated with chemoradiotherapy were correlated to the histologic findings in the resected specimens. Chemoradiotherapy consisted of two courses of fluorouracil and cisplatin and a total of 30 Gy of radiation therapy. EUS criteria for prediction of a response were as follows: T0, complete response; Tw, microscopic evidence of tumor residue (major response); and T2-T4, no response, or minor response (depending on the primary stage prior to chemoradiotherapy). If the histologic findings in the resected specimen indicated no tumor (complete responder) or pT1 tumor (partial responder), patients were defined as responders. Kroep et al evaluated 13 patients with esophageal cancer who were treated with neoadjuvant cisplatin and gemcitabine plus granulocyte macrophage colony-stimulating growth factor.21 At EUS, the therapeutic response assessment was defined as complete if there was no visible tumor left, as partial after downstaging with the TNM criteria, as progressive in case of an increase in the TNM stage, or as stable when no change in TNM stage was determined. Pathologic response was assessed according to criteria of Mandard et al.47 The early (after 2 cycles) and late (after completed induction therapy) responses showed a specificity of 100% and a sensitivity of 100% in 12 patients who could be evaluated. Evaluation was not feasible in one patient due to development of liver metastases, which precluded surgical resection. In one patient, EUS after treatment was not feasible because of the impossibility of esophageal passage caused by the tumor. This patient, however, was classified as a nonresponder and not excluded from the analysis.

Volume measurementIsenberg et al conducted a study in 31 patients to determine whether the estimation of tumor size at EUS could be used to assess the response to preoperative chemoradiation (cisplatin and carboplatin with fluorouracil and concurrent mediastinal radiation of at least 30 Gy).31 An EUS response was defined as a 50% reduction in maximal cross-sectional area of the tumor. A shortcoming of this study is the absence of a definition of pathologic responders and nonresponders, the lack of which makes it impossible to reproduce the data. Chak et al measured maximal cross-sectional area in 50 patients before and after neoadjuvant therapy (cisplatin or carboplatin and fluorouracil concurrently administered with a total of 50 Gy radiation therapy).26 Patients with more than a 50% reduction were classified as EUS responders. The authors compared survival and not pathologic findings, with patients classified as responders and those classified as nonresponders with EUS. Survival time

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in the group of responders was significantly longer than it was in the group of nonresponders (median survival of 17.6 months versus 14.5 months, P < 0.05). Hirata et al evaluated pre- and posttherapeutic EUS in 34 patients who underwent various preoperative treatments consisting of radiation therapy (to a total of 30 Gy), chemotherapy (bleomycin or cisplatin), and hyperthermia.29 In 17 patients, the tumor could not be passed before treatment; in these patients, the maximum area was measured only at the level of the most cranial portion. Response at EUS was defined as a 15% to 30% reduction and more than a 30% reduction in maximal cross-sectional area. Pathologic data were available of 27 patients who underwent surgery. Histopathologic response was graded according to the number of viable cells in the entire lesion. Therapy was considered ineffective when viable cells occupied more than two-thirds of the entire tumor. Hirata et al found a correlation between percentage of reduction in maximal cross-sectional area and histologic evidence of effectiveness of neoadjuvant therapy. There was a significant difference (P = 0.05) in overall survival rates among the three groups, according to a reduction in the area of the tumor: less than 15%, 15% to 30%, and more than 30%. Willis et al correlated responses as measured by EUS in 41 patients with a defined pathologic tumor regression grade as proposed by Mandard et al.34,47 Patients received cisplatin or carboplatin and fluorouracil concurrently with a total of 50 Gy of radiation therapy. A positive response at EUS was defined as more than a 50% reduction in maximal cross-sectional area. Willis et al found a strong correlation between the EUS therapeutic response and chemoradiotherapy-induced pathologic tumor regression.

Studies with FDG-PETArslan et al evaluated the value of the use of FDG-PET in 24 patients who underwent chemoradiation therapy consisting of administration of cisplatin/fluorouracil, cisplatin/taxotore, or carboplatin/fluorouracil and concurrent radiation therapy with 50.4 Gy.40 The response of the primary tumor was visually assessed and analyzed semiquantitatively with SUV before and after treatment. Patients were classified into two groups according to histopathologic findings at surgery: responding patients without gross disease and nonresponding patients with gross disease. Differences in quantitative FDG-PET data and between responders and nonresponders were calculated as a mean value for both groups and not on a per-patient basis. Therefore, accuracy could not be assessed. Kato et al described 10 patients who received nedaplatin and fluorouracil in combination with radiation therapy of 40 Gy.44 Histologic response, according to the Japanese Society of Esophageal Diseases, was correlated with the SUV after treatment and the FDG uptake length decrease; however, it was not correlated with the rate of SUV decrease.48

Downey et al assessed the prognostic value of FDG-PET in 17 patients with esophageal carcinoma who were treated with chemotherapy (paclitaxel/cisplatin), radiotherapy (50.4 Gy), and surgery.42 At a threshold of a 60% decrease in FDG uptake, they found a significant difference (P = 0.055) in 2-year disease-free survival between patients who had less decrease in SUV (38% survival) and patients who had a greater decrease in SUV (67% survival). In a study of Brucher et al, 27 patients were included who underwent external-beam radiation therapy and treatment with fluorouracil as a continuous infusion.41 Pathologic response was assessed according to the criteria of Mandard et al.47 At a threshold level of

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52% decrease in FDG uptake compared with the baseline value, sensitivity for prediction of a response was 100%, with a corresponding specificity of 55%. The positive and negative predictive values were 72% and 100%, respectively. Median survival was 22.5 ± 2.4 in responders evaluated with FDG-PET versus only 6.7 ± 5 in nonresponders evaluated with FDG-PET (P < 0.001). Weber et al reported a series of 40 patients who received chemotherapy of 72 days duration.45 After 14 days of therapy, mean reduction of tumor FDG uptake, according to criteria of Mandard et al, was significantly different between responders (54% ± 17%) and nonresponders (15% ± 21%). An optimal differentiation was achieved by using a cutoff value of 35%. The 2-year survival rate was 60% in responders evaluated with FDG-PET versus 37% in nonresponders evaluated with FDG-PET (P < 0.04). Flamen et al included 36 patients in their study with T4 esophageal cancer, who received concomitant external-beam radiation therapy plus cisplatin and fluorouracil.43 Patients were classified as major responders evaluated with FDG-PET when a strong reduction in FDG uptake was demonstrated at posttherapy PET. A patient was classified as a major responder to therapy when the histologic findings of the primary tumor in the resection specimen indicated a classification of pT0-pT2 or pT3 (if the residual tumor consisted of small foci of viable tumor on a background of extensive histopathologic response) and there was no sign of any tumoral viability beyond the primary tumor site. After patients completed chemoradiotherapy, the sensitivity of serial FDG-PET for a major response was 71% (10 of 14 patients), and specificity was 82% (18 of 22 patients). Major responders evaluated with FDG-PET had a median survival of 16.3 months, and nonmajor responders, 6.4 months (P=0.005). Kroep et al evaluated 13 patients with esophageal cancer who were treated with neoadjuvant cisplatin and gemcitabine plus granulocyte macrophage colony-stimulating growth factor.21 The pathologic response was assessed according to criteria of Mandard et al. Evaluation of early (after two cycles) and late (after completed induction therapy) response yielded a specificity of 86% and 100%, respectively, and a sensitivity of 100% at both intervals, with cutoff values of 40% for early responses and 60% for late responses.

Comparison of diagnostic accuracyThree studies with CT,19-21 four with EUS,21,28,29,34 and four with FDG-PET21,41,43,45 provided enough data to permit calculation of sensitivity and specificity (Figure 1). The sensitivity of CT, EUS and FDG-PET ranged from 33% to 55%, 50% to 100%, and 71% to 100%, respectively. The specificity ranged from 50% to 71%, 36% to 100%, and 55% to 100%, respectively. Summary ROC curves for the three modalities are given in Figure 2. The maximum joint sensitivity and specificity (Q-point) values for CT, EUS, and FDG-PET were 54% (95% confidence interval (CI): 31% to 77%), 86% (95% CI: 80% to 93%), and 85% (95% CI: 77% to 93%), respectively. Overall accuracy of CT was significantly lower than was the accuracy of EUS (P < 0.003) and of FDG-PET (P < 0.006). Overall accuracy of EUS was similar to that of FDG-PET (P = 0.84). The estimated specificity values of CT, EUS and FDG-PET (values that corresponded to a desired level of sensitivity of 90%) were 13%, 78%, and 78%, respectively. Evaluation of neoadjuvant therapy in the analyzed studies was not feasible by using PET in 1 (< 1%) of 116 patients, and it was not feasible by using EUS in seven (6%) of 120 patients. EUS was suboptimal in 17 (14%) of 120 patients. In contrast, CT was always feasible.

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FIGURE 1 Forrest plots of sensitivities (A) and specificities (B) for all 11 studies. Plots show variation in estimates between studies and modalities. Confidence intervals are large in the majority of studies because of small sample sizes. (EUS = en-doscopic ultrasonography, TP = true positives; FN = false nega-tives; TN = true negatives; FP = false positives)

(A)

(B)

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FIGURE 2Summary ROC curves for all three modalities. The Q-points can be found at the intersection of the diagonal line with the summary ROC-curve. Accuracy of CT is poorer than that of EUS and PET. (squares indicate studies with CT; circles indicate studies with EUS; triangles indicate studies with PET).

DISCUSSIONTo determine the best diagnostic tool for the evaluation of the response to neoadjuvant therapy response in patients with esophageal cancer, we systematically reviewed the literature in regard to the role of CT, EUS, and FDG-PET. The included studies showed limited methodological quality. In our review, researchers in all studies with CT reported a low accuracy for the assessment of response in esophageal cancer, and this was significantly lower than that of FDG-PET and EUS. In the studies with FDG-PET and EUS, accuracy was good end equivalent for both modalities. CT generally is considered the state-of-the-art diagnostic modality for monitoring nonsurgical therapy in solid tumors. For therapeutic response assessment in esophageal cancer, however, accuracy was low with CT. This is probably related to the difficulty in the differentiation between viable tumor and reactive changes, including edema and scar tissue, at CT. Another reason may be the knowledge that CT is of limited value for initial tumor staging, because of poor differentiation between tumors with staged to T3. It is far less accurate than is EUS, which is presently considered the standard for staging of the primary tumor. Although only a limited number of studies with far from optimal methods were available, we conclude that single-detector row CT is a poor diagnostic tool for the determination of the pathologic tumor response after chemoradiotherapy in patients with

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esophageal cancer. The articles with CT included in this review concerned studies in which thick collimation was used. With the introduction of multi-section scanners, the use of thinner collimation has become possible. Thinner collimation can be expected to lead to improved delineation of the tumor and, hence, improved 3D measurements and more accurate and reproducible measurements of tumor volume. This may improve the results of CT in the near future for monitoring of the response with respect to tumor volume. EUS has been developed over the past decade and has been shown to be highly accurate for the initial staging of the primary tumor. In contrast to staging of untreated esophageal cancer, the value of restaging with EUS after neoadjuvant therapy appears to be limited by the difficulty in the differentiation of residual carcinoma from inflammation and fibrosis.30,35 This is supported by the finding that restaging with EUS after therapy had a poor accuracy, with pathological staging as the reference standard; accuracy ranged from 27% to 82%. Nevertheless, the accuracy of EUS for therapeutic response assessment in our review was significantly higher than the accuracy of CT and was comparable to the accuracy of FDG-PET. These results should be interpreted with caution, because they were based on four studies with poor to moderate methodological quality. Factors that may limit EUS for assessment of a nonsurgical response are postradiation esophagitis, luminal stenosis, and compression of the tumor caused by the endoscope.30,49 In the four studies with EUS that were included for ROC analysis in this review, EUS was not feasible in 6%21,28 and was suboptimal in 14% of patients.29 In addition, to be useful for therapeutic response assessment, performance of repeated measurement with high reproducibility is of crucial importance, and this can only be achieved if well-trained and experienced operators are available. Overall accuracy of FDG-PET was similar to that of EUS. The maximum joint sensitivity and specificity was 85% and 86%, respectively. Metabolic imaging with FDG-PET enables discrimination of viable tumor from necrotic scar tissue in patients with esophageal cancer after neoadjuvant therapy. Nonspecific glucose uptake by tissue with inflammation caused by chemotherapy and/or radiation therapy may be a limitation for FDG-PET in therapeutic response assessment. Although the suboptimal sensitivity by false-negative results for response assessment in some studies41,43 could be explained by this mechanism, this finding is rare and not observed in other studies.21,45 Most likely, the contribution of FDG uptake caused by inflammation to total FDG uptake is low, and, moreover, the threshold for FDG decrease to define responders can be adjusted to select responders almost exclusively (i.e. sensitivity of 100% with 100% negative predictive values only as performed by Weber et al and Kroep et al).50

A wide range of cutoff values, from 30% to 80% and expressed as SUV, for reduction in FDG uptake has been reported for use in the discrimination between responders and nonresponders. This range of cutoff values suggests a lack of standardization, but it also might be explained by factors such as spectrum of disease, differences in therapy (e.g. severity in tumor kill, and timing of evaluation of the therapy). Kroep et al used an optimal cutoff value of 40% after two cycles and of 60% after completion (four to six cycles) of chemotherapy. Still, an advantage of FDG-PET is the high reproducibility, with a change of greater than 20% considered to reflect a true biological effect.50-53 Furthermore, various analytical models (SUV with corrections for body surface

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area, simplified kinetic model, nonlinear regression analysis, etc), are available and have been tested to optimize therapeutic response monitoring by using FDG-PET. These models have been described in detail by Hoekstra et al and have been described particularly for esophageal cancer by Kroep et al.21,54 Because assessment of SUV combines accuracy with simplicity, this model is used in most studies. Further research and validation, focussing on the cutoff values with the different analytical models for optimal discrimination between responders and nonresponders, has to be done. For this review, we used histopathologic findings as a valid reference standard. The ultimate aim, however, was to identify patients with a poor clinical outcome early in the course of neoadjuvant therapy; in only seven studies was survival reported, and these studies included one with CT,19 two with EUS,26,29 and four FDG-PET.41,43,45,55 In the study with CT, outcome was not predicted, whereas in both studies with EUS, a slightly but significantly higher survival was found in responders versus nonresponders. In all four studies with FDG-PET, striking differences with significantly longer survival in metabolically responding patients were found. Response to neoadjuvant treatment was evaluated after completion of this nonsurgical treatment in most studies. These findings may hold prognostic value as mentioned previously, but they will not alter the duration or intensity of neoadjuvant treatment. Only if evaluation is performed early in the course of neoadjuvant treatment and the test may accurately discriminates responders from nonresponders can the test results be used to aid in the decision about whether this toxic therapy should be continued, as in responders, or stopped, as in nonresponders. Researchers in only two studies investigated the role of FDG-PET in distinguishing responders from nonresponders early during the course of chemoradiotherapy.21,45 Kroep et al and Weber et al showed encouraging results, with high negative predictive values for the early response to neoadjuvant treatment in patients with esophageal cancer (95% and 100%, respectively).21,45

Early prediction of tumor response might be improved by taking other factors into account. For esophageal cancer, several histologic markers, such as the tumor suppressor gene p53, the proliferative marker Ki-67, and the epidermal growth factor receptor have been evaluated for the prediction of the therapeutic response even prior to neoadjuvant therapy.56 Neither a single marker nor a combination of markers, however, can currently be used to predict the response with sufficient accuracy. In the future, gene expression profiling may identify markers that can be used in combination with imaging results for prediction of the response to neoadjuvant therapy. In addition, there are some general limitations to this review, which should be kept in mind when one interprets the summary ROC curves. The number of studies and patients included in our review was small. Only 11 studies for the three modalities combined were eligible for ROC analysis, which provided a total of 318 patients. In none of the studies was a head–to–head comparison used to test directly for a difference in accuracy between modalities within the same group of patients. Although Kroep et al evaluated all three modalities in the same patient population, they did not directly compare accuracy, possibly because of the small number of patients who could be evaluated and who underwent examinations with all three modalities. Some potential sources of heterogeneity need to be addressed. First, neoadjuvant therapy schemes differed substantially among the studies, with a major difference in the

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Review of Response Assessment in Esophageal Cancer

use of chemotherapy alone in four studies versus the combination of chemotherapy and radiation therapy in 7 studies. Second, differences in the spectrum of disease can be an important source of heterogeneity. We restricted our review to studies that included patients who were eligible for curative surgery and, therefore, were candidates for neoadjuvant treatment. Nevertheless, tumor stage may vary from small T1 tumors to larger T3 tumors. Measurements of change in tumor volume or of FDG uptake may be less accurate in small tumors than they are in large tumors because of the larger influence of systematic errors and lower statistics. Moreover, small tumors may be missed at CT or FDG-PET at initial staging. Subanalyses in future larger studies are necessary to document the influence of initial tumor stage on therapeutic response assessment. Third, it is important to know whether researchers defined their cutoff value prior to the study or after they obtained the results. In the latter case, there is an increased likelihood that the authors selected the cutoff value to maximize a particular test characteristic, which reduces the likelihood that investigators in another study will be able to replicate the findings. Different methods or thresholds to define a positive test result can lead to a special source of variation. Response criteria were defined differently within each modality (Table 2). Two different parameters were used for EUS (i.e. restaging and maximal cross-sectional area). In all studies with CT, volume measurements were used, but the thresholds differed slightly. In all studies with FDG-PET, except that of Flamen et al, the SUV was used.43 Flamen et al used the delta tumor-to-liver uptake ration, which is comparable with the SUV, albeit with correction for liver activity. These differences, however, are small, and the summary ROC approach was developed to incorporate differences in accuracy that arise because of a change in threshold between studies for defining a test as positive. In conclusion, single-section CT for assessment of the response to neoadjuvant therapy in esophageal cancer is inaccurate and, therefore, is not recommended. EUS and FDG-PET have equivalent accuracy. EUS can be used to identify patients in whom a pathologic response was achieved, but is not always feasible during or shortly after chemoradiation and, therefore, is not routinely used for therapeutic response assessment. FDG-PET, which is used to measure alterations in tissue metabolism, seems to be a promising noninvasive tool for the assessment of the response to neoadjuvant therapy in patients with esophageal cancer. Larger studies with sufficient power that focus on the prediction of the tumor response early in the course of neoadjuvant therapy and that include direct comparisons of different modalities are needed.

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cancer to induction therapy: results of a prospective trial. J Clin Oncol 2003;21:428-32.Flamen P, Van Cutsem E, Lerut A, Cambier JP, Haustermans K, Bormans G, de Leyn P, Van Raemdonck D, De Wever W, Ectors N, Maes A, Mortelmans L. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol 2002;13:361-8.Kato H, Kuwano H, Nakajima M, Miyazaki T, Yoshikawa M, Masuda N, Fukuchi M, Manda R, Tsukada K, Oriuchi N, Endo K. Usefulness of positron emission tomography for assessing the response of neoadjuvant chemoradiotherapy in patients with esophageal cancer. Am J Surg 2002;184:279-83.Weber WA, Ott K, Becker K, Dittler HJ, Helmberger H, Avril NE, Meisetschlager G, Busch R, Siewert JR, Schwaiger M, Fink U. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19:3058-65.Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14.Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73:2680-6.Japanese Society for Esophageal Diseases. Guidelines for the clinical and pathological studies on carcinoma of the esophagus. Tokyo: Kanehara, 1999.Roubein LD, DuBrow R, David C, Lynch P, Fornage B, Ajani J, Roth J, Levin B. Endoscopic ultrasonography in the quantitative assessment of response to chemotherapy in patients with adenocarcinoma of the esophagus and esophagogastric junction. Endoscopy 1993;25:587-91.Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999;35:1773-82.Hoekstra CJ, Hoekstra OS, Stroobants SG, Vansteenkiste J, Nuyts J, Smit EF, Boers M, Twisk JW, Lammertsma AA. Methods to monitor response to chemotherapy in non-small cell lung cancer with 18F-FDG PET. J Nucl Med 2002;43:1304-9.Minn H, Zasadny KR, Quint LE, Wahl RL. Lung cancer: reproducibility of quantitative measurements for evaluating 2-[F-18]-fluoro-2-deoxy-D-glucose uptake at PET. Radiology 1995;196:167-73.Weber WA, Ziegler SI, Thodtmann R, Hanauske AR, Schwaiger M. Reproducibility of metabolic measurements in malignant tumors using FDG PET. J Nucl Med 1999;40:1771-7.Hoekstra CJ, Paglianiti I, Hoekstra OS, Smit EF, Postmus PE, Teule GJ, Lammertsma AA. Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography: an overview of different analytical methods. Eur J Nucl Med 2000;27:731-43.Downey RJ, Akhurst T, Ilson D, Ginsberg R, Bains MS, Gonen M, Koong H, Gollub M, Minsky BD, Zakowski M, Turnbull A, Larson SM, Rusch V. Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial. J Clin Oncol 2003;21:428-32.Duhaylongsod FG, Gottfried MR, Iglehart JD, Vaughn AL, Wolfe WG. The significance of c-erb B-2 and p53 immunoreactivity in patients with adenocarcinoma of the esophagus. Ann Surg 1995;221:677-83.

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4POSITRON EMISSION TOMOGRAPHY WITH 18F-FLUORO-

DEOXYGLUCOSE IN A COMBINED STAGING STRATEGY OF ESOPHAGEAL CANCER PREVENTS UNNECESSARY SURGICAL

EXPLORATIONSHL van Westreenen1

PAM Heeren1

HM van Dullemen2

EJ van der Jagt3

PL Jager4

H Groen5

JThM Plukker1

Departments of Surgery1, Gastroenterology2, Radiology3, Nuclear Medicine/PET center4, Office for Medical Technology Assessment5

University Hospital Groningen, The Netherlands

Journal of Gastrointestinal Surgery 2005;9:54-61

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ABSTRACTIntroduction: Distant metastases or local invasion are frequently found during the explorative phase of surgery for esophageal cancer. This study was performed to determine the rate of patients with incurable disease encountered during exploration and to examine the impact of preoperative staging, including positron emission tomography (PET), on the number of unnecessary explorations.Materials and Methods: The records of 203 patients with esophageal cancer who were eligible for curative resection were retrospectively reviewed. The surgical reports were analyzed to obtain the reasons for abandoning resection. Furthermore, the different staging modalities according to the related time interval were reviewed for each patient to analyze the influence of them on the number of explorations. Results: After exploratory surgery, resection was abandoned in 78 of the 203 patients (38%) because of distant metastases (n = 59; 29%), metastatic spread and local irresectability (n = 5; 2%), and local irresectability (n = 14; 7%). In a logistic regression model with all preoperative staging modalities and the year of examination as independent variables, 18F-fluorodeoxyglucose (FDG)-PET was the only modality that predicts intended curative resection in these patients (P < 0.001). Conclusion: In patients with esophageal cancer who are suitable for potentially curative surgery, resection was abandoned mainly because of distant metastases encountered during exploration. The addition of FDG-PET may have reduced the rate of unnecessary surgery in this group of patients.

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FDG-PET Prevents Unnecessary Surgical Explorations

INTRODUCTIONCurative treatment of patients with esophageal cancer mainly depends on the stage of disease. Until now, surgical resection is the only curative option in patients with locoregional stage of the disease, but is accompanied by substantial morbidity and even mortality.1

Patients with distant metastases (M1) or local invasion of adjacent vital structures by the primary tumor (T4) are beyond cure. These patients may benefit from less invasive methods, including stenting, external radiation and/or brachytherapy for palliation.2

The primary aim in staging of esophageal cancer is to assess the prognosis in order to select those patients who may benefit from surgery. Current preoperative staging is not completely reliable in determining curative resectability. As a result, distant metastases or local invasion are still found during the explorative phase of surgical treatment, rendering resection meaningless in these patients. Data on the number of unnecessary surgery in esophageal cancer are scarce. In the limited number of studies, unnecessary explorative surgery, including laparoscopy, is performed in 10% to 60% of patients.3-9 During the last decade, preoperative noninvasive staging modalities have improved. Computed tomography (CT) of thorax and abdomen has been the first-line method to determine local resectability and metastatic spread for many years.10 Later, endoscopic ultrasound (EUS) was introduced and has become the most reliable method of identifying the depth of primary tumor invasion and to assess regional and distant lymph node involvement, particularly in combination with fine-needle aspiration (FNA).11-13 Recently, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been gaining acceptance in the detection of distant metastatic disease.14,15 Invasive and more expensive staging methods such as laparoscopy and thoracoscopy are generally not implemented in the preoperative work-up.16 In this study, we analyzed the patients with esophageal cancer who were suitable for potentially curative surgery after preoperative staging. The number of missed metastases or irresectable T4 tumors, which were encountered during surgery, was determined. Furthermore, we documented the combination of different staging modalities of the time interval for each patient to estimate the impact of them on the number of unnecessary explorations in these patients. In addition, the influence of the different combinations of staging on survival was estimated.

MATERIALS AND METHODSA retrospective analysis was performed on medical records of 203 patients eligible for potentially curative surgery after an initial diagnosis of cancer of the esophagus or gastroesophageal junction (GEJ) between 1992 and 2002. All patients had biopsy- proved malignancy of the esophagus or GEJ. Patients with high-grade dysplasia, preoperative chemotherapy, or radiotherapy and patients who were unfit for surgery were excluded. Patient demographic and tumor characteristics are summarized in Table 1. Resection with curative intention was considered on the basis of preoperative staging results, including tumors staged as T1-3 N0-1 M0 according to the Union Internationale contre le Cancer 2002 system.17 All patients were staged with the available staging modalities (CT,

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EUS, PET) at the time of presentation. Patients were excluded from surgery if hematogenous (M1b) or distant lymph node metastases (M1a/1b) were present or if local invasion of adjacent vital structures by the primary tumor (T4) was established preoperatively. Therefore, all patients included in this analysis had resectable and curable disease at their preoperative staging. Esophagectomy as a palliative treatment was not performed. Surgery was carried out by or under the direct supervision of a surgeon with experience in esophageal surgery. The surgical procedures started with laparotomy in order to exclude distant metastases to the liver, peritoneum, rectovesical or rectouterine pouch (M1b) and lymph nodes at the celiac axis. Lymph nodes localized at the origin of the celiac trunk including para-aortic, splenic and hepatic artery lymph nodes were defined as distant lymph node

Table 1. Characteristics of 203 Patients

Characteristic No. of patients (%)

Gender Male 168 (82.8)

Female 35 (17.2)

Age (years) Median 62.0

Range 22-82

Histology Adenocarcinoma 171 (84.2)

Squamous cell carcinoma 32 15.8)

Localization Mid esophagus 9 (4.4)

Distal esophagus 102 (50.2)

Gastroesophageal junction 92 (45.3)

Surgical procedure Transthoracic esophagectomy 119 (58.6)

Transhiatal esophagectomy 6 (3.0)

Explorative laparotomy 65 (32.0)

Explorative laparothoracotomy 13 (6.4)

Surgical staging T1-3N0-1M0 125 (61.6)

T4N0-1Mx 14 (6.9)

T4N0-1M1 5 (2.5)

TxN0-1M1 59 (24.6)

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FDG-PET Prevents Unnecessary Surgical Explorations

metastases (M1a/b). Nodal involvement of celiac axis was considered as incurable due to the worse survival in these patients.18,19 In-growth in vital structures like aorta, inferior vena cava, pancreas, liver and/or extensive involvement of the diaphragm was considered to be irresectable (T4). Subsequently, an extended resection by right or left thoracotomy was usually performed, but in the case of delicate cardiopulmonary condition, a transhiatal resection was preferred. During thoracic exploration, resectability of the tumor was assessed and the mediastinum was inspected for the existence of lymphangitis. Pleural metastases were considered to be incurable, as was tumor in-growth in pulmonary vessels, trachea, aorta, and pericardium (T4). After assessment of curability, the tumor and its adjacent lymph nodes were resected en bloc, the so-called two-field lymphadenectomy. A gastric tube restored gastrointestinal continuity and cervical or intrathoracic anastomosis was performed.

Computed tomography CT from the neck to the upper abdomen including the liver was performed with a single slice Spiral CT (Tomoscan SR 7000, Philips Medical Systems, Best, The Netherlands) with 10-mm collimation. Reconstruction interval was 5 mm and 10 mm for thorax and abdomen respectively. Scans were performed with intravenous and oral contrast.

Endoscopic ultrasoundA radial scanner (GF-UM 20, 7.5-12 MHz, Olympus, Tokyo, Japan) was used for the performance of EUS since January 1997. Since 1999, EUS-guided FNA of suspected lymph node metastases was performed. The FNA was obtained via a separate linear-array echoendoscope (Pentax Benelux, FGUX-36, 5-7.5 MHZ, Pentax Benelux, Breda, The Netherlands). FNA was performed with a 22-Gauge, 8-cm needle (Wilson-Cook Medical Inc., Bloomington, IN, USA). If a stenotic tumor was not traversable with the GF-UM 20 scope, a small-caliber probe (MH-908, 7.5 MHz, Olympus) was used. One well-trained endoscopist performed all EUS procedures.

Positron emission tomographySince 1998, PET was performed with an ECAT 951/31 or an ECAT HR+ positron camera (Siemens/CTI, Knoxville, TN, USA). The ECAT 951/31 acquires 31 planes over 10.9 cm, and the HR+ camera 63 planes over a 15.8-cm axial field of view. All patients fasted for at least 4 hours before 400-580 MBq FDG was administered intravenously. Data acquisition started 90 minutes after injection in whole body mode, for 5 minutes per bed position from the skull to the knees. Transmission imaging was obtained during 3 minutes per bed position for attenuation correction. Images were reconstructed using an iterative reconstruction technique and were read from computer monitors.

Data analysisTo estimate the impact of different staging modalities on the occurrence of unnecessary surgery in patients eligible for potentially curative surgery, the preoperative work-up was documented. Comparison of proportions was performed using the chi-square test. For each patient, it was recorded whether CT, EUS and/or FDG-PET were performed. All staging procedures were performed within a median interval of 2 weeks (range, 1-4 weeks) to the time of surgery. These data and the year of examination were entered as independent

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variables in a logistic regression model to find a factor predicting the possibility to perform a curative resection. A binary logistic method with forward stepwise regression was used. Survival data were analyzed using the Kaplan-Meier method and differences in the cumulative survival rate between subgroups were compared with the log-rank test. A value of P < 0.05 was considered significant. Statistical analyses were executed with the statistical software package: SPSS version 10 (SPSS Inc, Chicago, IL, USA).

RESULTSSurgical outcomeResection was performed in 125 patients but was abandoned in 78 patients (38%). Resection was contraindicated because of M1 disease in 59 patients (29%), locally irresectable tumors (T4) in 14 patients (7%), and metastatic spread and local irresectability in 5 patients (2%) (Table 1). Nineteen patients had a tumor that invaded adjacent structures (T4). The tumor invaded the aorta in seven patients, the pancreas in five patients, the pulmonary vein in four patients, the diaphragm in one patient, the inferior vena cava in one patient, and the bronchus in one patient. Of the 19 T4 tumors, 6 were considered to be irresectable at laparothoracotomy, and 13, during laparotomy. In 64 patients, 68 metastases were encountered during surgical exploration, with resection abandoned in these patients. The localization of these 68 metastases is summarized in Table 2. Metastases were found at the celiac axis in 45 patients (45 of 64, 70%), including lymph nodes along hepatic and splenic artery. Two patients had celiac lymph node metastases and liver metastases. Metastases in the omentum or parietal peritoneum were present in 10 patients, of whom 2 patients had both peritoneal spread and liver metastases. Liver metastases alone were determined in one patient. Extensive nodal metastases with lymphangitis in the mediastinum and involvement of the aorto-pulmonary window was found in five patients and judged as pleuritis carcinomatosis. Therefore, the tumors in these patients were considered not to be curatively resectable. In one patient, a metastatic lymph node was determined at the distal part of the left pulmonary hilus and classified as a distant metastasis (M1b).

Preoperative stagingPatients were staged by different preoperative staging techniques and were retrospectively allocated in three groups according to the comprehensiveness of preoperative staging. The first group was staged with CT, the second group was staged with CT and EUS, and the remaining group was staged with CT, EUS and FDG-PET. The number of unnecessary surgery and the underlying reason to abandon resection regarding the three groups are represented in Figure 1 and Table 2. The presence of celiac axis metastases during surgical exploration was significant reduced in patients staged with EUS (13 of 97; 13%; P = 0.013) and with FDG-PET (4 of 61; 7%; P < 0.001) compared with the patients staged with CT alone (32%). The addition of FDG-PET reduces the rate of unnecessary surgery from approximately 44% and 50% to 21% (Table 2). The logistic regression model reveals preoperative FDG-PET without distant metastases as the only significant factor to predict curative resection in patients eligible for potentially curative resection (P < 0.001; 95%

57

FDG-PET Prevents Unnecessary Surgical Explorations

Table 2. Reasons why Surgical Explorations were Found to be Unnecessary in Patients with Different Preoperative Staging Modalities and the

Localization of Undetected Metastases by these MethodsPreoperative staging

CT CT+EUS CT+EUS+PET

No. of patients 106 36 61

Unnecessary exploration (n) 47 (44)* 18 (50) 13 (21)

Reason (n)

T4 7 1 6

M1 35 17 7

T4+M1 5 - -

Localization of 68 metastases

detected during exploration (n)

Celiac trunk 34 9 4

Omentum/peritoneum 5 4 1

Pleural carcinomatosis 1 3 1

Liver 3 2 -

Bronchial lymph nodes - - 1

*Values in parentheses are percentages

1998-2002 CT+EUS+PET

1997 CT+EUS

1992-1996 CT

No.

of p

atie

nts 120

100

80

60

40

20

0

eligible for surgery

unnecessary surgery

FIGURE 1Bar chart representing the number of patients of each group and the number of patients and the number of patients who underwent unnecessary surgery regarding the available staging methods for each time interval. CT: computed tomography; EUS: endoscopic ultrasound; PET: positron emission tomography.

58

CHAPTER 4

confidence interval, 1.55-6.25).

SurvivalThe median survival of 78 patients who underwent surgical exploration was 8.8 months compared with 36.4 months in 125 patients who had a curative esophagectomy (P < 0.001) (Figure 2(A)). Regarding the combination of preoperative staging, the median survival of the 125 patients who underwent a resection was 28.0 months for patients staged with CT, 25.6 months for patients staged with CT and EUS, and 48.2 months in patients staged with CT, EUS and FDG-PET (P = 0.34) (Figure 2(B)).

DISCUSSIONThe results from this study show that the resection rate in patients with esophageal cancer selected for potentially curative surgery depends on preoperative staging. The overall rate of unnecessary exploratory surgery in this study was 38% and is in the same range as reported in the literature.3-8 Irresectability because of local invasion (T4) was found in 36% of the patients who underwent exploration. However, resection was abandoned mostly because of distant metastases (M1), which were found in 82% of these patients. Most of the distant metastases in this study were located at the celiac axis. The optimal treatment in patients with celiac lymph node involvement is still a matter of debate.20 In our opinion, resection should be omitted in these patients based upon the worse survival rather than technical irresectability. As shown in this study and described in the literature, the poor median survival is ranging from 3 to 9 months.18,19,21 Currently applied neoadjuvant treatment might be of considerable value in this group of patients.22,23 Analysis of different staging modalities revealed a reduction of the number of unnecessary explorative surgery when the preoperative work-up was more advanced. The addition of FDG-PET reduced exploratory surgery in patients suitable for esophagectomy to a rate of approximately 20%. The impact of FDG-PET is confirmed by the logistic regression model, which shows that FDG-PET without presence of metastases is the only significant variable in the prediction of resection in patients eligible for potentially curative surgery. Furthermore, the patients who were staged with CT, EUS, and FDG-PET seem to have a better survival (Figure 2B). This might be related to a higher accuracy of FDG-PET for the detection of distant metastases, which precludes surgery in such patients. The exact impact of all staging modalities cannot be assessed in this study because the number of patients in who surgery was abandoned after each preoperative staging method is not known. For years, CT was the initial staging test to detect distant metastases, and CT is currently widely available in most developed countries.24,25 CT has poor accuracy for both the identification of metastatic spread to the celiac lymph nodes and the overall assessment of invasion into adjacent vital structures.26,27 EUS is the first-choice technique to assess local tumor invasion, with an accuracy about 89% for T4 tumors.28 Still, there is a substantial number of understaged patients and they are incorrectly enrolled for surgical treatment as seen in this study. Some possible reasons for understaging T4 tumors might be the reservation of the endoscopist for undertreatment and the lower accuracy, especially for tumors located at the GEJ.29 Our data show a substantial

59

FDG-PET Prevents Unnecessary Surgical Explorations

Follow-up (months)

160140120100806040200

Surv

ival 1,0

,8

,6

,4

,2

0,0

esophagectomy

surgical explorations

FIGURE 2(A)Kaplan-Meier cumulative survival plot of 203 pa-tients.

Follow-up (months)

160140120100806040200

Surv

ival 1,0

,8

,6

,4

,2

0,0

CT + EUS + PET CT + EUS CT

FIGURE 2(B)Kaplan-Meier cumula-tive survival plot of 125 patients who underwent esophagectomy. Groups are based on preoperative tests. CT: computed tom-ography; EUS: endoscopic ultrasound; PET: positron emission tomography.

60

CHAPTER 4

number of involved celiac lymph nodes in 47 patients (23%) encountered during exploration. This number was significantly reduced in the group of patients staged with EUS (13%) and FDG-PET (7%) compared with patients staged with CT (32%) in their preoperative staging (Table 2). Upstaging with FDG-PET has been reported to range from 15% to 17% in patients who were staged with CT due to higher accuracy in detection of distant metastases.14,30 Due to a high specificity and positive predictive value, FDG-PET is more reliable in the assessment of curability compared with CT.1,5 The introduction of FDG-PET in the preoperative staging of our patients seems to reduce unnecessary surgery to 20%. However, FDG-PET and CT are still complementary in the detection of metastases.31 The reduction in unnecessary surgery in the group of patients staged with FDG-PET is not only attributable to FDG-PET. Simultaneously, the experience with EUS-FNA and CT has increased. Furthermore, currently applied multidetector CT and imaging fusion of CT with PET are promising in the selection of these patients. The rate of unnecessary surgery in the patients who were not staged with FDG-PET was high (about 50%) compared with the rate of 20% in patients who were staged with FDG-PET. Percentages deduced from the literature are around 20%.3-5,8,9 A possible reason for the overall percentage of 38% found in our study might be the presence of celiac trunk metastases defined as incurable in contrast to others. Furthermore, the percentage of unnecessary surgery in relation the type of preoperative staging is not well described in the literature. Therefore, the comparison of our results to other centers is hampered, and other centers should report on this topic because the paucity of the literature. Recently, FDG-PET followed by EUS-FNA was proposed to be the most cost-effective strategy for preoperative staging and management of patients with carcinoma of the esophagus.32,33 However, the exact role of FDG-PET is still unknown. A prospective multi-center study to investigate the impact of FDG-PET in patients eligible for curative resection after conventional staging with ultrasound of the neck, EUS-FNA, and multidetector CT is currently ongoing at our center. In conclusion, this study shows a substantial rate of unnecessary surgery in patients suitable for curative treatment mainly because of distant metastases. Improvement of preoperative staging, especially by implementation of FDG-PET, may have reduced the rate of unnecessary surgery to approximately 20% in our center.

61

FDG-PET Prevents Unnecessary Surgical Explorations

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Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ. Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 2001;72:306-13.Sihvo EI, Pentikainen T, Luostarinen ME, Ramo OJ, Salo JA. Inoperable adenocarcinoma of the oesophagogastric junction: a comparative clinical study of laser coagulation versus self-expanding metallic stents with special reference to cost analysis. Eur J Surg Oncol 2002;28:711-5.Ellis FH, Jr., Heatley GJ, Krasna MJ, Williamson WA, Balogh K. Esophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria. J Thorac Cardiovasc Surg 1997;113:836-46.Hulscher JB, Nieveen van Dijkum EJ, de Wit LT, van Delden OM, van Lanschot JJ, Obertop H, Gouma DJ. Laparoscopy and laparoscopic ultrasonography in staging carcinoma of the gastric cardia. Eur J Surg 2000;166:862-5.Menon KV, Dehn TC. Multiport staging laparoscopy in esophageal and cardiac carcinoma. Dis Esophagus 2003;16:295-300.Sagar PM, Gauperaa T, Sue-Ling H, McMahon MJ, Johnston D. An audit of the treatment of cancer of the oesophagus. Gut 1994;35:941-5.Sariego J, Mosher S, Byrd M, Matsumoto T, Kerstein M. Prediction of outcome in “resectable” esophageal carcinoma. J Surg Oncol 1993;54:223-5.Sondenaa K, Skaane P, Nygaard K, Skjennald A. Value of computed tomography in preoperative evaluation of resectability and staging in oesophageal carcinoma. Eur J Surg 1992;158:537-40.Clements DM, Bowrey DJ, Havard TJ. The role of staging investigations for oesophago-gastric carcinoma. Eur J Surg Oncol 2004;30:309-12.Wakelin SJ, Deans C, Crofts TJ, Allan PL, Plevris JN, Paterson-Brown S. A comparison of computerised tomography, laparoscopic ultrasound and endoscopic ultrasound in the preoperative staging of oesophago-gastric carcinoma. Eur J Radiol 2002;41:161-7.Eloubeidi MA, Wallace MB, Reed CE, Hadzijahic N, Lewin DN, Van Velse A, Leveen MB, Etemad B, Matsuda K, Patel RS, Hawes RH, Hoffman BJ. The utility of EUS and EUS-guided fine needle aspiration in detecting celiac lymph node metastasis in patients with esophageal cancer: a single-center experience. Gastrointest Endosc 2001;54:714-9.Kelly S, Harris KM, Berry E, Hutton J, Roderick P, Cullingworth J, Gathercole L, Smith MA. A systematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma. Gut 2001;49:534-9.Parmar KS, Zwischenberger JB, Reeves AL, Waxman I. Clinical impact of endoscopic ultrasound-guided fine needle aspiration of celiac axis lymph nodes (M1a disease) in esophageal cancer. Ann Thorac Surg 2002;73:916-20.Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, de Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18:3202-10.Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy. Br J Cancer 1998;78:521-7.Lightdale CJ. Esophageal cancer. American College of Gastroenterology. Am J Gastroenterol 1999;94:20-9.Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edition. New York: John Wiley&Sons, 2003.Eloubeidi MA, Wallace MB, Hoffman BJ, Leveen MB, Van Velse A, Hawes RH, Reed CE. Predictors of survival for esophageal cancer patients with and without celiac axis lymphadenopathy: impact of staging endosonography. Ann Thorac Surg 2001;72:212-9.Hiele M, de Leyn P, Schurmans P, Lerut A, Huys S, Geboes K, Gevers AM, Rutgeerts P. Relation between endoscopic ultrasound findings and outcome of patients with tumors of the esophagus or esophagogastric junction. Gastrointest Endosc 1997;45:381-6.Clark GW, Peters JH, Ireland AP, Ehsan A, Hagen JA, Kiyabu MT, Bremner CG, DeMeester TR. Nodal metastasis and sites of recurrence after en bloc esophagectomy for adenocarcinoma. Ann Thorac

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Surg 1994;58:646-53.Van Westreenen HL, Pultrum BB, Plukker JT. Outcome in patients with stage IV esophageal cancer detected during explorative surgery. Eur J Surg Oncol 2004;30:182-3 (abstract). Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359:1727-33.Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979-84.Kumbasar B. Carcinoma of esophagus: radiologic diagnosis and staging. Eur J Radiol 2002;42:170-80.Lightdale CJ. Positron emission tomography: another useful test for staging esophageal cancer. J Clin Oncol 2000;18:3199-201.Romagnuolo J, Scott J, Hawes RH, Hoffman BJ, Reed CE, Aithal GP, Breslin NP, Chen RY, Gumustop B, Hennessey W, Van Velse A, Wallace MB. Helical CT versus EUS with fine needle aspiration for celiac nodal assessment in patients with esophageal cancer. Gastrointest Endosc 2002;55:648-54.Thompson WM, Halvorsen RA, Jr. Staging esophageal carcinoma II: CT and MRI. Semin Oncol 1994;21:447-52.Rice TW. Clinical staging of esophageal carcinoma. CT, EUS, and PET. Chest Surg Clin N Am 2000;10:471-85.Salminen JT, Farkkila MA, Ramo OJ, Toikkanen V, Simpanen J, Nuutinen H, Salo JA. Endoscopic ultrasonography in the preoperative staging of adenocarcinoma of the distal oesophagus and oesophagogastric junction. Scand J Gastroenterol 1999;34:1178-82.Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Sundaresan SR, Patterson GA, Cooper JD. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography. Am J Roentgenol 1997;168:417-24.Van Westreenen HL, Heeren PA, Jager PL, van Dullemen HM, Groen H, Plukker JT. Pitfalls of positive findings in staging esophageal cancer with f-18-fluorodeoxyglucose positron emission tomography. Ann Surg Oncol 2003;10:1100-5.Harewood GC, Wiersema MJ. A cost analysis of endoscopic ultrasound in the evaluation of esophageal cancer. Am J Gastroenterol 2002;97:452-8.Wallace MB, Nietert PJ, Earle C, Krasna MJ, Hawes RH, Hoffman BJ, Reed CE. An analysis of multiple staging management strategies for carcinoma of the esophagus: computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy. Ann Thorac Surg 2002;74:1026-32.

21.

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31.

32.

33.

5ADDITIONAL VALUE OF POSITRON EMISSION TOMOGRAPHY

IN STAGING ESOPHAGEAL CANCER: A PROSPECTIVE COHORT STUDY AND COST ANALYSIS

HL van Westreenen1

M Westerterp2

GW Sloof3

H Groen4

PMM Bossuyt5

PL Jager6

EFI Comans7

HM van Dullemen8

P Fockens9

J Stoker10

EJ van der Jagt11

JJB van Lanschot2

JThM Plukker1

Departments of Surgery1, Office for Medical Technology Assessment4, Nuclear Medicine/PET center6, Gastroenterology8, Radiology11

University Hospital Groningen, The NetherlandsDepartments of Surgery2, Nuclear Medicine3, Clinical Epidemiology and

Biostatistics5, Gastroenterology9, Radiology10

Academic Medical Center, Amsterdam, The NetherlandsDepartment of Nuclear Medicine7

VU Medical Center, Amsterdam, The Netherlands

Submitted

64

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ABSTRACTIntroduction: Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) has been suggested as the most accurate method to detect distant dissemination in patients with esophageal cancer (EC), possibly preventing unnecessary surgical explorations. We prospectively studied the diagnostic value and costs of FDG-PET in EC patients after a state-of-the-art conventional preoperative work-up. Methods: We performed a prospective multicenter cohort study. Eligible patients had histologically proven cancer of the esophagus or gastroesophageal junction. All patients were staged with multidetector computed tomography (MDCT), endoscopic ultrasound (EUS) and external ultrasound of the neck, both combined with fine-needle aspiration (FNA) on indication. Patients without evidence of distant metastases and/or locally irresectable disease on this conventional preoperative work-up underwent additional FDG-PET. Results: Between October 2002 and August 2004, 199 patients were included in this study. FDG-PET revealed suspected hypermetabolic lesions in 30 patients (positivity rate 15%; 95% confidence interval (CI), 11% to 21%) which were confirmed in 8 cases (4%; 95% CI, 1.3% to 6.7%). In 6 patients (3%; 95% CI, 0.6% to 5.4%) distant metastases were confirmed by additional investigations preventing unnecessary surgery. In 2 patients, explorative surgery was necessary for histological confirmation. The 8 cases of upstaging were all staged as stage III-IV on conventional staging (n = 122, 6.6%, 95% CI, 2.2% to 10.9%). FDG-PET detected synchronous neoplasms in 7 patients (3.5%, 95% CI, 2.1% to 4.8%). Suspicious lesions in the remaining 15 patients did not show progression during 6 months of follow-up and were classified as false-positive. Additional costs of the introduction on FDG-PET (€ 300,034 for this cohort of 199 patients) were not compensated by the cost reduction of the 6 prevented surgical explorations (€ 55,980) (mean additional costs per patient € 1,226) Conclusions: FDG-PET improves the selection for potentially curative surgery, especially in stage III-IV EC patients. However, the diagnostic yield is limited after extensive conventional staging including EUS-FNA and MDCT. The additional costs of FDG-PET were not compensated by the cost reduction of prevented surgery.

65

Additional Value of FDG-PET in Esophageal Cancer

INTRODUCTIONThe incidence of esophageal carcinoma (EC) has been rising steadily during the last two decades.1 Surgical resection is currently the best option for a potentially curative treatment in patients without distant metastases and locally irresectable tumor growth. Currently, the most common conventional imaging modalities for staging of esophageal cancer (EC) are computed tomography (CT), endoscopic ultrasound (EUS), and external ultrasound of the neck, both combined with fine-needle aspiration (FNA) on indication. Occasionally, diagnostic laparoscopy is employed.2 Despite these efforts preoperatively, metastatic spread is encountered during operation in 10% to 20% of patients.3 Esophageal resection is a major surgical procedure associated with substantial perioperative morbidity and mortality. So there is a need for more accurate preoperative staging to select those patients who will benefit from surgery and to avoid unnecessary operations in patients with distant metastases. During the last decades, positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has gained acceptance as a noninvasive staging method in EC, especially for the detection of distant lymphatic node and hematogenous metastases.4 Addition of FDG-PET to conventional staging has been shown to change patient management in 3% to 20% of patients.5

The introduction of FDG-PET to the preoperative work-up of patients with EC may lead to a more reliable selection of patients with curable disease with a corresponding reduction of unnecessary surgery among EC patients. Therefore, we studied the additional value of FDG-PET in detecting distant metastases in patients with EC who were eligible for potentially curative surgery based upon state-of-the-art conventional preoperative staging. Costs of FDG-PET, additional diagnostic procedures, and surgical exploration were assessed and a comparison was made of costs and effects of the diagnostic process with and without FDG-PET.

PATIENTS AND METHODSStudy designA prospective cohort study was performed in three university medical centers. UMCG is specialized in EC surgery and PET, AMC in EC surgery, and VUMC in PET. The medical ethics committees of these participating hospitals approved the study protocol. Eligible patients had histologically proven cancer of the thoracic esophagus or of the gastric cardia substantially involving the distal esophagus, without evidence of distant metastases or locally irresectable disease based on conventional preoperative work-up. Excluded were patients younger than 18 years and patients unable to undergo major surgery. Additional exclusion criteria were a history of malignancy in the previous 5 years, high-grade dysplasia, and pregnancy. Between October 2002 and August 2004, 199 eligible patients were consecutively invited to the study and presented with written information. Consenting patients underwent FDG-PET scanning if they were able to fast for at least 6 hours and lie supine for more than 1 hour.

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Conventional preoperative work-upAll patients underwent a standard work-up, including multidetector computed tomography (MDCT), EUS and external ultrasound on the neck, both combined with FNA on indication. All tests were performed within two weeks. The order was determined based upon waiting times and availability. These investigations were performed and/or interpreted by experienced physicians in the field.

Computed tomographyMDCT was performed with a 4-ring or 16-ring CT scanner (Philips MX 8000, Philips Medical Systems, Best, The Netherlands; Somatom Sensation, Siemens Medical Systems, Erlangen, Germany) of the lower neck, chest, and upper abdomen including the liver. The patient had to drink 500 mL of oral contrast directly before examination. CT examination comprised two consecutively performed scans after an intravenous injection of contrast medium (120 mL iodixanol (Visipaque, GE Healthcare Worldwide) at 3.5 mL/s). After a delay of 20 seconds after start of contrast injection, a multidetector scan (collimation 4 x 2.5 mm; effective slice thickness 4 x 3.2 mm; reconstruction 3 mm contiguous slices) was performed of chest and neck to the base of the skull within one breath hold. After a delay of 70 seconds after start of contrast injection a second spiral scan was performed of the upper abdomen, at least including the liver and celiac region. Lymph nodes measuring 10 mm or more at their maximum cross-sectional diameter were considered to be pathologic.

Endoscopic ultrasound A radial scanner (GF-UM130 or GF-UM160, 5-20 MHz, Olympus Medical Systems, Tokyo, Japan) was used for the performance of EUS. EUS-guided FNA was obtained by a separate linear-array echoendoscope (FF-UC140P, Olympus Medical Systems, Tokyo, Japan or FGUX-36, 5-7.5 MHz, Pentax Benelux, Breda, The Netherlands). FNA was performed with a 22-Gauge needle (Echotip, Wilson-Cook Medical Inc., Winston-Salem, NC, USA). In case of a stenotic tumor that did not allow passage of the standard echoendoscope, a small-caliber probe (MH-908, 7.5 MHz, Olympus Medical Systems, Tokyo, Japan) was used in an attempt to traverse the tumor. EUS was performed with the patient in a left decubitus position under conscious sedation using 2.5-10 mg midazolam intravenously.

Ultrasound of the neckThe cervical region was examined by a 7.5-13.5 MHz linear array transducer (Siemens Antaris, Siemens Medical Systems, Erlangen, Germany). Round hypo-echoic lymph nodes with a smallest diameter of more than 5 mm were considered as suspect and were investigated by cytology after ultrasound-guided fine-needle biopsy. The examination was performed by an experienced radiologist.

BronchoscopyOnly patients with an esophageal carcinoma at or above the level of the carina underwent a bronchoscopy to rule out ingrowth in the trachea.

StagingAll tumors were staged according to the 2003 TNM classification of the International Union

67

Additional Value of FDG-PET in Esophageal Cancer

Against Cancer (UICC).6 Local resectability of the tumor was based upon the T stage as assessed by EUS. Patients with T4 tumors invading vital structures and patients with distant hematogenous and/or lymphatic metastases (M1b) were excluded from this study. Celiac trunk lymph nodes were defined as lymph nodes located within 1 cm of the origin of the celiac trunk (station 18,19 and 20).7 They are typically located dorsally, within the 5-7 o’clock area. Lymph nodes located right lateral or right anterior from the stomach between 7-12 o’ clock were considered left gastric nodes (station 17), not fulfilling the criteria for M1 disease. Patients with massively enlarged (> 2 cm) positive celiac nodes, especially if fixed to surrounding structures, were not candidates for curative surgery. Thus, patients who were staged as T1-3 N0-1 M0-1a based upon the conventional preoperative staging were eligible for potentially curative surgery.

Positron emission tomographyThe PET studies were performed using an ECAT EXACT HR+ (Siemens/CTI Inc., Knoxville, TN, USA). Prior to PET imaging, patients were instructed to fast for at least 4 hours. Patients were also instructed to drink 500mL of water prior to imaging to stimulate FDG excretion from the renal calyces and stimulate subsequent voiding. Scans were performed in 2D whole body mode, using an emission-emission transmission-transmission protocol. Emissions scans (mid-skull to mid-femur) of 5 minutes per bed position were performed 90 minutes after intravenous injection of a mean dose FDG of 396 MBq (range 190-810, depending on body weight, s.e. 7.5 MBq). Transmission images were obtained for 3 minutes per bed position to allow for attenuation correction. All scans were corrected for decay, scatter and randoms, and reconstructed using an ordered subset expected maximization (OSEM) with two iterations and 16 subsets followed by post-smoothing of the reconstructed image using a 5 mm FWHM Gaussian filter.8 Images were read from computer monitors. FDG-PET scans were interpreted independently by two experienced nuclear medicine physicians aware of the presence and location of the esophageal tumor, but unaware of other clinical and other diagnostic data. The CT scan however was available for localization purposes. A lesion was considered positive if there was focally enhanced uptake other than physiological. Each reader reported the localization, intensity and interpretation of the lesions suspected to be metastases or synchronous neoplasms on FDG-PET. Intensity was scored on a four-point scale: ‘normal’ (physiological), ‘little’, ‘moderate’, and ‘high’. Interpretation was scored on a five-point scale: ‘definitely benign’, ‘probably benign’, ‘indeterminate’, ‘probably malignant’, and ‘definitely malignant’. In case of disagreement, a third reader was consulted and a final conclusion was made after a consensus meeting.

Verification of FDG-PET resultsLesions on FDG-PET suspected to be distant metastases had to be confirmed by histological/cytological examination or by pathognomonic findings on dedicated imaging techniques. If distant dissemination could be confirmed, esophagectomy was precluded in these patients. If confirmation could not be achieved, the patient was scheduled for surgery with evaluation of the suspicious lesion by intraoperative biopsy and subsequent frozen

68

CHAPTER 5

section analysis. If suspicious PET lesions could not be confirmed, the esophagectomy was performed as planned. All patients were followed for 6 months. Progression of a suspected but histologically unconfirmed lesion during 6 months of follow-up was considered as proof of malignancy.

Neoadjuvant therapyAs part of a prospective trial, 20 patients received neoadjuvant therapy including chemotherapy (paclitaxel and carboplatin), radiotherapy (41.4 Gy in 23 fractions), and hyperthermia.

SurgeryIn patients suitable for surgery, a transthoracic or transhiatal esophagectomy was performed. During laparotomy, the peritoneal cavity was explored to exclude metastatic disease. When enlarged para-aortic and/or irresectable celiac trunk lymph nodes were encountered during laparotomy, resection was abandoned after histological confirmation with frozen section. If no metastases were encountered, either limited transhiatal esophageal resection or transthoracic esophageal resection with en bloc two-field lymphadenectomy was performed. The lymph nodes were examined histologically according to the standard histological procedures.

Power calculation and analysisThe number of patients was determined with lesions suspected to be metastases (i.e. scored as highly increased FDG uptake and definitely malignant, or high uptake and probably malignant, or moderate uptake and definitely malignant, moderate uptake and probably malignant) on FDG-PET leading to upstaging as well as the number of lesions verified as metastases, the number of additional investigations, the number of prevented surgical explorations, and the incremental costs of adding FDG-PET to the staging work-up. Based on the available literature (until 2000), 20% of the patients would have suspicious lesions on FDG-PET, with a positive predictive value (PPV) of 80%. FDG-PET was expected to influence clinical management in half of the patients with a positive FDG-PET (overall 10%). Establishing the 95% confidence interval (CI) of the positivity rate with a clinically acceptable precision of 5% in both directions required a number of 180 patients.

Economic evaluationAn economic evaluation was performed to assess the incremental costs of adding FDG-PET to the staging strategy in relation to the improved accuracy of the staging process. Incremental costs of staging were calculated up to and including the surgical exploration which precedes a resection. The evaluation was performed from a hospital point of view; only direct medical costs were included. Resource use was determined from expert opinions and by direct observations. The actual costs of PET and of exploratory surgery were calculated using the 2004 price level, based on the costs of personnel, equipment, and materials. Hospital overhead costs were calculated using a 35% surcharge. Costs of hospital admission were calculated on the basis of the actual number of admission days in the ward and in the ICU and the recommended Dutch unit prices of

69

Additional Value of FDG-PET in Esophageal Cancer

hospitalization per day for university hospitals.9 Costs of diagnostic studies to confirm findings on FDG-PET were assessed on the basis of Dutch tariffs. Sensitivity analyses were carried out to assess the influence that changes in the major cost elements would have on the results.

RESULTSIn total, 199 patients were included in this study. None of the eligible patients refused participation and all patients were evaluable. Patient and tumor characteristics are summarized in Table 1. One hundred sixty patients had an adenocarcinoma (80%) and the tumor was predominantly localized in the distal part of the esophagus (67%). Seventy-seven patients (39%) had a clinical stage I or II disease determined by conventional staging and the remaining 122 (61%) patients had stage III-IV disease. Table 2 specifies conventional and additional diagnostic procedures during standard work-up, prior to FDG-PET. Complete EUS was not possible in 16 patients because of a stenotic tumor. Bronchoscopy was performed in 14 patients to exclude ingrowth of the tumor in the trachea. Based upon findings encountered during conventional work-up, different types of additional investigations were employed (Table 2). The mean time period to obtain all conventional and additional staging procedures plus FDG-PET was 16 (s.e. 1.0) days.

Table 1. Clinicopathological Characteristics of 199

Patients who were Additionally Staged with FDG-PET

Characteristics Value (%)

Gender Male 165 (83)

Female 34 (17)

Age (years) Mean 64

Range 29-82

Histology Adenocarcinoma 160 (80)

Squamous cell carcinoma 39 (20)

Localization Mid esophagus 17 (9)

Distal esophagus 133 (67)

Gastroesophageal junction 49 (25)

Clinical staging (UICC)* Stage I 13 (7)

Stage II 64 (32)

Stage III 106 (53)

Stage IV 16 (8)

Table 2. Conventional Staging Techniques and Related

Additional Investigations Before FDG-PET Scanning

Investigations Number

Conventional staging Multidetector CT 199

EUS 199

FNA during EUS 16

US of the neck 199

FNA during US of the neck 25

Bronchoscopy 14

Additional investigations US of the abdomen 17

MRI of the liver 2

CT abdomen/thorax 1

CT thorax 1

US of the kidney 1

US guided FNA of the liver 1

CT guided FNA of the liver 1

Thoracotomy with wedge excision of the lung 1

*Staging based upon conventional staging without FDG-PETUICC: International Union Against Cancer

CT: computed tomography, EUS: endoscopic ultrasound, FNA: fine-needle aspiration, US: ultrasound

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CHAPTER 5

Conventional work-up

FDG-PET(n=199)

Positive(n=30)

No surgery(n=2)

Surgery(n=167)

Additional work-up

Negative(n=19)

Pos/Indet(n=11)

SurgerySurgery

Surgery prevented(n=6)

Exploration(n=22)

Exploration(n=2)

Exploration(n=1)

Resection(n=3)

Resection(n=145)

Resection(n=18)

Negative(n=169)

Follow-up = 6 months

Follow-up = 6 months

FIGURE 1Flowchart of 199 patients. Pos: positive, Indet: indeter-minate, FDG: 18F-fluorodeoxy-glucose, PET: positron emission tomography

Figure 1 shows the study flow of the 199 included patients through the study procedures. FDG-PET visualized the primary tumor in 177 patients (89%). Eighteen of the 22 primary tumors that were not visualized were in the group of patients who were staged as T1-T2 tumors with EUS.

Negative FDG-PET FDG-PET did not show suspicious lesions in 169 patients. Two of these patients were not suitable for surgery because of progressive disease during chemoradiation combined with hyperthermia in one patient, while one patient refused surgery after completion of preoperative work-up. The remaining 167 patients with a negative FDG-PET were enrolled for potentially curative surgery. Resection was abandoned in 22 patients (14%).

Positive FDG-PET FDG-PET detected suspicious lesions in 30 patient: positivity rate 15% (95% CI, 11% to 21%).

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Additional Value of FDG-PET in Esophageal Cancer

Details of these 30 patients are summarized in Table 3. A series of additional investigations was performed for verification of these lesions (Table 4). FDG-PET led to upstaging in 8 patients (4%; PPV 27%; 95% CI, 14% to 44%). In 6 of these patients, distant metastases were proven by additional work-up and unnecessary surgery was prevented in these patients (2, 4, 5, 6, 7, 8). In 2 other patients (1, 3), metastases were detected in the suspected lesions during explorative laparotomy. One of these two patients had irresectable celiac trunk lymph nodes, which would also have been encountered during routinely performed explorative laparotomy. However, the other patient had a very small peritoneal deposit. Thorough exploration of this area, however, would not have been performed routinely but was specifically guided by FDG-PET. Thus, in this specific patient, FDG-PET found distant metastasis which would have otherwise been missed and therefore in total, esophagectomy was prevented in 7 patients (3.5%). Synchronous neoplasms were detected in 7 patients (3.5%, 95% CI, 2.2% to 4.8%) by FDG-PET. In 5 patients, an adenoma in the rectosigmoid was confirmed by colonoscopy.

§: based upon conventional staging, GEJ: gastroesophageal junction, SCC: squamous cell carcinoma, AC: adenocarcinoma, US: ultrasound, FNA: fine needle aspiration, MR: magnetic resonance imaging, CT: computed tomography, BAL: bronchial alveolar lavage, #: based on physical examination

Table 3. Details of 30 Patients with New Suspicious Lesions on FDG-PET not Detected During Conventional StagingNo. Sex Age Location Histology Stage§ Hotspot Additional Investigations Results Upstaging False-positive

1. F 64 GEJ AC III Peritoneal Laparoscopy, laparotomy AC + -

2. M 68 Distal AC III Scapula / back MR shoulder + biopsy subscapular muscle AC + -

3. M 57 Distal AC III Celiac trunk Laparotomy AC + -

4. F 72 GEJ AC III Liver US abdomen Metastases + -

5. M 68 Distal AC III Bone MR vertebral column, pelvis, CT guided FNA AC + -

6. F 46 Distal AC III Bone X-ray, MR vertebral column, CT guided FNA AC + -

7. M 69 Distal SCC III Bone MR vertebral column Metastases + -

8. M 56 Distal AC IV Bone MR vertebral column Metastases + -

9. F 69 Mid SCC III Supraclavicular MR neck, US of the neck + FNA Hürthle cell tumor - -

10. M 65 Distal AC III Colon Colonoscopy AC - -

11. M 62 Distal AC II Colon Colonoscopy Adenoma - -

12. M 70 Distal AC III Colon Colonoscopy Adenoma - -

13. M 65 Distal AC III Colon Colonoscopy Adenoma - -

14. M 53 Distal SCC III Rectum Sigmoidoscopy + colonoscopy Adenoma - -

15. M 69 Distal AC III Rectum Colonoscopy Adenoma - -

16. F 46 Distal SCC III Bone X-ray, bone scan Hematoma# - +

17. M 55 Distal SCC II Bone Bone scan No metastases - +

18. M 74 GEJ AC III Bone X-ray, bone scan No metastases - +

19. M 77 Distal SCC III Bone MR vertebral column No metastases - +

20. M 57 Distal AC II Bone Bone scan No metastases - +

21. M 55 GEJ AC II Supraclavicular US of the neck + FNA Lymfoid cells - +

22. M 56 Distal AC III Lung CT thorax Atelectasis - +

23. M 50 Distal AC III Lung CT thorax No metastases - +

24. F 67 Distal SCC III Lung / ovaries Bronchoscopy + BAL, CT abdomen/pelvis No metastases - +

25. M 51 GEJ AC III Celiac trunk Laparotomy Reactive - +

26. M 70 Distal AC III Celiac trunk Laparotomy Benign - +

27. M 63 Distal AC III Celiac trunk Laparotomy Benign - +

28. M 63 Distal AC II Groin US of the groin + FNA Reactive - +

29. F 72 Distal AC III Colon Sigmoidoscopy Diverticulitis - +

30. M 48 Distal AC II Rectum Sigmoidoscopy Diverticulitis - +

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In patient 10, an adenocarcinoma of the colon was encountered. In patient 9, a Hürthle cell tumor of the thyroid was initially suspected to be a supraclavicular metastasis. Since the prognosis of these patients depended on the esophageal carcinoma and not on the second primary tumor, all patients underwent an esophagectomy. Patient 10 underwent a hemicolectomy in the same session, and patient 9 underwent a subtotal hemithyroidectomy three months after the initial operation. Both patients developed no metastases of both tumors during the follow-up period. In the remaining 15 patients with a lesion on FDG-PET, additional observations did not reveal evidence of malignancy, nor was there progression of the lesion during a follow-up period of at least 6 months. In 3 of these patients (25, 26, 27), FDG-PET was positive for celiac trunk metastases, however, explorative laparotomy with frozen section revealed no metastases and subsequently curative resection was performed. Another one of these 15 patients had a lung lesion suspicious for metastasis on FDG-PET, which was not confirmed by additional work-up, however, surgical exploration revealed peritoneal metastases, missed on preoperative CT and FDG-PET. The rate of false-positive findings was 7.5% (95% CI, 3.9% to 11.2%) and 50% of all positive test results.

Table 4. Numbers and Costs of Additional Investigations for Verification of

Suspected FDG-PET Findings

Investigation (costs) Number Costs (euros)

X-ray humerus (40) 1 40

X-ray pelvis (40) 1 40

X-ray femur (40) 1 40

Bone scan (161) 4 644

CT thorax (212) 2 424

CT abdomen + pelvis (184) 1 184

CT guided FNA (260) 2 520

US of the neck + FNA (132) 2 265

US of the groin + FNA (132) 1 132

US of the abdomen (57) 1 57

Bronchoscopy + BAL (382) 1 382

MR shoulder (212) 1 212

MR vertebral column (212) 4 848

MR vertebral column + pelvis (424) 1 424

MR neck (255) 1 255

Biopsy muscle (153) 1 153

Sigmoidoscopy (335) 3 1,004

Colonoscopy (370) 6 2,217

Laparoscopy (1056) 1 1,056

Total 8,897

CT: computed tomography, FNA: fine needle aspiration, US: ultrasound, MR: magnetic reso-nance, BAL: bronchial alveolar lavage

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Additional Value of FDG-PET in Esophageal Cancer

Surgical proceduresIn total, esophagectomy was performed by a transthoracic approach in 113 patients, and by a transhiatal approach in 48 patients, while total gastrectomy was performed in 5 patients. Surgical exploration was performed in 25 patients. Two surgical explorations were performed to verify FDG-PET findings, while resection was abandoned in 23 patients because of ingrowth of the tumor into adjacent organs (n = 14, 7%) or unexpected distant metastases (n = 9, 4%), not detected by CT, EUS and FDG-PET (Table 5).

FDG-PET characteristics In summary, FDG-PET results were positive in 30 patients (positivity rate 15%; 95% CI, 11% to 21%), of which distant metastases were confirmed in 8 (4%; PPV 27%; 95% CI, 14% to 44%) and surgical exploration was prevented in 6 (3% of the total group). Noncurative esophagectomy was prevented in 7 patients (3.5%, 95% CI, 2.1% to 4.8%).

CostsA summary of the costs of FDG-PET and surgical exploration are presented in Table 6. FDG

Table 5. Localization of False-Negative Findings

Encountered During Surgical Exploration in 9 Patients

Localization Number

Peritoneal/omentum 3

Para-aortic 2

Liver 2

Right recurrent nerve node 1

Celiac trunk region 1

Table 6. Costs of FDG-PET, Additional Investigations, and Surgical Exploration

Procedure Costs (euros) per patient Costs (euros) whole group

199 patients

FDG-PET 1,463 291,137Costs of personnel 179 35,621

Costs of equipment 495 98,505

Costs of FDG 789 157,011

Additional investigations 8,897

6 patients

Surgical exploration 9,330 55,980Costs of surgery 2,109 12,654

Costs of ICU stay 1,050 6,300

Costs of ward 6,170 37,020

FDG: 18F-fluorodeoxy-glucose, PET: positron emission tomography, ICU: intensive care unit

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constituted the main part of the total costs of FDG-PET (€ 291,137), while the costs of additional investigations because of findings on FDG-PET were estimated at € 8,897.Costs of surgical exploration were based on the data of the 23 explorations. Costs of stay in the ICU (mean 0.8 days, € 1,284 per day) and on the ward (mean 16.5 days, € 374 per day) were the main contributors to total costs (€ 55,980).The total costs of FDG-PET and additional investigations in this cohort of 199 patients (€ 300,034) were not compensated for by the cost reduction because of the prevention of unnecessary surgery in 6 patients (€ 55,980) (mean additional costs € 1,226 per patient) (Table 7). In a sensitivity analysis using the Dutch tariff for FDG-PET (€ 1,020), the cost was € 783 per patient. Increasing the costs of surgical exploration by 20% resulted in an average costs per patient of € 1,170.

Subgroup analysisUpstaging by FDG-PET was found 8 patients that had been staged at least stage III (n = 122) by conventional staging. The rate of upstaging in this subset of patients is therefore 6.6% (95% CI, 2.2% to 11%), and stage of disease was a prediction for positive PT findings. No other items (i.e. age, histology, localization) were predictive for suspicious PET findings. Exclusion of patients with stage I-II disease would have led to a reduction of patients with positive FDG-PET findings from 30 to 24 patients leading to a reduction of cost regarding FDG-PET and related additional investigations. The additional mean costs of FDG-PET in this subgroup of patients are € 1,067 per patient.

DISCUSSIONIn this prospective multicenter cohort study, additional FDG-PET after conventional staging revealed distant metastases in 4% of the patients with esophageal cancer, preventing unnecessary surgery in 3% of patients. All cases of upstaging were observed in advanced

Table 7. Summary of Effects and Costs of FDG-PET in Esophageal Cancer Staging

Effects

Number of clinically relevant findings 15

Number of patients with synchronous neoplasms 7

Number of patients with detected metastases 8

Number of patients with metastases detected without surgery 6

Costs (euros) FDG-PET 291,137

Additional work-up 8,897

Prevented surgical explorations -55,980

Total costs for 199 patients 244,054Mean costs per patient 1,226

FDG: 18F-fluorodeoxy-glucose, PET: positron emission tomography

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Additional Value of FDG-PET in Esophageal Cancer

(stage III-IV) EC patients considered resectable after work-up with MDCT and EUS leading to a rate of 7% upstaging. In addition, FDG-PET detected synchronous neoplasms in 3.5% of this cohort of patients. The non-malignant cause of FDG uptake in all cases could be assessed by simple noninvasive additional investigations or exploratory surgery routinely performed before esophagectomy and was finally confirmed by follow-up. The costs of adding FDG-PET were not compensated by cost savings of prevented surgical explorations. A substantial amount of false-positive and false-negative findings were encountered in this study. False-positive findings are usually caused by accumulation of FDG in inflammatory or reactive tissue. In some cases (e.g. diverticulitis, organizing hematoma), the benign cause for abnormal FDG accumulation (scored as high uptake and probably malignant) could be clarified by additional investigations like physical examination (hematoma) or colonoscopy (diverticulitis). These findings underline the need to confirm positive findings on FDG-PET by additional work-up before denying patients surgical therapy.10 False-negative findings were encountered in 5% of patients. Metastatic deposits on the liver and omentum were missed on each modality, including FDG-PET, because they were very small and in case of PET adjacent to FDG avid organs/structures, i.e. liver. Also para-aortic and cervical lymph nodes were not always effectively detected because these nodes were not enlarged. In addition, the exact localization of positive PET findings in lymph nodes at the locoregional resectable celiac trunk and in nonregional sites (para-aortic region) can be difficult because of the lack of anatomic information on FDG-PET to distinguish locoregional from distant lymph node metastases. The introduction of PET/CT might be of additional value under these circumstances but the incremental value of this technique still has to be determined.11,12 The considerable number of patients with ingrowth of the tumor into adjacent organs (8%) indicates that conventional techniques such as EUS and MDCT are not completely reliable and efforts directed at improving this false-negative rate may be worthwhile. The rate of upstaging in the present study was in the lower range as the rate claimed in the literature when the present study started (3% to 28%).13,14 There may be several reasons for this discrepancy. We analyzed the additional value of FDG-PET after extensive work-up encompassing state-of-the-art techniques with predefined minimal requirements, including EUS-FNA and the recently introduced MDCT. This is in contrast to most studies which investigated FDG-PET as an integral part of a standard diagnostic work-up.13,15 Moreover, we performed a prospective multicenter cohort study with a wide spectrum of disease (T1-3 N0-1 M0-1a) thereby avoiding selection bias. Previous studies were retrospective16,17 and included only advanced stages of disease18,19 which is related with a higher incidence of distant metastatic disease. Furthermore, this study was performed in specialized hospitals and therefore a selected group of patients with potentially curable disease were referred to our centers. This fact may hamper the generalizability of our results. The improved detection rate of distant metastases by an increased spatial resolution of MDCT and dedicated reading may be another reason for the relatively low rate of upstaging by FDG-PET in the present study. During the inclusion period, a substantial number of patients were not enrolled in this study because MDCT revelad metastasis that were not detected by single-slice spiral CT as performed in some referral hospitals. Recently, Kneist et al have also reported a low yield of FDG-PET in upstaging of patients with EC. They found only 1% upstaging in a group of 81 patients.5 The main reason for the lower rate of upstaging

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mentioned in that study, was the use of MDCT and revised lymph node size threshold. The routine addition of FDG-PET to the preoperative work-up resulted in incremental costs of € 1,226 per patient. The cost analysis was restricted to the diagnostic process up to and including surgical exploration which is performed prior to each resection. In five out of the eight upstaged patients, the distant metastases detected on FDG-PET were localized in the bone or muscle. These metastases would never have been detected during surgical exploration in a hypothetical situation where FDG-PET had not been performed. Therefore, FDG-PET prevented not only surgical exploration but also a noncurative resection in these 5 patients. We investigated the costs of staging and did not include the costs of treatment in our analysis. The mean total costs of a transthoracic esophagectomy were recently calculated at € 28,918 as described by Hulscher et al20 while the costs of palliative treatment were calculated to be around € 8,000 by Homs et al21 Taking these differences in costs into consideration, the need for accurate staging is emphasized, since it will prevent the costs and burden of unnecessary surgery in patients with a poor prognosis. A fully comprehensive analysis of staging strategies should include the downstream consequences and consider survival and quality of life as ultimate patient outcome measures. Such an analysis was beyond the scope of this study. The present study and the literature show the diagnostic yield of FDG-PET regarding upstaging may vary. Among several factors, differences in study design, spectrum of disease and diagnostic work-up may explain this variety and the conclusions drawn have a limited generalizability. Therefore, a univocal recommendation to implement FDG-PET in the diagnostic work-up of EC cannot be given. In summary, FDG-PET improves the selection for potentially curative surgery, especially in stage III-IV EC patients. However its yield after extensive conventional staging including EUS-FNA and MDCT is limited. The additional costs of FDG-PET were not compensated by the cost reduction of prevented surgery.

ACKNOWLEDGMENTThis study was supported by a grant from ZonMw Health Care Efficiency Research (945-11-002). The authors thank the nuclear medicine physicians J Pruim, RHJA Slart (University Hospital Groningen, The Netherlands) and OS Hoekstra (VU Medical Center, Amsterdam, The Netherlands) for their FDG-PET interpretations and reviewing the manuscript. We also like to thank SSKS Phoa and CY Nio for their CT interpretations, and NJ Smits for performing the ultrasonography of the neck.

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Additional Value of FDG-PET in Esophageal Cancer

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Pera M, Pera M. Recent changes in the epidemiology of esophageal cancer. Surg Oncol 2001;10:81-90.Rice TW. Clinical staging of esophageal carcinoma. CT, EUS, and PET. Chest Surg Clin N Am 2000;10:471-85.Van Westreenen HL, Heeren PA, van Dullemen HM, van der Jagt EJ, Jager PL, Groen H, Plukker JT. Positron emission tomography with F-18-fluorodeoxyglucose in a combined staging strategy of esophageal cancer prevents unnecessary surgical explorations. J Gastrointest Surg 2005;9:54-61.Van Westreenen HL, Westerterp M, Bossuyt PM, Pruim J, Sloof GW, van Lanschot JJ, Groen H, Plukker JT. Systematic Review of the Staging Performance of 18F-Fluorodeoxyglucose Positron Emission Tomography in Esophageal Cancer. J Clin Oncol 2004;22:3805-12.Kneist W, Schreckenberger M, Bartenstein P, Menzel C, Oberholzer K, Junginger T. Prospective evaluation of positron emission tomography in the preoperative staging of esophageal carcinoma. Arch Surg 2004;139:1043-9.Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edition. New York: John Wiley&Sons, 2003.Casson AG, Rusch VW, Ginsberg RJ, Zankowicz N, Finley RJ. Lymph node mapping of esophageal cancer. Ann Thorac Surg 1994;58:1569-70.Lonneux M, Borbath I, Bol A, Coppens A, Sibomana M, Bausart R, Defrise M, Pauwels S, Michel C. Attenuation correction in whole-body FDG oncological studies: the role of statistical reconstruction. Eur J Nucl Med 1999;26:591-8.Oostenbrink JB, Koopmanschap MA, Rutten FFH. Manual for costing: Methods and standard costs for economic evaluation in health care. (In Dutch). Amstelveen, The Netherlands: Health Insurance Council, 2000.Van Westreenen HL, Heeren PA, Jager PL, van Dullemen HM, Groen H, Plukker JT. Pitfalls of positive findings in staging esophageal cancer with f-18-fluorodeoxyglucose positron emission tomography. Ann Surg Oncol 2003;10:1100-5.Bar-Shalom R, Guralnik L, Tsalic M, Leiderman M, Frenkel A, Gaitini D, Ben Nun A, Keidar Z, Israel O. The additional value of PET/CT over PET in FDG imaging of oesophageal cancer. Eur J Nucl Med Mol Imaging 2005.Antoch G, Vogt FM, Freudenberg LS, Nazaradeh F, Goehde SC, Barkhausen J, Dahmen G, Bockisch A, Debatin JF, Ruehm SG. Whole-body dual-modality PET/CT and whole-body MRI for tumor staging in oncology. JAMA 2003;290:3199-206.Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, de Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18:3202-10.Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy. Br J Cancer 1998;78:521-7.Luketich JD, Friedman DM, Weigel TL, Meehan MA, Keenan RJ, Townsend DW, Meltzer CC. Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans. Ann Thorac Surg 1999;68:1133-6.Block MI, Patterson GA, Sundaresan RS, Bailey MS, Flanagan FL, Dehdashti F, Siegel BA, Cooper JD. Improvement in staging of esophageal cancer with the addition of positron emission tomography. Ann Thorac Surg 1997;64:770-6.Wren SM, Stijns P, Srinivas S. Positron emission tomography in the initial staging of esophageal cancer. Arch Surg 2002; 137:1001-6.Kato H, Kuwano H, Nakajima M, Miyazaki T, Yoshikawa M, Ojima H, Tsukada K, Oriuchi N, Inoue T, Endo K. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer 2002;94:921-8.Rankin SC, Taylor H, Cook GJ, Mason R. Computed tomography and positron emission tomography in the preoperative staging of oesophageal carcinoma. Clin Radiol 1998;53:659-65.Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, Stalmeier PF, ten Kate FJ, van Dekken H, Obertop H, Tilanus HW, van Lanschot JJ. Extended transthoracic resection

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compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347:1662-9.Homs MY, Steyerberg EW, Eijkenboom WM, Tilanus HW, Stalpers LJ, Bartelsman JF, van Lanschot JJ, Wijrdeman HK, Mulder CJ, Reinders JG, Boot H, Aleman BM, Kuipers EJ, Siersema PD. Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial. Lancet 2004;364:1497-504.

6SYNCHRONOUS PRIMARY NEOPLASMS DETECTED ON POSITRON EMISSION TOMOGRAPHY IN STAGING OF

PATIENTS WITH ESOPHAGEAL CANCER

HL van Westreenen1

M Westerterp2

PL Jager3

HM van Dullemen4

GW Sloof5

EFI Comans6

JJB van Lanschot2

T Wiggers1

JThM Plukker1

Departments of Surgery1, Nuclear Medicine/PET center3, Gastroenterology4 University Hospital Groningen, The Netherlands

Departments of Surgery2, Nuclear Medicine5

Academic Medical Center, Amsterdam, The NetherlandsDepartment of Nuclear Medicine6

VU Medical Center, Amsterdam, The Netherlands

Journal of Nuclear Medicine 2005;46;1321-1325

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ABSTRACTIntroduction: Because of improvements in diagnostic technology, the incidental detection of synchronous primary tumors during the preoperative work-up of patients with esophageal cancer has increased. The aim of this study was to determine the rate and clinical relevance of synchronous neoplasms seen on FDG-PET in staging of esophageal cancer. Methods: From January 1996 to July 2004, 366 patients with biopsy-proven malignancy of the esophagus underwent FDG-PET for initial staging. This series of patients was retrospectively reviewed for the detection of synchronous primary neoplasms. Results: Twenty synchronous primary neoplasms were identified in 366 patients (5.5%). Eleven neoplasms were localized in the colorectum, 5 in the kidney, and 2 in the thyroid gland, 1 in the lung, and 1 in the gingiva. One of the thyroid lesions and the lung lesion were erroneously interpreted as metastases, leading to incorrect upstaging of the esophageal tumor. Conclusions: FDG-PET detected unexpected synchronous primary neoplasms in 5.5% of patients with esophageal cancer. Sites of pathologic FDG uptake should be confirmed by dedicated additional investigations before treatment, because synchronous neoplasms may mimic metastases.

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Synchronous Neoplasms in Esophageal Cancer

INTRODUCTIONThe association between synchronous primary tumors in the aerodigestive tract is a well-known phenomenon that has been explained by the concept of ‘field cancerization’.1,2 The mucous epithelium of the head and neck, lung, and esophagus is exposed to common carcinogenic agents, leading to multiple carcinomas in these regions. Strong epidemiological evidence implicates tobacco as the main carcinogen and alcohol as a promoter of carcinogenesis.3

The incidence of synchronous cancers in patients with esophageal cancer ranges from 3.6% to 27.1%.4,5 Most of these synchronous cancers are in the head and neck region. Other frequently reported sites of synchronous cancer associated with esophageal cancer are in the stomach, lung, and urinary bladder.6,7 The detection of incidental synchronous tumors in patients with esophageal cancer has increased along with recent improvements in diagnostic technology. Whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been used successfully with increasing frequency in the evaluation and clinical management of many tumors.8-10 Routine interpretation of FDG-PET scans may reveal incidental hypermetabolic foci that are probably unrelated to the neoplasms for which these patients are initially scanned. On the other hand, lesions on FDG-PET that are interpreted as metastatic deposits of the primary tumor may, in fact, reflect accumulated FDG in a second synchronous tumor.11 The aim of this study was to determine the rate and clinical relevance of unexpected synchronous neoplasms seen of FDG-PET scans obtained during the preoperative evaluation of patients with esophageal cancer.

MATERIALS AND METHODSPatients From January 1996 to July 2004, a total of 366 patients with biopsy-proven malignancy of the esophagus were treated in 2 academic hospitals (University Hospital Groningen, Academic Medical Center, Amsterdam) and retrospectively analyzed for this study. All patients underwent FDG-PET, endoscopic ultrasonography (EUS), computed tomography (CT) of the thorax and abdomen, and external sonography of the cervical region for initial staging. Staging was according to the 2003 classification of the International Union Against Cancer classification.12

Positron emission tomography PET was performed with an ECAT 951/31 or an ECAT HR+ positron camera (Siemens/CTI, Knoxville, TN, USA). The 951/31 acquires 31 planes over 10.9 cm, the HR+, 63 planes over a 15.8 cm axial field of view. All patients fasted for at least 4 hours before a mean dose of 410 MBq FDG was administered intravenously. The number of bed positions ranged from 7 to 9, depending of the length of the patient, and all patients were scanned from the crown the mid femoral region. Data acquisition in whole body mode started 90 minutes after injection, with data being acquired for 5 minutes per bed position from the skull to the knees. Transmission imaging for attenuation correction was performed for 3 minutes per bed position

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for attenuation correction. Data from multiple bed positions were iteratively reconstructed (ordered-subset expectation maximization) into attenuated and nonattenuated whole-body PET images.13

InterpretationFDG-PET findings were interpreted on computer monitors by 1 of 2 nuclear medicine physicians. Possible sites of metastatic disease for esophageal cancer were reported. FDG accumulation in regions not likely to be site of metastatic spread from esophageal cancer were reported as susgestive of synchronous tumor, depending on intensity and pattern. All PET reports were retrospectively analyzed.

RESULTSIn this series of 366 patients who underwent FDG-PET during initial staging of esophageal cancer, synchronous primary lesions were identified in 20 patients (5.5%). Except for the 5 renal tumors, the described neoplasms were not detected by routine staging procedures. Details of these 20 patients are summarized in Table 1. Sixteen unexpected foci of uptake

M: male; F: female; GEJ: gastroesophageal junction; AC: adenocarcinoma; SCC: squamous cell carcinoma

Table. 1 Characteristics of 20 Patients with Esophageal Cancer and a Synchronous Neoplasm

Esophageal cancer Synchronous primary neoplasms

No. Sex/Age Localization Histology Localization Histology

1. F/69 Distal AC Right colon AC

2. M/65 Distal AC Right colon AC

3. M/71 GEJ AC Right kidney Grawitz

4. M/67 Distal AC Right kidney Grawitz

5. M/68 GEJ AC Right kidney Grawitz

6. M/69 GEJ AC Right kidney Grawitz

7. M/47 Mid esophagus SCC Left kidney Grawitz

8. M/72 Distal SCC Lung SCC

9. F/70 Mid esophagus SCC Thyroid Hürthle cell tumor

10. M/58 Mid esophagus SCC Gingiva SCC

11. M/55 Distal SCC Right colon -

12. M/74 GEJ AC Right colon -

13. M/64 Distal AC Left colon Tubulovillous adenoma

14. M/63 Distal AC Left colon Tubulovillous adenoma

15. M/70 Distal AC Left colon Tubulovillous adenoma

16. M/70 Distal AC Rectum Tubulovillous adenoma

17. M/70 GEJ AC Rectum Tubular adenoma

18. M/53 Mid esophagus SCC Rectum Tubular adenoma

19. M/71 Distal AC Rectum -

20. M/64 Distal AC Thyroid -

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Synchronous Neoplasms in Esophageal Cancer

could be pathologically confirmed. Ten patients (50%) had a malignant synchronous tumor, and the remaining 10 patients had a benign or premalignant neoplasm.

Malignant lesions FDG-PET suggested a synchronous neoplasm in the ascending colon in patients 1 and 2. Colonoscopy revealed adenocarcinoma in both patients, and they underwent a transthoracic esophagectomy (Ivor-Lewis method) and right hemicolectomy in a single surgical session. A synchronous primary tumor was found in the kidney in 5 patients (3, 4, 5, 6 and 7). In all these patients, initial abdominal CT also revealed a mass in the renal region. Patient 3 underwent a diagnostic laparoscopy revealing peritonitis carcinomatosa, and therefore, no surgical therapy was indicated. In patient 4, cytology revealed a Grawitz’s tumor; however, the tumor of the esophagus was not eligible for curative therapy. Patient 5 underwent a curative esophageal resection followed by a curative nephrectomy 3 months later. Patients 6 and 7 were considered eligible for esophagectomy and nephrectomy in a single surgical session (Figure 1). However, in patient 7, after a successful nephrectomy the tumor of the esophagus was considered unresectable because of unexpected invasion of the thoracic aorta. Pathological examination revealed a Grawitz’s tumor in both patients. In patient 8, with a squamous cell carcinoma of the esophagus, FDG-PET revealed a

FIGURE 1FDG-PET scan in patient 7 with a synchronous carcinoma of the mid esophagus and a Grawitz’s carcinoma of the left kidney (coronal view).

Table. 1 Characteristics of 20 Patients with Esophageal Cancer and a Synchronous Neoplasm

Esophageal cancer Synchronous primary neoplasms

No. Sex/Age Localization Histology Localization Histology

1. F/69 Distal AC Right colon AC

2. M/65 Distal AC Right colon AC

3. M/71 GEJ AC Right kidney Grawitz

4. M/67 Distal AC Right kidney Grawitz

5. M/68 GEJ AC Right kidney Grawitz

6. M/69 GEJ AC Right kidney Grawitz

7. M/47 Mid esophagus SCC Left kidney Grawitz

8. M/72 Distal SCC Lung SCC

9. F/70 Mid esophagus SCC Thyroid Hürthle cell tumor

10. M/58 Mid esophagus SCC Gingiva SCC

11. M/55 Distal SCC Right colon -

12. M/74 GEJ AC Right colon -

13. M/64 Distal AC Left colon Tubulovillous adenoma

14. M/63 Distal AC Left colon Tubulovillous adenoma

15. M/70 Distal AC Left colon Tubulovillous adenoma

16. M/70 Distal AC Rectum Tubulovillous adenoma

17. M/70 GEJ AC Rectum Tubular adenoma

18. M/53 Mid esophagus SCC Rectum Tubular adenoma

19. M/71 Distal AC Rectum -

20. M/64 Distal AC Thyroid -

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lesion in the right upper lobe suggestive of lung metastasis or synchronous lung carcinoma. Additional bronchoscopic examination provided cytological evidence of a primary squamous cell carcinoma of the lung. The patient underwent right upper lobectomy and esophagectomy in a single session. In patient 9, a supraclavicular metastasis was suspected on the basis of FDG-PET findings (Figure 2). However, neither initial CT nor sonography of the cervical region showed any lymphatic abnormalities, nor did additional magnetic resonance imaging of the cervical region. A second sonographic examamination with fine-needle aspiration demonstrated a Hürthle cell thyroid tumor, for which a thyroidectomy was performed several months after the initial esophagectomy. FDG-PET showed in patient 10 a focus suggestive of a synchronous neoplasm in the oral cavity. Examination by a maxillofacial surgeon revealed a small squamous cell carcinoma of the gingiva. The gingival carcinoma in this patient was resected, but because of severe comorbidity the esophageal tumor was treated with combined intraluminal and extraluminal irradiation with curative intention.

Benign lesionsSynchronous neoplasms were suspected in the ascending colon of patients 11 and 12, and in the descending colon of patient 13-15. Colonoscopy revealed a tubulovillous adenoma

FIGURE 2Tumor in the mid esophagus and a synchronous Hürthle cell thyroid tumor as confirmed by fine-needle aspiration in patient 9 (coronal view).

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in patient 13-15, which was resected endoscopically. In patients 11 and 12, no histologic exam was performed before surgery. Patient 11 underwent a transthoracic esophagectomy with curative intent. However, because locoregional recurrence developed shortly after resection, follow-up of this synchronous lesion was not possible. In patient 12, diagnostic laparoscopy, which is standard in the diagnostic work-up of a cardia carcinoma, revealed peritonitis carcinomatosa, and the lesion in the colon was therefore not analyzed further. In 4 patients, an unexpected FDG accumulation was observed in the rectum and considered suggestive of a neoplasm. Sigmoidoscopy revealed tubulovillous adenoma in patient 16 (Figure 3), and tubular adenoma in patients 17 and 18. All these adenomas were resected endoscopically. In patient 19, no histologic exam was performed. All the patients underwent esophagectomy with curative intention. Patient 19 died postoperatively; therefore, no histologic exam was performed. In patient 20, FDG-PET showed a lesion suggestive of a neoplasm in the thyroid gland. Additional sonography of the neck showed a hypoechogenic lesion suggestive of thyroid adenoma, and the lesion did not progress during 6 months follow-up.

FIGURE 3FDG-PET scan in patient 16 with a distal esophageal tumor and a syn-chronous rectal adenoma (saggital view).

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DISCUSSIONThe rate of synchronous neoplasms seen on FDG-PET in this unselected group of 366 patients with esophageal cancer was 5.5%. Most lesions were in the colon or rectum (11/20; 55%). Sixteen lesions were evaluated histologically. The rate of unexpected synchronous neoplasms in this study lies within the range of synchronous tumors for esophageal cancer as reported in the literature.4,6,7 In general, the occurrence of synchronous cancers strongly depends on the type of the initial cancer. Synchronous malignant tumors were detected in 9% to 18% in patients with head and neck cancer, whereas in an inhomogeneous group of various cancer types the rate of malignant and premalignant tumors was 1.7%.14-16 Misinterpretation of synchronous primary neoplasms may lead to incorrect upstaging of the primary tumor, as is demonstrated in patients 8 and 9. These patients were initially suspected of having distant metastases (stage IV), on the basis of PET finding, and would have erroneously been considered ineligible for surgery if histologic conformation had not been sought. Therefore, additional investigations are mandatory to confirm the PET findings before any therapeutic decision is made. However, 4 lesions were histologically verified in this study. In some patients, it was argued that the esophageal cancer heavily determined prognosis and that, therefore, the verification of assumed benign or premalignant lesions was not necessary. Nevertheless, the 2 lesions of the colorectum that turned out to be carcinomas are an argument in favor of verification of any positive PET finding. Another reason to verify positive PET findings is the well-known risk of false-positive results. FDG is not a tumor-specific substance, and false-positive results may occur as a result of increased glucose metabolism in benign lesions (e.g. inflammatory tissue). Therefore, positive findings on FDG-PET must be confirmed by additional investigations, preferably by percutaneous or ultrasound- or CT-guided cytologic biopsy, or dedicated radiography, before patients are denied surgery with curative intent.11 Usually, physiologic colonic activities appears more tubular and diffuse than do separate colonic tumors, which appear more focal and of higher intensity. Because the renal excretion pattern of FDG is similar to that of other radiopharmaceuticals, physiologic activities in renal collecting systems are easily detectable based on the precise location of activity, intensity of distribution, shape of the calyces and pelvis, and overall pattern of both kidneys. The detection of synchronous tumors by whole-body FDG-PET poses a dilemma in the choice of the most suitable therapeutic strategy. For synchronous cancers, including esophageal cancer, the highest-priority treatment priority should focus on the tumor most limiting the prognosis.6 Therefore, optimal pretreatment staging of both tumors to assess their prognosis is the first step in clinical assessment. If discrimination between 2 independent primary tumors versus metastatic disease is not possible based on conventional histology, cytogenetic analysis such as determination of loss of heterozygosity and p53 aberrations may be helpful to therapeutic decision making.17 Resection of both neoplasms with curative intention frequently offers the best long-term survival; however, even in the case of an incurable synchronous cancer (e.g. metastatic prostate cancer), esophagectomy is not always contraindicated.18 The type of treatment for such esophageal carcinomas strongly depends on the type and prognosis of the synchronous malignancy.

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Evidence-based arguments about whether to perform a simultaneous or a staged operation are not available. Suzuki et al reported that simultaneous resection of both neoplasms has acceptable morbidity and mortality rates.18 However, for each patient, the risks and benefits of simultaneous surgery should be weighed against those of a second operation.19 The incidental detection of synchronous colorectal polyps or cancers and other malignancies by FDG-PET is not uncommon.16,20,21 Unfortunately, FDG-PET is not able to differentiate between colorectal adenoma and carcinoma.22 A true association between adenocarcinoma of the esophagus and colonic neoplasms would suggest common causes and might indicate the existence of an inherited general genetic defect. Another possible explanation might be exposure to environmental factors such as alcohol, smoking and a fatty diet. In addition, increased expression of the cyclooxygenase 2 enzyme is central to the predisposition of both esophageal and colorectal cancers.23,24 However, a population-based cohort study in Sweden did not demonstrate an association between colorectal cancer and adenocarcinoma of the esophagus.25

In conclusion, FDG-PET may detect synchronous primary neoplasms in patients with esophageal cancer. Sites of suspected metastases should be confirmed histologically before treatment, because synchronous neoplasms can mimic metastatic disease.

ACKNOWLEDGMENTThis study was supported by a ZonMw program for Health Care Efficiency Research.

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Poon RT, Law SY, Chu KM, Branicki FJ, Wong J. Multiple primary cancers in esophageal squamous cell carcinoma: incidence and implications. Ann Thorac Surg 1998;65:1529-34.Van Rees BP, Cleton-Jansen AM, Cense HA, Polak MM, Clement MJ, Drillenburg P, van Lanschot JJ, Offerhaus GJ. Molecular evidence of field cancerization in a patient with 7 tumors of the aerodigestive tract. Hum Pathol 2000;31:269-71.Castellsague X, Quintana MJ, Martinez MC, Nieto A, Sanchez MJ, Juan A, Monner A, Carrera M, Agudo A, Quer M, Munoz N, Herrero R, Franceschi S, Bosch FX. The role of type of tobacco and type of alcoholic beverage in oral carcinogenesis. Int J Cancer 2004;108:741-9.Kagei K, Hosokawa M, Shirato H, Kusumi T, Shimizu Y, Watanabe A, Ueda M. Efficacy of intense screening and treatment for synchronous second primary cancers in patients with esophageal cancer. Jpn J Clin Oncol 2002;32:120-7.Voormolen MHJ, Van Deelen RAJ, Tilanus HW, van Lanschot JJB. Esophageal carcinoma and multiple primary tumors. Dis Esophagus 1995;8:218-21.Kumagai Y, Kawano T, Nakajima Y, Nagai K, Inoue H, Nara S, Iwai T. Multiple primary cancers associated with esophageal carcinoma. Surg Today 2001;31:872-6.Nagasawa S, Onda M, Sasajima K, Takubo K, Miyashita M. Multiple primary malignant neoplasms in patients with esophageal cancer. Dis Esophagus 2000;13:226-30.Czernin J, Phelps ME. Positron emission tomography scanning: current and future applications. Annu Rev Med 2002;53:89-112.Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. J Nucl Med 2001;42:1S-93S.Van Westreenen HL, Westerterp M, Bossuyt PM, Pruim J, Sloof GW, van Lanschot JJ, Groen H, Plukker JT. Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 2004;22:3805-12.Van Westreenen HL, Heeren PA, Jager PL, van Dullemen HM, Groen H, Plukker JT. Pitfalls of positive findings in staging esophageal cancer with f-18-fluorodeoxyglucose positron emission tomography. Ann Surg Oncol 2003;10:1100-5.Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edition. New York: John Wiley&Sons, 2003.Lonneux M, Borbath I, Bol A, Coppens A, Sibomana M, Bausart R, Defrise M, Pauwels S, Michel C. Attenuation correction in whole-body FDG oncological studies: the role of statistical reconstruction. Eur J Nucl Med 1999;26:591-8.Schwartz DL, Rajendran J, Yueh B, Coltrera M, Anzai Y, Krohn K, Eary J. Staging of head and neck squamous cell cancer with extended-field FDG-PET. Arch Otolaryngol Head Neck Surg 2003;129:1173-8.Stokkel MP, Moons KG, ten Broek FW, van Rijk PP, Hordijk GJ. 18F-fluorodeoxyglucose dual-head positron emission tomography as a procedure for detecting simultaneous primary tumors in cases of head and neck cancer. Cancer 1999;86:2370-7.Agress H, Jr., Cooper BZ. Detection of clinically unexpected malignant and premalignant tumors with whole-body FDG PET: histopathologic comparison. Radiology 2004;230:417-22.Van der Sijp JR, van Meerbeeck JP, Maat AP, Zondervan PE, Sleddens HF, van Geel AN, Eggermont AM, Dinjens WN. Determination of the molecular relationship between multiple tumors within one patient is of clinical importance. J Clin Oncol 2002;20:1105-14.Suzuki S, Nishimaki T, Suzuki T, Kanda T, Nakagawa S, Hatakeyama K. Outcomes of simultaneous resection of synchronous esophageal and extraesophageal carcinomas. J Am Coll Surg 2002;195:23-9.Morris HL, da Silva AF. Co-existing abdominal aortic aneurysm and intra-abdominal malignancy: reflections on the order of treatment. Br J Surg 1998;85:1185-90.Tatlidil R, Jadvar H, Bading JR, Conti PS. Incidental colonic fluorodeoxyglucose uptake: correlation with colonoscopic and histopathologic findings. Radiology 2002;224:783-7.Zhuang H, Hickeson M, Chacko TK, Duarte PS, Nakhoda KZ, Feng Q, Alavi A. Incidental detection of colon cancer by FDG positron emission tomography in patients examined for pulmonary nodules. Clin Nucl Med 2002;27:628-32.

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22.

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Yasuda S, Fujii H, Nakahara T, Nishiumi N, Takahashi W, Ide M, Shohtsu A. 18F-FDG PET detection of colonic adenomas. J Nucl Med 2001;42:989-92.Buskens CJ, Van Rees BP, Sivula A, Reitsma JB, Haglund C, Bosma PJ, Offerhaus GJ, van Lanschot JJ, Ristimaki A. Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology 2002;122:1800-7.Church RD, Fleshman JW, McLeod HL. Cyclo-oxygenase 2 inhibition in colorectal cancer therapy. Br J Surg 2003;90:1055-67.Lagergren J, Nyren O. No association between colon cancer and adenocarcinoma of the oesophagus in a population based cohort study in Sweden. Gut 1999;44:819-21.

7PITFALLS OF POSITIVE FINDINGS IN STAGING ESOPHAGEAL

CANCER WITH 18F-FLUORODEOXYGLUCOSE POSITRONEMISSION TOMOGRAPHY

HL van Westreenen1

PAM Heeren1

PL Jager2

HM van Dullemen3

H Groen4

JThM Plukker1

Departments of Surgery1, Nuclear Medicine/PET center2,Gastroenterology3, Office for Medical Technology Assessment4

University Hospital Groningen, The Netherlands

Annals of Surgical Oncology 2003;10:1100-1105

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ABSTRACTIntroduction: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is valuable in staging of esophageal cancer. However, FDG-PET may falsely upstage patients leading to incorrect exclusion from surgical treatment. This study was performed to determine the false-positive rate and possible causes. Patients and Methods: The rate of false-positive lesions on FDG-PET was documented in 86 out of a group of 98 patients. Lesions were defined as false-positive when pathological examination was negative or as absence of tumor activity within 6 months of follow-up. To evaluate the influence of a learning curve on the false-positive rate, the PET scans were revised recently. Results: False-positive lesions were found in 13 patients (13 of 86; 15%). FDG-PET incorrectly revealed only locoregional node metastases in 5 patients in whom surgery with curative intent was performed. Ten lesions in the other 8 patients were classified as distant organ or as nonregional node metastases (M1a/1b). Finally, 5 patients upstaged to M1a/1b underwent a curative resection. The number of false-positive lesions decreased from 16 to 5 (6%) after revision. Conclusion: Proper interpretation of FDG-PET in staging esophageal cancer is impeded by false-positive results. Even after completion of the learning curve, positive FDG-PET findings still have to be confirmed by additional investigations.

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INTRODUCTIONThe incidence of esophageal cancer is currently reported 3.2 per 100,000 persons. The incidence has shown a rising trend for 15 years. Surgical resection is still the only treatment with curative intent, and accurate staging is essential to select patients for esophagectomy. Traditionally, staging of esophageal cancer consists of computed tomography (CT), endoscopic ultrasonography (EUS), and sonographic examination of the neck.1 During the last decade, positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) as a tracer, has gained more and more acceptance as an additional staging tool in the preoperative work-up. Conventional staging modalities have the potential to give anatomic and morphological information about tumor extension, organ and lymph node metastases, whereas PET scanning identifies metabolically active cancer tissue based on a high glucose metabolism. FDG-PET has high sensitivity (70% to 90%) and specificity (90% to 100%) in detecting distant organ (M1b) and distant lymph node metastasis (M1a/1b).2-9 The main benefit of the high accuracy of FDG-PET in staging esophageal cancer is the reduction of useless surgery in patients with distant metastases. Whether whole-body FDG-PET can be used as a single-method imaging survey in esophageal cancer patients, however is questionable. The pitfall lies in the FDG-PET false-positive results, which may lead to improper upstaging of patients, and incorrect exclusion from curative treatment. Several studies have demonstrated that false-positive FDG-PET results are usually caused by inflammatory reactions.5,10,11 Other studies hypothesize inhomogeneous tracer uptake in the primary tumor site as a possible explanation for the occurrence of false-positive results.3,4 For most false-positive cases in staging of esophageal cancer in the literature, a clear reason is not described, nor has literature suggested ways to reduce false-positive FDG-PET results. As in other diagnostic areas, the learning curve in the rating of PET images may also play an important role in the accuracy of staging with FDG-PET, but this has not yet been investigated in staging of esophageal cancer. The aim of this study was to document the false-positive rate in staging esophageal cancer with FDG-PET and to study potential causes of the false-positive results and their impact on clinical management. The role of a learning curve in reducing false-positive FDG-PET results was investigated as well.

MATERIALS AND METHODSPatientsA retrospective review was performed on the records of 98 consecutive patients with a biopsy-proven malignancy of the esophagus. All patients were staged with CT thorax and abdomen, EUS, and sonography of the neck and diagnosed between January 1996 and March 2002. In addition all patients underwent FDG-PET. Treatment of all patients was based on the conventional staging or confirmed FDG-PET findings. None of these patients received neoadjuvant treatment. The location of lesions was correlated to the pathological findings of resected specimens and biopsies obtained during surgery. If pathology was not available, lesions were verified by at least 6 months of follow-up time.12,13 Hotspots were defined as false

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positive when pathological examination was negative for metastatic disease or when there was no clinical and radiological evidence for metastatic activity within 6 months of follow-up. Lesions seen by PET but not histologically confirmed were considered to be true-positive if clinical findings appeared at the site identified by FDG-PET within the 6 months of follow-up. An exclusion criterion was the absence of the standard reference. Based on this criterion, 86 patients (72 male and 14 female) were included (Table 1). Twelve patients (8 male/4 female) were excluded because the follow-up was shorter than 6 months. One patient died postoperatively; all other patients had an advanced stage of disease.

Positron emission tomographyFDG was produced according to the robotic method described by Hamacher et al14 with a radiochemical purity over 98%. An ECAT 951/31 or an ECAT HR+ positron camera (Siemens/CTI, Knoxville, KY, USA) was used for data acquisition. The ECAT 951/31 acquires 31 planes over 10.9 cm, and the HR+ camera acquires 63 planes over a 15.8 cm axial field of view. All patients fasted for at least 4 hours before 400-580 MBq FDG was administered intravenously into an antecubital vein. Data acquisition started 90 minutes after injection in whole body mode, for 5 minutes per bed position from the skull to the knees. Transmission imaging was obtained during 3 minutes per bed position for attenuation correction. Images were reconstructed using an iterative reconstruction technique and were read from computer monitors. All PET-scans were originally interpreted by one of two nuclear medicine physicians

Table 1. Characteristics of Included Patients (n=86)

No. of patients (%)

SexMale 72 (84)

Female 14 (16)

Age* 21-78 (61)

Localization Gastroesophageal junction 43 (50)

Distal esophagus 38 (44)

Mid esophagus 7 (6)

Histopathology Adenocarcinoma 67 (78)

Squamous cell carcinoma 14 (16)

Other malignancies 5 (6)

*Range (median)

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False-Positive PET Results in Esophageal Cancer

without knowledge of the CT findings nor EUS data and pathologic information. All hotspots of a non-physiologic FDG uptake were considered indicative for metastatic disease. Differentiation between locoregional and distant lymph node involvement was based on the location of the hotspot and the distance to the primary tumor. Tumors were classified as N0, N1, M1a or M1b by translation of positive PET findings to the current tumor, node, metastasis staging system of the International Union Against Cancer (UICC). All positive PET scans were recently revised by an experienced nuclear physician (PLJ) to investigate the effect of the learning curve as a possible cause of false-positive results. The nuclear physician was blinded for all clinical information and previous staging results and gave a classification according to the tumor, node, metastasis system. To compare the reduction of false-positive results after revision to the initial interpretation a paired-samples t-test was used. A value of P < 0.05 was considered significant.

RESULTSAfter comparing initial FDG-PET findings with pathological and/or follow-up results, we identified 13 (15%) patients with false-positive FDG-PET scans with a total number of 16 false-positive foci of metabolic lesions (Table 2). Three patients (6,7, and 13) had two false-positive lesions in different locations. In five patients (1-5), FDG-PET showed foci suspected for locoregional metastases leading to incorrect N1 upstaging. Patient 6 was upstaged to

Table 2. Details of 16 False-Positive FDG-PET Results in 13 Patients

Patient Localization Upstaged Type of additional

investigations Results Treatment Reference

1. Locoregional N1 - - Resection Pathology

2. Locoregional N1 - - Resection Pathology

3. Locoregional N1 - - Resection Pathology

4. Locoregional N1 - - Resection Pathology

5. Locoregional N1 - - Resection Pathology

6. Locoregional N1 - - Resection Pathology

Cervical region M1b Sonography Negative Follow-up

7. Celiac region M1a - - Explorative laparotomy Follow-up

8. Liver M1b Sonography Negative Resection Pathology

Rectum M1b Colonoscopy Colitis Pathology

9. Lung M1b - - Resection Follow-up

10. Rectum M1b Colonoscopy Adenoma Explorative laparotomy Pathology

11. Ribs M1b Bone scan Negative Resection Follow-up

12. Brain M1b - - Palliation Follow-up

13. Cheek M1b Dental tomography Negative Resection Follow-up

Cervical region M1b Sonography Negative Follow-up

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N1 and M1b disease because of both a locoregional (N1) and a distant metastasis (M1b) were present on FDG-PET. Seven patients (7-13) with FDG-PET findings suspected for distant organ metastases or nonregional lymph node metastases were incorrectly upstaged to M1a or M1b. Only one of them (12) was confirmed to M1a/1b by conventional staging methods. Therefore, the FDG-PET findings were disregarded and the remaining patients underwent surgery with curative intent.

Localization of false-positive lesionsSeven false-positive lesions on FDG-PET were suspected for distant organ metastases (M1b). Of these lesions, one was localized in the liver, one in a lung, two in the rectum, one in a rib, one in the mandible, and one in the brain. Of the three lesions misinterpreted for nonregional lymph node metastases, one was localized in the celiac region (M1a) and two in the cervical region (M1b).

Additional investigationsSeveral additional investigations were performed to investigate the positive FDG-PET results. Lesions classified as locoregional lymph node metastases (N1) were not additionally investigated, because the presence of metastatic spread in locoregional nodes is not a contra indication for curative intended surgery. The lesions in the rectum of two patients were evaluated with colonoscopy and revealed colitis and an adenoma in the other patient, which was resected endoscopically. A maxillofacial surgeon examined the patient with a lesion in the mandible and dental tomography did not show any sign of malignancy. Bone scintigraphy to objectify the rib lesion could not confirm malignancy. The lesions in the liver and cervical region were examined sonographically, which revealed no abnormalities.

Clinical management The five patients (1-5) who were upstaged to N1 only were enrolled for surgery, and they all had a curative resection. The resected specimens, however, did not reveal malignant lymph nodes. The patient (12) suspected of brain metastases on FDG-PET had other confirmed metastases at conventional staging methods and was restrained from surgical therapy. Two patients (7 and 10) upstaged to M1a and M1b underwent surgery, but their tumor was not curatively resectable, because of distant metastases neither visualized on conventional imaging methods or on FDG-PET. Therefore, these PET scans can be considered false-negative as well. In the remaining 5 patients (6,8,10,11, and 13) upstaged to M1b based on FDG-PET results, a curative resection was performed.

Follow-upSix patients (6,7,9, and 11-13) with a false-positive lesion, which could not be confirmed by histological or cytological examination, had a follow-up time of at least 6 months (range, 6-44 months). The patient (12) with false-positive brain lesions died after 6 months because of other confirmed metastases. The remaining patients had a follow-up time of at least 17 months (range, 17-44 months) without clinical tumor activity at the lesion.

FDG-PET revisionThe revision of all positive FDG-PET resulted in a reduction from 16 to 5 false-positive lesions.

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The 6 locoregional metastases in the initial FDG-PET interpretation were all correctly staged as N0 at revision. The 10 distant metastases (M1a/1b) were reduced to 5. The suspected foci located in the celiac region, liver, brain, cheek, and one of the hotspots in the rectum were interpreted benign at revision. After revision, five patients were falsely upstaged to M1b disease (5.8%). In the first period from 1996 to 1999 the reduction of false-positive lesions was slightly higher (P = 0.16) than in the second period from 2000 to 2002. A false positive rate of 16.2% (7/43) in the first period reduced to 4.7% (2/43) after revision compared to the reduction from 14.1% (6/43) to 7.0% (3/43) in the second period (Figure 1).

DISCUSSIONSurgical resection is still the only curative treatment in patients with esophageal cancer, but is associated with a considerable morbidity and even mortality. Proper selection for surgical treatment of patients is essential, because only a limited number of patients can be expected to profit from resection in advanced disease states. The role of whole body FDG-PET imaging in detecting metastatic disease that is already beyond cure has been demonstrated in several studies. Adding FDG-PET may alter the therapeutic management by correctly upstaging the classification in 10% to 15% of patients.3-5 However, interpretation of FDG-PET in staging of esophageal cancer, no less than in other disease states, is impeded by a substantial rate of false-positive results. The initial rate of false-positive findings in this study was 15%, consisting of 7% regional and 9% distant metastases. False-positive hotspots upstaged to M1a/1b disease in 5 of the 13 patients (38%) were additionally examined

2000-20021996-1999

Fals

e-po

sitiv

es (%

) 18

16

14

12

10

8

6

4

2

Initial

At revisionFIGURE 1Percentage of false-positive cases in the period 1996-1999 (n = 43) and in the period 2000-2002 (n = 43).

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by several investigations revealing no abnormality. Therefore, these 5 patients were still considered resectable and finally underwent a curative resection. These findings emphasize the need to investigate positive FDG-PET results additionally before denying patients a chance of curative surgery. Possible allocation of adjuvant chemoradiotherapy in patients with N1 disease emphasizes the need to describe false-positive lesions leading to incorrect upstaging to N1 disease. The lesions falsely upstaged to N1 lesions may be caused by inhomogeneous tracer uptake in the primary tumor.3,4 In this study, five patients presented with false-positive N1 foci, and one patient was incorrectly upstaged to M1a, due to a lesion in de portal region. Inflammatory pulmonary disease may also lead to increased uptake in reactive regional lymph nodes.10 Shreve et al15 stated that abnormal accumulation of FDG in lymph nodes can be a consequence of spurious delivery of the tracer via lymphatic drainage, because the tracer extravasates into tissue drained by a regional lymph node group. Cervical lesions may also be caused by muscle activation leading to increased FDG metabolism or due to degenerative disease of the sternoclavicular joints.15 Verification of lesions by histological or cytological analysis is preferable, but not always obtainable nor necessary if other dedicated investigations are performed. When pathologic examination was not performed, we used a minimum follow-up time of 6 months.13 One patient died beyond 6 months without developing metastases in the lesion, and the other patients remained in the follow-up for more than 17 months. Therefore, we assume this as a reliable time period, because none of the patients in this study developed tumor activity in the lesion within 6 months. The causes of false-positive FDG-PET results in this study were only determined in the patients with lesions in the rectum due to adenoma and colitis. The rectal lesions may indicate peritoneal metastases of the esophageal carcinoma to the rectovesical or rectouterine pouch. On the other hand, a second primary tumor is also a reliable cause of lesions in the rectum. Therefore, the interpretation of these two lesions as false-positive is debatable. Other false-positive results are more difficult to elucidate. This study does not demonstrate more processes leading to increased FDG accumulation in nontumorous tissues, because the lack of cytological or histopathological examinations of all hotspots. Although FDG is a highly sensitive tumor tracer, it is not very specific as confirmed by the described false-positive cases. The rate of 7% false-positive local metastasis in this study is comparable to the 3% to 17% reported in the literature.3,4,10,16,17 However, the rate of incorrect upstaging to M1a/1b disease of 9% compares unfavorably to the range of 1% to 6% reported in literature.3,5,6,9 Since November 1995, FDG-PET has been used in staging esophageal cancer in our center. During this period of 7 years, experience has been gained in the interpretation of FDG-PET in about 100 esophageal tumors. As a result, the rate of false-positive findings has decreased as shown in Figure 1. Revision of all positive FDG-PET scans by a blinded experienced nuclear medicine physician resulted in a lowering of the rate of false-positive findings from 15% to 5.8%, especially relating to locoregional lesions. The reduction of false-positive FDG-PET results was higher in the first period, however, not significantly. Consequently, there seems to have been a learning curve influencing the interpretation of FDG-PET that will reduce the occurrence of false-positive results. Another factor to improve interpretation of FDG-PET findings will be the use of PET/

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False-Positive PET Results in Esophageal Cancer

CT, especially of lesions located in the upper abdomen. This technique enables a precise mapping of increased FDG uptake to the anatomic background. However, no literature about this subject currently exists, and PET/CT is not yet available in our hospital. The increased glucose metabolism of malignant cells is the rationale behind FDG as the current most commonly used radiotracer in oncological PET studies.18 Several mechanisms have been proposed to account for FDG accumulation in tumors, including elevated levels of hexokinase and decreased activity of glucose-6-phosphatase. The increased glycolysis in malignant tumors with up-regulation of glucose transporter proteins is expressed by an enhancement of GLUT-1. GLUT-1 transporter is overexpressed in a wide variety of cancers including breast, lung cancer, colorectal, esophageal, and gastric adenocarcinoma.19 Misinterpretation of tumor staging with PET can also be found in inflammatory tissues, abscesses, autoimmune lesions, sarcoidosis, and some benign tumors. Focal hypermetabolic area due to high uptake of FDG in macrophages, lymphocytes, plasma cells, and neutrophils may render false-positive findings.11,20-23 To differentiate between malignant en benign lesions physiologic uptake of FDG is misleading. This physiology includes uptake in digestive tract, thyroid gland, skeletal muscle, myocardium, and bone marrow. The use of a semiquantitative measurement of standardized uptake value (SUV) in differentiating malignant tissue from benign on FDG-PET is still questionable.24 Optimal SUV is computed for some tumors to classify a hotspot as malignant or benign but other studies demonstrated the opposite. The interpretation of FDG-PET in staging esophageal cancer will be improved by several factors leading to a decrease of false-positive findings. At first the awareness of physiologic and inflammatory processes resulting in FDG accumulation. Second, the interpreter must be informed in detail about both clinical condition and history of the patient at the moment of scanning. Finally, the experience of the nuclear physician will be a valuable factor influencing the false-positive rate. In conclusion, this study demonstrates the pitfalls of staging esophageal cancer with FDG-PET due to the occurrence of false-positive results. We should remember that FDG is not a tumor-specific substance, and that false-positive results may occur as a result of increased glucose metabolism in benign lesions. This study showed that PET still has to be used complementary to conventional staging methods. From these observations, it is clear that positive findings on FDG-PET must be confirmed by pathological examination, whenever possible, before denying patients from surgery with curative intent.

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Rice TW. Clinical staging of esophageal carcinoma. CT, EUS, and PET. Chest Surg Clin N Am 2000;10:471-85.Block MI, Patterson GA, Sundaresan RS, Bailey MS, Flanagan FL, Dehdashti F, Siegel BA, Cooper JD. Improvement in staging of esophageal cancer with the addition of positron emission tomography. Ann Thorac Surg 1997;64:770-6.Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, de Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18:3202-10.Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Sundaresan SR, Patterson GA, Cooper JD. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography. Am J Roentgenol 1997;168:417-24.Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy. Br J Cancer 1998;78:521-7.Luketich JD, Schauer PR, Meltzer CC, Landreneau RJ, Urso GK, Townsend DW, Ferson PF, Keenan RJ, Belani CP. Role of positron emission tomography in staging esophageal cancer. Ann Thorac Surg 1997;64:765-9.Meltzer CC, Luketich JD, Friedman D, Charron M, Strollo D, Meehan M, Urso GK, Dachille MA, Townsend DW. Whole-body FDG positron emission tomographic imaging for staging esophageal cancer comparison with computed tomography. Clin Nucl Med 2000;25:882-7.Wallace MB, Nietert PJ, Earle C, Krasna MJ, Hawes RH, Hoffman BJ, Reed CE. An analysis of multiple staging management strategies for carcinoma of the esophagus: computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy. Ann Thorac Surg 2002;74:1026-32.Wren SM, Stijns P, Srinivas S. Positron emission tomography in the initial staging of esophageal cancer. Arch Surg 2002;137:1001-6.Choi JY, Lee KH, Shim YM, Lee KS, Kim JJ, Kim SE, Kim BT. Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET. J Nucl Med 2000;41:808-15.Zhuang H, Pourdehnad M, Lambright ES, Yamamoto AJ, Lanuti M, Li P, Mozley PD, Rossman MD, Albelda SM, Alavi A. Dual time point 18F-FDG PET imaging for differentiating malignant from inflammatory processes. J Nucl Med 2001;42:1412-7.Duarte PS, Zhuang H, Castellucci P, Alavi A. The receiver operating characteristic curve for the standard uptake value in a group of patients with bone marrow metastasis. Mol Imaging Biol 2002;4:157-60.Nguyen AT, Akhurst T, Larson SM, Coit DG, Brady MS. PET Scanning with (18)F 2-Fluoro-2-Deoxy-D-Glucose (FDG) in Patients with Melanoma. Benefits and Limitations. Clin Positron Imaging 1999;2:93-8.Hamacher K, Coenen HH, Stocklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 1986;27:235-8.Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 1999;19:61-77.Kato H, Kuwano H, Nakajima M, Miyazaki T, Yoshikawa M, Ojima H, Tsukada K, Oriuchi N, Inoue T, Endo K. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer 2002;94:921-8.Kim K, Park SJ, Kim BT, Lee KS, Shim YM. Evaluation of lymph node metastases in squamous cell carcinoma of the esophagus with positron emission tomography. Ann Thorac Surg 2001;71:290-4.Czernin J, Phelps ME. Positron emission tomography scanning: current and future applications. Annu Rev Med 2002;53:89-112.Phay JE, Hussain HB, Moley JF. Strategy for identification of novel glucose transporter family members by using internet-based genomic databases. Surgery 2000;128:946-51.Ishimori T, Saga T, Mamede M, Kobayashi H, Higashi T, Nakamoto Y, Sato N, Konishi J. Increased

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(18)F-FDG uptake in a model of inflammation: concanavalin A- mediated lymphocyte activation. J Nucl Med 2002;43:658-63.Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992;33:1972-80.Strauss LG. Fluorine-18 deoxyglucose and false-positive results: a major problem in the diagnostics of oncological patients. Eur J Nucl Med 1996;23:1409-15.Yamada S, Kubota K, Kubota R, Ido T, Tamahashi N. High accumulation of fluorine-18-fluorodeoxyglucose in turpentine- induced inflammatory tissue. J Nucl Med 1995;36:1301-6.Cremerius U, Wildberger JE, Borchers H, Zimny M, Jakse G, Gunther RW, Buell U. Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer?--Results of a study in 50 patients. Urology 1999;54:900-4.

21.

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24.

8PROGNOSTIC VALUE OF THE STANDARDIZED UPTAKE VALUE

IN ESOPHAGEAL CANCER

HL van Westreenen1

JThM Plukker1

DCP Cobben1

CJM Verhoogt2

H Groen3

PL Jager2

Departments of Surgery1, Nuclear Medicine/PET center2,Office for Medical Technology Assessment3

University Hospital Groningen, The Netherlands

American Journal of Roentgenology 2005;185;436-440

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ABSTRACTIntroduction: On positron emission tomography (PET), the level of tissue glycolysis can be quantified by the accumulation of 18F-fluorodeoxyglucose (FDG) expressed as the standard uptake value (SUV). The aims of this study were to investigate the relation between SUV and the stage of disease and whether SUV can be used to predict resectability and survival in patients with esophageal cancer.Materials and Methods: Forty patients with cancer of the esophagus or gastroesophageal junction were included in this analysis. Patients were retrospectively divided into two groups using the median SUV as cutoff value. SUV values were evaluated according to the stage of disease, histology, age, sex, and resectability. Survival was analyzed by using the log-rank test and Cox regression analysis. Results: The median SUVmax was 6.7 (range, 1.8-19.2) and median SUVmean was 5.7 (range, 1.4-15.7). SUVmax and SUVmean differed significantly for tumor stage and resectability. The mean survival of patients with SUVmax ≤ 6.7 and SUVmean ≤ 5.7 was 613 days compared with 262 days for patients with SUVmax > 6.7 and SUVmean > 5.7 (P = 0.016). Cox regression analysis did not reveal a significant impact of SUV on survival independent of resectability. Conclusions: SUV can be used to predict resectability; however, SUV is not an independent factor that can be used to assess survival in patients with esophageal cancer.

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Prognostic Value of the Standardized Uptake Value

INTRODUCTIONPositron emission tomography (PET) is a noninvasive imaging technique that is frequently applied in the diagnosis and staging of different types of cancer.1 The increased glucose metabolism of malignant cells is the driving force for the uptake of 18F-fluorodeoxyglucose (FDG), which is currently the most common radiotracer used for oncologic PET studies.2,3 FDG is phosphorylated solely intracellularly by the enzyme hexokinase, which causes intracellular entrapment as FDG-6 phosphate and enables adequate measurement of the tissue glycolysis level. In addition to staging, PET is able to quantify FDG uptake in malignant tissue. The usually applied quantification parameter in clinical FDG-PET is the standardized uptake value (SUV). SUV is determined by the ratio of activity in tissue (Bq/mL) and the decay-corrected activity of FDG injected into the patient (Bq/g).4 In general, the degree of tumor proliferation correlates with its metabolic activity. Because tumor proliferation is related to clinical behavior, which determines prognosis, SUV calculations may enable FDG-PET to be used to predict the prognosis with and the proliferation of several malignancies.5-7

In esophageal cancer, FDG-PET has been accepted as a useful tool for the detection of distant metastatic disease, and SUV might also be useful to predict patient survival and the aggressiveness of esophageal cancer before surgery.8-10 However, data about clinical application of SUV measurement in these patients are scarce.11,12

For this study, we quantitatively evaluated the metabolic activity of cancer of the esophagus and gastroesophageal junction using FDG-PET and SUV analyses. Furthermore, the predictive value of SUV independent of established prognostic factors was determined with univariate and multivariate analyses.

PATIENTS AND METHODSPatientsThis study comprises a retrospective analysis of 40 consecutive patients with cancer of the esophagus or gastroesophageal junction diagnosed between January 2001 and December 2002. FDG-PET was performed in patients who were fit to undergo surgery and those without evidence of metastases from routine history, physical examination, and laboratory test results. Ten patients who underwent FDG-PET on an ECAT 951/31 scanner (Siemens/CTI, Knoxville, TN, USA) were excluded from our analysis because there was no opportunity for attenuation correction of that data. The study group was composed of 24 men and 16 women with a median age of 64.6 years (range, 48-79). None of these patients was treated with preoperative chemotherapy. Patient characteristics are summarized in Table 1. All cases were staged further with endoscopic ultrasound (EUS) and computed tomography (CT) according to the UICC classification.13 Nineteen patients underwent a radical transthoracic esophagectomy. The remaining patients were treated with a palliative regimen including radiation therapy, endoluminal stenting, or both.

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Table 1. Standardized Uptake Values and Clinicopathologic Factors

Factor No. of patients

SUVmax

Mean � SE P value

SUVmean

Mean � SE P value

Sex 0.875 0.813

Male 24 7.54 � 4.6 6.15 � 3.8

Female 16 7.32 � 3.7 5.88 � 3.0

Age (years) 0.793 0.778

� 65 21 7.62 � 3.8 6.19 � 3.1

> 65 19 7.27 � 4.8 5.87 � 3.9

Histology 0.112 0.118

Adenocarcinoma 28 6.76 � 4.0 5.48 � 3.3

Squamous cell carcinoma 12 9.08 � 4.5 7.35 � 3.6

Localization 0.627 0.622

Mid esophagus 7 8.87 � 4.7 7.20 � 3.9

Distal esophagus 23 7.22 � 4.3 5.86 � 3.5

Gastroesophageal junction 10 6.99 � 3.9 5.64 � 3.2

UICC stage* 0.002 0.003

Stage I-II 10 4.31 � 2.2 3.48 � 1.9

Stage III 13 6.84 � 2.5 5.59 � 2.0

Stage IV 17 9.77 � 4.9 7.89 � 4.0

T stage 0.037 0.041

T1-T2 6 4.17 � 2.5 3.40 � 2.1

T3-T4 34 8.03 � 4.2 6.50 � 3.5

N stage 0.003 0.003

N0 9 3.90 � 1.9 3.14 � 1.6

N1 31 8.49 � 4.2 6.88 � 3.4

M stage 0.002 0.003

M0 23 5.74 � 2.6 4.67 � 2.2

M1 17 9.77 � 4.9 7.89 � 4.0

Treatment 0.001 0.002

Esophagectomy 19 5.30 � 2.6 4.31 � 2.2

Radiotherapy or stent 21 9.40 � 4.5 7.61 � 3.7

SUV: standardized uptake value; SE: standard error; UICC: International Union Against Cancer

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Prognostic Value of the Standardized Uptake Value

Table 1. Standardized Uptake Values and Clinicopathologic Factors

Factor No. of patients

SUVmax

Mean � SE P value

SUVmean

Mean � SE P value

Sex 0.875 0.813

Male 24 7.54 � 4.6 6.15 � 3.8

Female 16 7.32 � 3.7 5.88 � 3.0

Age (years) 0.793 0.778

� 65 21 7.62 � 3.8 6.19 � 3.1

> 65 19 7.27 � 4.8 5.87 � 3.9

Histology 0.112 0.118

Adenocarcinoma 28 6.76 � 4.0 5.48 � 3.3

Squamous cell carcinoma 12 9.08 � 4.5 7.35 � 3.6

Localization 0.627 0.622

Mid esophagus 7 8.87 � 4.7 7.20 � 3.9

Distal esophagus 23 7.22 � 4.3 5.86 � 3.5

Gastroesophageal junction 10 6.99 � 3.9 5.64 � 3.2

UICC stage* 0.002 0.003

Stage I-II 10 4.31 � 2.2 3.48 � 1.9

Stage III 13 6.84 � 2.5 5.59 � 2.0

Stage IV 17 9.77 � 4.9 7.89 � 4.0

T stage 0.037 0.041

T1-T2 6 4.17 � 2.5 3.40 � 2.1

T3-T4 34 8.03 � 4.2 6.50 � 3.5

N stage 0.003 0.003

N0 9 3.90 � 1.9 3.14 � 1.6

N1 31 8.49 � 4.2 6.88 � 3.4

M stage 0.002 0.003

M0 23 5.74 � 2.6 4.67 � 2.2

M1 17 9.77 � 4.9 7.89 � 4.0

Treatment 0.001 0.002

Esophagectomy 19 5.30 � 2.6 4.31 � 2.2

Radiotherapy or stent 21 9.40 � 4.5 7.61 � 3.7

Computed tomographyCT was performed using a single-detector helical scanner (Tomoscan SR 7000, Philips Medical Systems, Best, The Netherlands). CT scans were obtained from the neck to the upper abdomen including the liver. CT of both the thorax and abdomen was performed with 10-mm collimation. The reconstruction interval was 5 and 10 mm for thorax and abdomen, respectively. Beginning in January 2002, examinations were performed on a MDCT scanner (Somatom Sensation Siemens, Medical Systems, Erlangen, Germany) MDCT scans were obtained with 3-mm collimation and reconstruction interval of 1.5 mm. Scans were obtained with both intravenous and oral contrast material.

Endoscopic ultrasoundA radial scanner (GF-UM20, 7.5-12 MHz, Olympus, Tokyo, Japan) was used for the performance of EUS. EUS-guided fine-needle aspiration of suspected celiac lymph node metastases was performed. The biopsy sample was obtained via a separate linear array echoendoscope (FGUX-36, 5-7.5 MHz, Pentax Benelux, Breda, The Netherlands). If a stenotic tumor could not be passes with the GF-UM20 scope, a small-caliber probe (MH-908, 7.5 MHz, Olympus, Tokyo, Japan) was used in an attempt to traverse the tumor.

Positron emission tomographyPET was performed using an ECAT HR+ positron emission camera (Siemens/CTI, Knoxville, TN, USA). This camera acquires 63 planes over a 15.8-cm axial field of view. Patients fasted for at least 4 hours before 130-690 MBq (median, 230 MBq) of FDG was administered intravenously (3 MBq/kg). Data acquisition started 90 minutes after injection in whole body mode (2D), and data were acquired for 5 minutes per bed position from the knees to the skull. Transmission imaging was performed for 3 minutes per bed position for attenuation correction using the emission-emission transmission-transmission (EETT) method. Data from multiple bed positions were iteratively reconstructed (ordered subset expectation maximization) yielding both attenuated and nonattenuated whole-body PET images.14

Evaluation of FDG uptakeA 3D region of interest (ROI) was selected semiautomatically using a dedicated software program. The ROI was placed over the tumor on multiple slices using a threshold of 70% of the maximum pixel value within the tumor. The maximum SUV (SUVmax) denotes the maximum SUV value within the tumor ROI, and mean SUV (SUVmean) is the mean value averaged over all voxels. The values were calculated according to the following equation:

SUV =

with Ci as the activity concentration, A as the injected activity, and M as the body mass. In patients with metastases, only the primary tumor was analyzed in this way. The operators who performed this method were unaware of all clinical data.

Data analysisThe relationships between FDG uptake of primary esophageal carcinomas and the characteristics of the patients, including sex and age, and the characteristics of the tumor,

Ci

A/M

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Table 2. Univariate Survival Analysis

Factor No. of patients

Survival (mean � SE)

(days) P value

Sex 0.596

Male 24 494 � 78

Female 16 353 � 75

Age (years) 0.846

� 65 21 454 � 84

> 65 19 402 � 69

Histology 0.618

Adenocarcinoma 28 488 � 75

Squamous cell carcinoma 12 352 � 81

Localization 0.693

Mid esophagus 7 310 � 104

Distal esophagus 23 368 � 57

Gastroesophageal junction 10 556 � 125

UICC stage* 0.063

Stage I-II 10 648 � 116

Stage III 13 442 � 89

Stage IV 17 268 � 54

T stage 0.100

T1-T2 6 582 � 63

T3-T4 34 423 � 66

N stage 0.075

N0 9 688 � 122

N1 31 345 � 51

M stage 0.022

M0 23 584 � 84

M1 17 268 � 54

SUVmax 0.016

� 6.7 20 613 � 89

> 6.7 20 262 � 47

SUVmean 0.016

� 5.7 20 613 � 89

> 5.7 20 262 � 47

Treatment 0.0001

Esophagectomy 19 712 � 77

Radiotherapy or stent 21 198 � 39

SUV: standardized uptake value; SE: standard error; UICC: International Union Against Cancer

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Prognostic Value of the Standardized Uptake Value

including the UICC stage, histology, and resectability, were assessed by the Student’s t test or analysis of variance as appropriate. For survival analysis, the study group was divided into two subgroups: one with low SUVs and one with high SUVs using the median SUVmax value or median SUVmean value as the cutoff value. Survival data were analyzed using the Kaplan-Meier method, and differences in the cumulative survival rate between subgroups were compared with the log-rank test. Furthermore, SUVs and survival data were entered in a linear regression analysis. To discover independent prognostic factors, we performed stepwise multivariate analysis of survival Cox’s proportional hazards model. The following factors were entered as independent variables: sex; patient age; and tumor histology, localization, UICC stage, SUVmax, SUVmean; and type of treatment. All P values were two-tailed, and significance was considered as a P value of less than 0.05.

RESULTSTen of the 40 patients had stage I or II disease (T1-2 N0-1 M0), 13 had locally advanced stage III disease (T3-4 N1 M0), and the remaining 17 had stage IV disease (Tx Nx M1). Nineteen patients had a curative resection including a two-field lymphadenectomy. Twenty-one patients underwent palliative treatment including intraluminal stent placement, radiation therapy, or both. The median SUVmax for all 40 patients was 6.7, ranging from 1.8 to 19.2. The SUVmean

ranged from 1.4 to 15.7 (median, 5.7). The median follow-up time after PET was 321 days (range, 7-934 days). One patient died postoperatively on day 7. Patient characteristics and comparisons of SUVmax and SUVmean in each of the subgroups are summarized in Table 1. No significant differences in the SUVmax and SUVmean with respect to patient sex, patient age, or tumor localization were detected. However, SUVmax and SUVmean differed significantly for UICC stage; T, N, and M classification separately; and type of treatment. Univariate survival analysis for various patient characteristics is shown in Table 2. The cumulative survival rate was significantly decreased in patients with distant metastases (P = 0.022) and in patients who were not eligible for resection (P < 0.001). Patients with high SUVmax (SUV > 6.7) and high SUVmean (SUV > 5.7) had a worse survival rate than patients with low SUVs (P = 0.016). Figure 1 shows the comparison between SUVmax and SUVmean of the primary tumor versus patient survival. Linear regression analysis showed a low correlation between SUV and survival (r = 0.36). Figure 2 shows the Kaplan-Meier cumulative survival plot for patients with high SUVs and those with low SUVs; the survival plots for SUVmax and SUVmean were identical. Because of possible interrelationships among prognostic factors, multivariate analysis was performed. Multivariate Cox regression analysis showed that resection was the only independent predictor of survival (P = 0.001, 95% confidence interval, 0.065-0.445). SUV did not have an additional impact on estimating patient survival independent of resectability.

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Follow-up (days)

10008006004002000

SU

Vm

ax 20

15

10

5

0

death

alive

Follow-up (days)

10008006004002000

SU

Vm

ean 20

15

10

5

0

death

alive

(A)

(B)

FIGURE 1 Comparison of standardized uptake values (SUVs) and pa-tient survival. Scattergrams show comparison between maximum SUV (SUVmax) (A) and mean SUV (SUVmean) (B) of primary tumor versus patient survival. Linear regression analysis shows low correlation between SUV and survival (r = 0.36 for both).

111

Prognostic Value of the Standardized Uptake Value

DISCUSSIONThe results from this study show that patients with high SUVs have a poorer survival rate than patients with low SUVs. This was found for both the SUVmax (cutoff value, 6.7) and SUVmean (cutoff value, 5.7). However, multivariate analysis showed that resection was the only independent factor for the prediction of patient survival. This is expressed by a significantly lower SUV in the patients who were eligible for resection. Therefore, SUV value did not have a significant additional impact on estimating patient survival. Literature about the relationship between SUV and survival in patients with esophageal cancer is scarce. Several authors reported that survival was significantly lower in patients who had SUVs and reported a great variety in the cutoff values, ranging from 3 to 7.11 These results are in agreement with those from this study. However, the other studies did not examine the role of SUV in the prediction of patient survival using multivariate analysis. Most patients in this study had an adenocarinoma, whereas the patients of most other studies had squamous cell carcinoma. Overexpression of glucose transporter 1 (GLUT-1) has been shown especially in squamous cell carcinoma and was correlated with a higher SUV and a worse prognosis.15-17 No differences in GLUT-1 expression between adenocarcinoma and squamous cell carcinoma of the esophagus and gastroesophageal junction were reported. Both types showed a significant number of cases expressing this transporter.18 Menzel et al found no differences in FDG uptake between squamous cell carcinoma and adenocarcinoma, underlining that both histologic types are comparable regarding their

Follow-up (days)

10008006004002000

Sur

viva

l 1,0

,8

,6

,4

,2

0,0

SUVmax � 6.7

SUVmax > 6.7

FIGURE 2Kaplan-Meier cumulative surviv-al plot shows results for patients with maximum standardized uptake value (SUVmax) of 6.7 or less and for those with SUVmax of greater than 6.7 (P = 0.016).

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FDG uptake.19

The retrospective design of our study hampers us from drawing solid conclusions from our results. Also, the actual cutoff values used in this study cannot be extrapolated to other series because technical issues such as ROI definitions, scan processing, and acquisition protocols vary among centers. A large prospective trial may reveal the use of SUVs in the prediction of survival in patients with esophageal cancer, especially in a large series of patients with identical treatment and scanning protocols. In conclusion, SUV analysis should be performed because a high SUV seems to be related to advanced stages of esophageal carcinoma; unresectability; and, therefore, poor prognosis. However, SUV is not useful as an independent predictor of survival in patients with esophageal cancer. Because esophagectomy is the only potentially curative option, patient survival is strongly predicted by the eligibility for surgery.

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Prognostic Value of the Standardized Uptake Value

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Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. J Nucl Med 2001;42:1S-93S.Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL. Intratumoral distribution of tritiated-FDG in breast carcinoma: correlation between Glut-1 expression and FDG uptake. J Nucl Med 1996;37:1042-7.Lowe VJ, Naunheim KS. Current role of positron emission tomography in thoracic oncology. Thorax 1998;53:703-12.Graham MM, Peterson LM, Hayward RM. Comparison of simplified quantitative analyses of FDG uptake. Nucl Med Biol 2000;27:647-55.Ahuja V, Coleman RE, Herndon J, Patz EF, Jr. The prognostic significance of fluorodeoxyglucose positron emission tomography imaging for patients with nonsmall cell lung carcinoma. Cancer 1998;83:918-24.Oshida M, Uno K, Suzuki M, Nagashima T, Hashimoto H, Yagata H, Shishikura T, Imazeki K, Nakajima N. Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2-deoxy-2-fluoro[18F]-D-glucose. Cancer 1998;82:2227-34.Oyama N, Akino H, Suzuki Y, Kanamaru H, Miwa Y, Tsuka H, Sadato N, Yonekura Y, Okada K. Prognostic value of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging for patients with prostate cancer. Mol Imaging Biol 2002;4:99-104.Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, de Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18:3202-10.Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy. Br J Cancer 1998;78:521-7.Rasanen JV, Sihvo EI, Knuuti MJ, Minn HR, Luostarinen ME, Laippala P, Viljanen T, Salo JA. Prospective analysis of accuracy of positron emission tomography, computed tomography, and endoscopic ultrasonography in staging of adenocarcinoma of the esophagus and the esophagogastric junction. Ann Surg Oncol 2003;10:954-60.Fukunaga T, Okazumi S, Koide Y, Isono K, Imazeki K. Evaluation of esophageal cancers using fluorine-18-fluorodeoxyglucose PET. J Nucl Med 1998;39:1002-7.Kato H, Kuwano H, Nakajima M, Miyazaki T, Yoshikawa M, Ojima H, Tsukada K, Oriuchi N, Inoue T, Endo K. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer 2002;94:921-8.Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edition. New York: John Wiley&Sons, 2003.Lonneux M, Borbath I, Bol A, Coppens A, Sibomana M, Bausart R, Defrise M, Pauwels S, Michel C. Attenuation correction in whole-body FDG oncological studies: the role of statistical reconstruction. Eur J Nucl Med 1999;26:591-8.Kato H, Takita J, Miyazaki T, Nakajima M, Fukai Y, Masuda N, Fukuchi M, Manda R, Ojima H, Tsukada K, Kuwano H. Glut-1 glucose transporter expression in esophageal squamous cell carcinoma is associated with tumor aggressiveness. Anticancer Res 2002;22:2635-9.Kato H, Takita J, Miyazaki T, Nakajima M, Fukai Y, Masuda N, Fukuchi M, Manda R, Ojima H, Tsukada K, Kuwano H, Oriuchi N, Endo K. Correlation of 18-F-fluorodeoxyglucose (FDG) accumulation with glucose transporter (Glut-1) expression in esophageal squamous cell carcinoma. Anticancer Res 2003;23:3263-72.Phay JE, Hussain HB, Moley JF. Strategy for identification of novel glucose transporter family members by using internet-based genomic databases. Surgery 2000;128:946-51.Younes M, Pathak M, Finnie D, Sifers RN, Liu Y, Schwartz MR. Expression of the neutral amino acids transporter ASCT1 in esophageal carcinomas. Anticancer Res 2000;20:3775-9.Menzel C, Dobert N, Rieker O, Kneist W, Mose S, Teising A, Junginger T, Bottcher HD, Bartenstein P, Grunwald F. [18F-Deoxyglucose PET for the staging of oesophageal cancer: influence of histopathological subtype and tumour grading]. Nuklearmedizin 2003;42:90-3.

9COMPARISON OF 18F-FLT PET AND 18F-FDG PET IN

ESOPHAGEAL CANCER

HL van Westreenen1

DCP Cobben1

PL Jager2

HM van Dullemen3

J Wesseling4

PH Elsinga2

JThM Plukker1

Departments of Surgery1, Nuclear Medicine/PET center2, Gastroenterology3, Pathology4

University Hospital Groningen, The Netherlands

Journal of Nuclear Medicine 2005;46:400-404

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ABSTRACTIntroduction: 18F-FDG PET has gained acceptance for staging of esophageal cancer. However, FDG is not tumor specific and false-positive results may occur by accumulation of FDG in benign tissue. The tracer 18F-fluoro-3’deoxy-3’-L-fluorothymidine (18F-FLT) might not have these drawbacks. The aim of this study was to investigate the feasibility of 18F-FLT PET for the detection and staging of esophageal cancer and to compare 18F-FLT PET with 18F-FDG PET. Furthermore, the correlation between 18F-FLT and 18F-FDG uptake and proliferation of the tumor was investigated. Materials and Methods: Ten patients with biopsy-proven cancer of the esophagus or gastroesophageal junction were staged with CT, endoscopic ultrasonography, and ultrasound of the neck. In addition, all patients underwent a whole-body 18F-FLT PET and 18F-FDG PET. Standardized uptake values were compared with proliferation expressed by Ki-67 positivity. Results: 18F-FDG PET was able to detect all esophageal cancers, whereas 18F-FLT PET visualized the tumor in 8 out of 10 patients. Both 18F-FDG PET and 18F-FLT PET detected lymph node metastases in 2 out of 8 patients. 18F-FDG PET detected 1 cervical lymph node that was missed on 18F-FLT PET, whereas 18F-FDG PET showed uptake in benign lesions in 2 patients. The uptake of 18F-FDG (median standardized uptake value (SUVmean), 6.0) was significantly higher than 18F-FLT (median SUVmean, 3.4). Neither 18F-FDG maximum SUV (SUVmax) nor 18F-FLT SUVmax correlated with Ki-67 expression in the linear regression analysis. Conclusion: In this study, uptake of 18F-FDG in esophageal cancer is significantly higher compared with 18F-FLT uptake. 18F-FLT scans show more false-negative findings and fewer false-positive findings than do 18F-FDG scans. Uptake of 18F-FDG or 18F-FLT did not correlate with proliferation.

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INTRODUCTIONMost patients with esophageal cancer are treated in specialized institutes and staged by endoscopic ultrasonography (EUS), computed tomography (CT) of the chest and abdomen, and ultrasound examination (US) of the cervical region.1 However, these traditional methods for staging esophageal cancer have limited sensitivity and specificity. The presence of distant metastases prior to surgery, which is not detected by conventional imaging techniques, is relatively high, as indicated by detection of metastases during operation in approximately 25% of the patients.2

Positron emission tomography (PET) using 18F-FDG is a noninvasive metabolic imaging technique and its usefulness has been established for a number of malignancies.3 18F-FDG is the most widely used tracer for staging tumors with PET.3 18F-FDG is a glucose analogue that enters the cells via the same membrane transporters as glucose. Glucose as well as 18F-FDG are phosphorylated by the enzyme hexokinase. In contrast to glucose-6-phosphate, 18F-FDG-6-phosphate is not a substrate for further metabolism in the glycolytic pathway. Therefore, 18F-FDG-6-phosphate is trapped in the cells in proportion to their glycolytic activity.3,4 There is evidence for improved preoperative staging of esophageal cancer with 18F-FDG PET. Sensitivities of 67% to 74% have been reported, especially with regard to the detection of nonregional lymphatic or hematogenic disease.5,6 Although these results may indicate an important role for 18F-FDG PET, 18F-FDG is not a tumor-specific tracer and false-positive results may occur.7,8 For example, macrophages and neutrophils can demonstrate increased FDG uptake, which can lead to false positive results.9,10

18F-Fluoro-3’deoxy-3’-L-fluorothymidine (18F-FLT) was introduced as a PET prolife-ration tracer by Shields et al, which might not have these drawbacks.11,12 18F-FLT is monophosphorylated by thymidine kinase 1 (TK1), which leads to intracellular trapping. Since the TK 1 concentration is especially increased during the S phase of the cell cycle, the uptake of 18F-FLT is supposed to depend on proliferation.12 The aim of this study was to investigate the feasibility of 18F-FLT PET for the detection and staging of esophageal cancer compared with 18F-FDG PET. Furthermore, the correlation between uptake of 18F-FLT or 18F-FDG and proliferation of the tumor was investigated.

MATERIALS AND METHODSPatientsThis prospective study consisted of ten patients with biopsy-proven malignancy of the esophagus or gastroesophageal junction. All patients were staged with multidetector CT (Somatom Sensation Siemens, Medical Systems, Erlangen, Germany) of the chest and abdomen, EUS (GF-UM20, 7.5-12 MHz, Olympus, Tokyo, Japan) and ultrasound (US) of the cervical region. Patients were included from November 2003 until February 2004. All patients gave written informed consent. Only patients with liver and kidney functions and hematological parameters (hemoglobin, hematocrit, erythrocytes, thrombocytes, leukocytes and white cell count) within normal limits were included because of the toxicity of FLT in high concentrations. The medical ethics committee of the Groningen University Hospital approved the study protocol.

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18F-FDG and 18F-FLT synthesis18F-FDG was produced according to the method described by Hamacher et al using the coincidence 18F-FDG synthesis module.13 Synthesis of 18F-FLT was performed according to the method of Machulla et al.14 18F-FLT was produced by 18F-fluorination of the 4,4’-dimethoxytrityl-protected anhydrothymidine, followed by a deprotection step. After purification by reversed phase high-performance liquid chromatography, the product was made isotonic and passed through a 0.22-μm filter. 18F-FLT was produced with a radiochemical purity of >95% and specific activity of >10 TBq/mmol. The radiochemical yield was 6.7% ± 3.7% (decay corrected).

Positron emission tomography The studies were performed using an ECAT EXACT HR+ (Siemens/CTI, Knoxville, TN, USA). Before PET imaging, patients were instructed to fast for at least 6 hours to keep both study protocols comparable. Patients were also instructed to drink 500 mL of water before imaging to stimulate 18F-FDG and 18F-FLT excretion from the renal calyces and stimulate subsequent voiding. Data acquisition started 90 and 60 minutes after injection of 18F-FDG and 18F-FLT, respectively. Scans were performed in whole body mode, for 5 minutes per bed position from femur to the crown. Transmission imaging was obtained for 3 minutes per bed position for attenuation correction. Images were reconstructed using an iterative reconstruction technique and were read from computer monitors.15

Pathologic evaluationTissue was fixed in 4% buffered formalin, routinely processed, and embedded in paraffin. Subsequently, 4-µm sections were cut. For morphology, slides were routinely stained with haematoxylin and eosin. Proliferating cells were detected using the monoclonal antibody MIB-1, which recognizes an epitope of the Ki-67 nuclear antigen that is present during DNA synthesis.16 For this immunohistochemistry, slides were pretreated for 30 minutes in Tris buffer (pH 9.5) at 98º C. Staining was performed using the automated immunohistochemistry slide-staining system NexES (Ventana Medical Systems Inc., Illkirch, France). As first step, the monoclonal antibody MIB-1 (DakoCytomation BV, Heverlee, The Netherlands) detecting the cell proliferation marker Ki-67 was applied. As the second step, a basic 3,3’-diaminobenzidine detection system was used (Ventana Medical Systems Inc., Illkirch, France). All reagents and equipment were used according to the instructions of the suppliers. The MIB-1 score was estimated by counting the percentage of MIB-1-positive cell nuclei per 1,000 tumor cells in the region of the tumor with the greatest density of staining, which, in most instances, corresponds to areas with the highest mitotic activity. The pathologist was unaware of the results of the PET images.

Data analysisPatients were staged according to the tumor, node, metastasis (TNM) staging system of the International Union Against Cancer on the basis of CT, EUS and US.17 The gold standard for the presence or absence of metastases was either histopathologic examination or follow-up. If this information was not available, other staging modalities were used as reference. Both 18F-FDG PET and 18F-FLT PET scans were interpreted independently by experienced nuclear

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physicians who were unaware of clinical data and information from the other PET scan. Three-dimensional regions of interest (ROIs) were placed semiautomatically using a dedicated software program over the primary tumor on multiple slices, using a threshold of 70% of the maximum pixel value within the tumor. The maximum standardized uptake value (SUVmax) and mean SUV (SUVmean) were calculated according to the equation:

SUV =

with Ci is the activity concentration, A is the injected radioactivity and M is the body mass. SUVmax denotes the maximum SUV value within the tumor ROI, and SUVmean denotes the mean value averaged over all voxels.

Statistical analysisThe results of the visually interpreted PET images were compared with the histological data or dedicated radiographic imaging, which were used as standard. 18F-FDG and 18F-FLT uptakes were compared using the Wilcoxon signed rank test. The amount of Ki-67-positive cells and SUVs for 18F-FDG and 18F-FLT were compared using linear regression analysis. Two-tailed P values < 0.05 were considered significant.

RESULTSPatientsTen patients were included with a median age of 61 years (range, 48-75 years). Patient characteristics are summarized in Table 1. Patients received 18F-FDG with a median dose of 368 MBq (range, 250-750 MBq) and received 18F-FLT with a median dose of 410 MBq (range, 340-450 MBq). Eight patients underwent esophagectomy and two patients received an expendable metal stent because of an irresectable T4 tumor on preoperative staging in patient 5 and an irresectable tumor encountered during surgical exploration in patient 7.

Ci

A/M

M: male; F: female; Mid: mid-esophagus; GEJ: gastroesophageal junction; AC: adenocarcinoma; SCC: squamous cell carcinoma; EUS: endoscopic ultrasound; CT: computed tomography; SUV: standardized uptake value; NA: not applicable; PA: pathology; SE: standard error

Table 1. Patient Characteristics and Staging Results

Staging 18F-FDG PET 18F-FLT PET Proliferation

No. Sex Age Localization Histology Treatment EUS CT FDG-PET FLT-PET Surgery/PA SUVmax SUVmean SUVmax SUVmean Ki-67 (% � SE)

1. M 73 Distal AC Esophagectomy T3N1M0 T3N1M0 T+N1M0 T+N1M0 T3N1M0 7.82 6.22 3.85 3.15 78 ± 1.97

2. M 75 Mid AC Esophagectomy T3N1M0 T3N1M0 T+N0M0 T+N0M0 T3N1M0 8.90 7.24 4.93 3.85 65 ± 2.19

3. M 68 GEJ AC Esophagectomy T3N1M0 T3N1M0 T+N0M0 T+N0M0 T3N1M0 12.16 9.79 2.85 2.32 85 ± 3.55

4. M 70 Distal AC Esophagectomy T1N1M0 TxN1M0 T+N0M1a T-N0M0 T2N1M0 6.99 5.71 NA NA 76 ± 2.56

5. F 57 Mid AC Stent T3N1M0 T4N1M1b T+N1M1b T+N0M0 NA 5.92 4.74 5.11 4.09 68 ± 2.89

6. M 48 GEJ AC Esophagectomy T3N0M0 T3N0M0 T+N0M0 T+N0M0 T3N0M0 5.67 4.59 4.41 3.58 77 ± 3.35

7. M 56 Mid SCC Stent T3N1M0 T3N0M0 T+N0M0 T+N0M0 T4N1Mx 14.04 11.50 5.25 4.27 62 ± 5.15

8. F 50 Distal AC Esophagectomy T3N1M0 T3N0M1 T+N0M0 T+N0M0 T3N1M0 5.50 4.62 2.89 2.30 72 ± 2.49

9. F 57 Mid SCC Esophagectomy T3N0M0 T3N1M0 T+N0M0 T+N1M0 T3N1M0 8.12 6.76 3.63 2.99 74 ± 5.85

10. M 65 Distal AC Esophagectomy T3N1M0 T4N0M0 T+N1M0 T-N0M0 T4N1M0 4.40 3.58 NA NA 57 ± 6.61

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FIGURE 1 FDG-PET (A) and FLT-PET (B) of patient 2 with a long esophageal tumor.

(A)

(B)

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18F-FDG PET and 18F-FLT PET in Esophageal Cancer

Detection of esophageal cancer18F-FDG PET visualized all primary tumors, whereas 18F-FLT visualized 8 of 10 esophageal cancers (Table 1). In patients 4 and 10, no uptake of 18F-FLT could be observed. Therefore, the SUV could not be calculated for 18F-FLT in these 2 patients.

Staging of esophageal cancer with 18F-FDG PET and 18F-FLT PETPathology for assessment of lymph nodes was available in 9 patients. 18F-FDG PET and 18F-FLT PET were comparable with regard to the detection of regional lymph nodes. Both 18F-FDG PET and 18F-FLT PET correctly detected regional lymph node metastases in only 2 out of 8 patients. 18F-FDG PET showed false-positive uptake in the celiac trunk region in patient 4, whereas all other staging modalities, including 18F-FLT PET, did not show any abnormality. Pathologic examination revealed cellular reactivity in the celiac trunk lymph nodes in this patient, and the uptake on 18F-FDG PET was scored as a false-positive result. In patient 5, 18F-FDG PET and CT showed a cervical lymph node metastasis. 18F-FLT PET did not detect this metastasis and was scored as a false-negative result.

Comparison between 18F-FDG and 18F-FLT uptakeThe median SUVmax and median SUVmean for 18F-FDG were 7.4 and 6.0 and for 18F-FLT were 4.1 and 3.4. Uptake of 18F-FDG was significantly higher than 18F-FLT, whether expressed in SUVmax (P = 0.012) or SUVmean (P = 0.012). Figure 1 shows 18F-FDG PET and 18F-FLT-PET of patient 2.

Correlation of 18F-FDG and 18F-FLT uptake with MIB-1 scoreAll tissue specimens contained immunoreactivity to Ki-67 antigen. Ki-67 positivity ranged from 57% to 85%, with a median of 73% (Table 1). Linear regression analysis indicated no correlation between 18F-FDG SUV and Ki-67 or between 18F-FLT SUV and Ki-76 (18F-FDG SUVmax vs. Ki-67, r = 0.14; 18F-FLT SUVmax vs. Ki-76, r = -0.76; 18F-FDG SUVmean vs. Ki-67, r = 0.13; 18F-FLT SUVmean vs. Ki-76, r = -0.74).

Additional findingsIn patient 6, 18F-FDG PET showed uptake in the rectosigmoid. However, 18F-FLT PET did not show any abnormality in that region. Additional investigation by sigmoidoscopy revealed diverticulitis. In patient 10, a hypermetabolic lesions in the ascending colon was found on 18F-FDG PET and proven to be a carcinoma by colonoscopy. However, 18F-FLT PET did not detect this synchronous neoplasm.

DISCUSSIONThis pilot study was conducted on 10 patients and showed that 18F-FDG PET could detect all esophageal cancers whereas 18F-FLT PET visualized the tumor in 8 patients. Both 18F-FDG PET and 18F-FLT PET detected lymph node metastases in 2 out of 8 patients. The uptake of 18F-FDG (median SUVmean, 6.0; range, 3.6-11.5) in esophageal cancer was significantly higher than that of 18F-FLT (median SUVmean, 3.4; range, 2.3-4.3). Furthermore, neither 18F-FDG nor 18F-FLT uptake reflects proliferation as determined by Ki-67 immunostaining.

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18F-FDG PET was able to detect all primary esophageal cancers, whereas 18F-FLT PET missed two of them. This fact may be related to the lower uptake of 18F-FLT compared with 18F-FDG, which has been reported earlier for several other tumors.18-21 The 18F-FLT phosphorylation rate in vitro is known to be about 30% of the phosphorylation rate of serum thymidine by TK1, which could explain the low 18F-FLT uptake in the tumor.22,23 Although plasma levels are low, thymidine may compete with 18F-FLT for the active site of nucleoside carriers in cell membranes and also for the active site of the trapping enzyme TK1. Moreover, the affinity of human TK1 for thymidine has been reported to be 4-fold higher than is the affinity for 18F-FLT.22,24 Both 18F-FDG PET and 18F-FLT PET had low sensitivity for the detection of regional lymph node metastases (2 of 8 patients). Several studies have reported the moderate sensitivity of 18F-FDG PET for detection of regional lymph node metastases, which ranges from 8% to 67%.25-27 18F-FLT PET did not improve the regional staging of esophageal cancer. This can be explained by low tissue uptake of 18F-FLT (as described) or by the detection limit of PET for small tumor deposits.28

A strong correlation between 18F-FLT uptake and proliferation expressed as Ki-67-positive cells was found for lung cancer and sarcoma.18,29 However, we did not find a correlation between 18F-FLT uptake and Ki-67 or between 18F-FDG uptake and Ki-67. A correlation between 18F-FLT uptake and proliferation was not reported for breast cancer or thoracic tumors.18,21,30 The rationale of 18F-FLT uptake in malignant tissue is based upon TK1 dependence of proliferation.12,18 However, tumors vary in the relative contribution of de novo and salvage nucleotide biosynthesis. Dominance of de novo pathways, although uncommon, would mask proliferation-dependent increases in TK1 activity.31 Furthermore, in cells for which proliferation is less dependent on TK1, the correlation between tracer uptake and TK1 activity were poor.18,31 We did not obtain full kinetic parameters of 18F-FLT, which might be explain why a correlation between 18F-FLT and proliferation was not found. For example, the correlation between the rate of phosphorylation of 18F-FLT and SUV should be investigated to assess proliferation.32 In addition, Ki-67 is not a perfect measure of DNA synthesis, since it just measures the number of cells in a proliferating state.16 Moreover, Ki-67 was assessed in a proliferating part of the tumor and was compared with the SUV value of a tumor volume. This comparison might be flawed. Its small sample size and the absence of evaluation after therapy limit drawing solid conclusions from this study. 18F-FDG PET is able to identify nonresponders early during neoadjuvant chemoradiotherapy for esophageal cancer.33 Therefore, it will be worthwhile to investigate the ability of 18F-FLT PET in identifying nonresponders to neoadjuvant treatment regimens. At present, 18F-FDG is the tracer of choice for the staging of esophageal cancer. Despite the lower incidence of false-positive results with 18F-FLT, false-negative results will increase by using 18F-FLT, which is a major disadvantage for the staging of esophageal cancer.

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ACKNOWLEDGMENTThis study was supported by a ZonMw program for Health Care Efficiency Research and the Dutch Cancer Foundation.

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Dohmen BM. PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging 2004;31:720-4.Munch-Petersen B, Cloos L, Tyrsted G, Eriksson S. Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. J Biol Chem 1991;266:9032-8.Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y. Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 2002;29:281-7.Kong XB, Zhu QY, Vidal PM, Watanabe KA, Polsky B, Armstrong D, Ostrander M, Lang SA, Jr., Muchmore E, Chou TC. Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3’-fluoro-3’-deoxythymidine and 3’-azido-3’-deoxythymidine. Antimicrob Agents Chemother 1992;36:808-18.Jager PL, Que TH, Vaalburg W, Pruim J, Elsinga P, Plukker JT. Carbon-11 choline or FDG-PET for staging of oesophageal cancer? Eur J Nucl Med 2001;28:1845-9.Kato H, Kuwano H, Nakajima M, Miyazaki T, Yoshikawa M, Ojima H, Tsukada K, Oriuchi N, Inoue T, Endo K. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer 2002;94:921-8.Yoon YC, Lee KS, Shim YM, Kim BT, Kim K, Kim TS. Metastasis to Regional Lymph Nodes in Patients with Esophageal Sqaumous Cell Carcinoma: CT versus FDG PET for Presurgical Detection-Prospective Study. Radiology 2003;227:764-70.Cobben DC, Jager PL, Elsinga PH, Maas B, Suurmeijer AJ, Hoekstra HJ. 3’-18F-fluoro-3’-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? J Nucl Med 2003;44:1927-32.Cobben DC, Elsinga PH, Suurmeijer AJ, Vaalburg W, Maas B, Jager PL, Hoekstra HJ. Detection and grading of soft tissue sarcomas of the extremities with (18)F-3’-fluoro-3’-deoxy-L-thymidine. Clin Cancer Res 2004;10:1685-90.Dittmann H, Dohmen BM, Paulsen F, Eichhorn K, Eschmann SM, Horger M, Wehrmann M, Machulla HJ, Bares R. [(18)F]FLT PET for diagnosis and staging of thoracic tumours. Eur J Nucl Med Mol Imaging 2003;30:1407-12.Schwartz JL, Tamura Y, Jordan R, Grierson JR, Krohn KA. Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. J Nucl Med 2003;44:2027-32.Visvikis D, Francis D, Mulligan R, Costa DC, Croasdale I, Luthra SK, Taylor I, Ell PJ. Comparison of methodologies for the in vivo assessment of 18FLT utilisation in colorectal cancer. Eur J Nucl Med Mol Imaging 2004;31:169-78.Wieder HA, Brucher BL, Zimmermann F, Becker K, Lordick F, Beer A, Schwaiger M, Fink U, Siewert JR, Stein HJ, Weber WA. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 2004;22:900-8.

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10SUMMARY AND FUTURE PERSPECTIVES

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SUMMARYCurative treatment of patients with esophageal cancer mainly depends on the stage of disease. Until now, surgical resection is the only curative option in patients with locoregional stage of the disease, but is accompanied by substantial morbidity and even mortality. Patients with distant metastases (M1) or local invasion of adjacent vital structures by the primary tumor (T4) are beyond cure. These patients may benefit from less invasive methods, including stenting, external radiation and/or brachytherapy for palliation. The primary aim in staging of esophageal cancer is to assess the prognosis in order to select those patients who may benefit from surgery. Therefore, several techniques are employed to stage these patients. During the last decade, preoperative noninvasive staging modalities have improved. Computed tomography (CT) of thorax and abdomen has been the first-line method to determine local resectability and metastatic spread for many years. Later, endoscopic ultrasound (EUS) was introduced and has become the most reliable method of identifying the depth of primary tumor invasion and to assess regional and distant lymph node involvement, particularly in combination with fine-needle aspiration (FNA). Recently, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been gaining acceptance in the detection of distant metastatic disease. This thesis discusses several aspect of PET in staging patients with cancer of the esophagus or gastroesophageal junction. In chapter 2, the literature concerning staging esophageal cancer with FDG-PET was systematically reviewed. FDG-PET was found to have moderate sensitivity and specificity in the detection of locoregional lymph node metastases, with considerable heterogeneity across the included studies. In the detection of distant nodal and hematogenous metastases, FDG-PET has reasonable sensitivity and specificity, with a lower degree of heterogeneity. As M stage determines patient management, we feel that the potential contribution of FDG-PET to staging should carry more weight than its role in N staging when deciding whether or not to implement FDG-PET in the standard preoperative work-up of patient with esophageal cancer. Chapter 3 describes a systematic review of CT, EUS and FDG-PET for the response assessment to neoadjuvant therapy in patients with esophageal cancer. Single slice CT scanning to assess the response to neoadjuvant therapy in esophageal cancer is inaccurate and therefore not recommended. EUS and FDG-PET have equivalent accuracy. EUS can identify patients who have achieved a pathological response, but is not always feasible during or shortly after chemoradiation and therefore not routinely used for therapy response assessment. FDG-PET, measuring alterations in tissue metabolism, seems a promising noninvasive tool for neoadjuvant therapy response assessment in esophageal cancer. In chapter 4, the impact of FDG-PET on the rate of unnecessary surgical explorations is investigated. This study shows a substantial rate of unnecessary surgery in patients suitable for curative treatment mainly because of distant metastases. Improvement of preoperative staging, especially by implementation of FDG-PET, may have reduced the rate of unnecessary surgery to approximately 20%. Chapter 5 describes the additional value of FDG-PET after a state-of-the-art conventional staging and the additional costs related to FDG-PET. FDG-PET improves the selection for potentially curative surgery, especially in stage III-IV esophageal cancer patients.

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However its yield after extensive conventional staging including EUS-FNA and multidetector CT is limited. The additional costs of FDG-PET were not compensated by the cost reduction of prevented surgery. Chapter 6 discusses the clinical importance of synchronous neoplasms, which are detected on FDG-PET that was obtained for the preoperative staging of esophageal cancer patients. FDG-PET may detect unexpected synchronous primary neoplasms in patients with esophageal cancer. Sites of suspected metastases should be confirmed histologically before treatment, as synchronous neoplasms can mimic metastatic disease. In chapter 7, the possible pitfalls of FDG-PET are described. This study demonstrates the pitfalls of staging esophageal cancer with FDG-PET due to the occurrence of false-positive results. We should remember that FDG is not a tumor-specific substance, and that false-positive results may occur as a result of increased glucose metabolism in benign lesions. This study shows that PET still has to be used complementary to conventional staging methods. From these observations, it is clear that positive findings on FDG-PET must be confirmed by pathological examination, whenever possible, before denying patients from surgery with curative intent. Besides imaging, FDG-PET offers the opportunity for quantification of FDG uptake in the primary tumor. Chapter 8 discusses the role of the standardized uptake value (SUV) in the assessment of prognosis in esophageal cancer. SUV analysis should be performed because a high SUV seems to be related with advanced stages of esophageal carcinoma, irresectability and therefore with poorer prognosis. However, SUV is not useful as an independent predictor of survival in patients with esophageal cancer. Since esophagectomy is the only potentially curative option, survival is strongly predicted by the eligibility for surgery. In chapter 9, the new tracer 18F-fluoro-3’deoxy-3’-L-fluorothymidine (FLT) is investigated in a feasibility study. At present, 18F-FDG is the tracer of choice for the staging of esophageal cancer. FLT seems to be more tumor specific. Despite the lower incidence of false-positive results with 18F-FLT, false-negative results will increase by using 18F-FLT, which is a major disadvantage for the staging of esophageal cancer.

FUTURE PERSPECTIVESThe last decades have been characterized by the development of high-resolution imaging techniques such as FDG-PET but also the multidetector CT. Further improvements of several techniques are expected and they will play a role in increasing the accuracy for the staging of several types of cancer. This paragraph describes some new techniques that will be implemented in the management of esophageal cancer patients.

Multidetector CTAs is discussed in chapter 5, the role of CT has increased for staging esophageal cancer by use of a multidetector technique. The spatial resolution of this type of CT will further increase by the currently available 64-row multidetector CT. The reliability of the CT in detecting distant metastases will increase but also the assessment of tumor invasion into surrounding structures will be improved. Therefore, multidetector CT will have a key role for the initial staging of esophageal cancer.

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PET/CTRecently, dual-modality PET/CT tomographs have become available. PET/CT is currently the fastest growing imaging technology worldwide. The PET/CT machines combine morphological CT and functional PET imaging within one system served by a single examination table. CT and PET images are obtained in series with the patient remaining in the same table position thereby providing accurately fused morphological and functional data. Initial experience has amply demonstrated, that PET and CT information are highly synergistic in identifying en specifying lesions such as tumor metastases. The interaction of high lesion sensitivity as afforded by PET with precise anatomic referencing as provided by CT appears very relevant. In addition, there are technical synergies for PET/CT, which translate into shorter imaging times than when PET is used alone: transmission correction of PET data can be done with the CT data, abbreviating imaging data taking by of the order of 25%. This translates into improved patient comfort and into more efficient use of FDG. For colorectal cancer, PET/CT leads to a significant improvement of the TNM-staging results as compared to both imaging modalities alone as well as CT and PET viewed side by side. For esophageal cancer, PET/CT may have advantages especially for the assessment of lymph node metastases in the cervical region and in the abdomen. However, studies are not yet available on this topic.

MR-USPIORecently, magnetic resonance (MR) with ultrasmall superparamagnetic iron oxide (USPIO) is gaining acceptance as a noninvasive method for detection of lymph node metastases in several tumors. MR provides images with excellent anatomical detail and soft tissue contrast but is relatively insensitive for lymph node metastases due to limited sensitivity of current nodes size criteria in differentiating benign from malignant nodes. However, the MR results can be improved by using a superparamagnetic contrast using USPIO. After intravenous administration, USPIO particles reach lymph nodes by two distinct pathways. The major pathway is that of direct transcapillary passage through high endothelial venules within individual lymph nodes. Once within the nodal parenchyma, phagocytic cells of the mononuclear phagocyte system engulf the particles. The second pathway is via nonselective endothelial transcytosis across permeable capillaries throughout the body into the interstitium. USPIO particles are subsequently taken up from then interstitium by lymphatic vessels and transported to regional lymph nodes. A lymph node with normal phagocytic function takes up a substantial amount of USPIO and therefore markedly reduces the signal intensity following intravenous administration of iron oxide agents secondary to the magnetic susceptibility and T2 shortening effects of the iron oxide particles. In metastatic lymph nodes, tumor cells replace the normal cells. This results in a decrease in the number of macrophages and can therefore result in a decrease in the uptake of a lymph node-specific tracer and maintains a relatively high signal intensity. As well as high sensitivities ranging from 81% to 92% as specificities, ranging from 80% to 98%, have been reported for different types of tumors. These encouraging results warrant further investigation especially in tumors like esophageal cancer which an early and whimsical pattern of nodal spread.

Response assessmentThe best option for curative treatment is radical surgery for patients with esophageal cancer,

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with a long-term survival of only 25%. Therefore, various forms of neoadjuvant or adjuvant multimodality therapy have been evaluated in an effort to improve these survival results. Neoadjuvant therapy aims at eradication of lymphatic and/or hematogenous metastases with improvement of survival and at shrinkage of the primary tumor with an improved radical resectability rate. However, in a large proportion of patients insufficient objective response is achieved. These patients do not benefit from neoadjuvant therapy, but do suffer from toxic side effects, while appropriate surgical therapy is delayed. For this reason, a diagnostic test that can accurately predict tumor response early in the course of neoadjuvant therapy is of crucial importance. As described in chapter 3, FDG-PET is a promising noninvasive tool for the identification of responders to neoadjuvant therapy. FDG-PET reflects alterations in tissue metabolism that generally precede anatomic change. Therefore, FDG-PET will be implemented early during neoadjuvant therapy schedules for a proper selection of patients. In 2005, a prospective multicenter trial started in The Netherlands to investigate the exact role of FDG-PET in identifying responders to neoadjuvant therapy. Furthermore, the cost-effectiveness of implementing FDG-PET for early response assessment will be investigated.

11SAMENVATTING

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SAMENVATTINGDe behandeling van patiënten met slokdarmkanker wordt voornamelijk bepaald door het stadium van de ziekte ten tijde van de diagnose. Tot op heden is de chirurgische behandeling de beste mogelijkheid om genezing (curatie) te bewerkstelligen. Echter, een slokdarmresectie gaat gepaard met een aanzienlijke kans op operatie morbiditeit en mortaliteit. Patiënten met uitzaaiingen (metastasen) op afstand (M1) en/of ingroei van de tumor in omliggende organen (T4) komen niet meer in aanmerking voor een slokdarmresectie, omdat in deze categorie patiënten geen curatie bereikt kan worden. Minder belastende en minder invasieve technieken zoals het plaatsen van een stent, radiotherapie of brachytherapie zijn geschikt om voor deze patiënten palliatie te verkrijgen. Het primaire doel van de stadiëring van patiënten met slokdarmkanker is om inzicht te verkrijgen in de factoren die noodzakelijk zijn voor het selecteren van patiënten die in aanmerking komen voor een slokdarmresectie. Daarom worden verschillende onderzoeken verricht ter stadiëring van de patiënt. In het laatste decennium is de kwaliteit van de preoperatieve stadiëring sterk verbeterd. Computer tomografie (CT) van thorax en abdomen was jarenlang het onderzoek van eerste keus om de lokale uitgebreidheid van de tumor vast te stellen alsmede voor het opsporen van metastasen op afstand. Later is de endoscopische echografie (EUS) geïntroduceerd als de meest betrouwbare techniek voor het vaststellen van de mate van ingroei van de tumor in de diverse lagen van de slokdarmwand. Tevens is de EUS van groot belang in het detecteren van locoregionale en truncus coeliacus lymfkliermetastasen, alsmede bij het verkrijgen van cytologie van deze klieren middels de dunne naald biopsie (FNA). Recentelijk is 18F-fluorodeoxyglucose positron emissie tomografie (FDG-PET) toegevoegd aan de preoperatieve stadiëring, met name voor het detecteren van metastasen op afstand. Dit proefschrift bespreekt diverse aspecten van PET voor de stadiëring van patiënten met kanker van de slokdarm of gastro-oesofageale overgang. In hoofdstuk 2 is de literatuur betreffende de stadiëring van het slokdarmcarcinoom m.b.v. FDG-PET systematisch gereviewed. FDG-PET had een matige sensitiviteit en specificiteit voor het detecteren voor locoregionale lymfklieren, met een behoorlijke heterogeniteit van de verschillende studies. Voor de detectie van lymfkliermetastasen op afstand alsmede hematogene metastasen heeft FDG-PET een redelijke sensitiviteit en specificiteit met een mindere mate van heterogeniteit van de verschillende studies. Omdat de keuze van behandeling met name wordt bepaald door de aanwezigheid van metastasen op afstand (M stadium), zijn wij van mening dat de keuze om FDG-PET te implementeren als standaard bij de preoperatieve stadiëring van het oesofaguscarcinoom meer wordt bepaald door de waarde van FDG-PET voor de detectie van metastasen op afstand dan voor de detectie van metastasen in locoregionale lymfklieren (N stadium). Hoofdstuk 3 beschrijft een systematische review van CT, EUS en FDG-PET voor het bepalen van response op neo-adjuvante therapie bij patiënten met slokdarmkanker. Single slice CT is niet accuraat voor de response bepaling en daarom niet aanbevolen. EUS and FDG-PET hebben gelijkwaardige kwaliteiten t.a.v. response bepaling. EUS is in staat patiënten te identificeren met een pathologische response, echter de betrouwbaarheid is beperkt tijdens en kort na de chemoradiotherapie en daarom niet altijd geschikt. FDG-PET meet veranderingen in weefsel metabolisme en is daarom een veelbelovende niet invasieve

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techniek voor response bepaling in patiënten met slokdarmkanker. In hoofdstuk 4 is de invloed onderzocht van FDG-PET op het aantal onnodige chirurgische exploraties. Dit onderzoek toonde aan dat een deel van de patiënten die in aanmerking komen voor een in opzet curatieve resectie een onnodige chirurgische exploratie ondergaan. Meestal was dit omdat er tijdens de operatie metastasen op afstand werden ontdekt. Verbetering van de preoperatieve stadiëring, met name de introductie van FDG-PET, heeft geleid tot een reductie van het aantal onnodige chirurgische exploraties tot ongeveer 20%. Hoofdstuk 5 bespreekt de toegevoegde waarde van FDG-PET na een state-of-the-art conventionele stadiëring en de additionele kosten die hieraan verbonden zijn. FDG-PET verbetert de selectie van patiënten die in aanmerking komen voor een potentieel curatieve resectie, met name in patiënten met stadium III-IV. Echter, de toegevoegde waarde na een uitgebreide conventionele stadiëring o.a. middels EUS-FNA en multidetector CT is beperkt. De additionele kosten van de toevoeging van FDG-PET werden niet gecompenseerd door de gemaakte kosten in het voorkomen van onnodige chirurgische exploraties. In hoofdstuk 6 wordt de klinische relevantie beschreven van synchrone tumoren die gedetecteerd werden m.b.v. FDG-PET, die vervaardigd was voor een initiële stadiëring van patiënten met slokdarmkanker. FDG-PET detecteert onverwachte synchrone tumoren bij deze patiënten. Derhalve dienen voor metastase verdachten afwijkingen op FDG-PET histologisch bevestigd te worden alvorens een behandeling wordt gekozen, omdat een synchrone tumor ten onrechte geduid kan worden als een metastase van het slokdarmcarcinoom. In hoofdstuk 7 wordt een van de valkuilen van FDG-PET beschreven, namelijk het optreden van fout-positieve resultaten. FDG is geen tumor specifiek substraat en fout-positieve resultaten treden op als gevolg van een toegenomen glucose metabolisme in benigne afwijkingen. Deze studie toont aan dat FDG-PET complementair aan de conventionele technieken gebruikt dient te worden. Tevens maken deze bevindingen duidelijk dat positieve FDG-PET resultaten cytologisch bevestigd dienen te worden alvorens patiënten uit te sluiten van curatieve therapie. Behalve beeldvorming stelt FDG-PET ons in staat om de FDG opname in de tumor te kwantificeren. Hoofdstuk 8 bespreekt de rol van de standardized uptake value (SUV) als prognostische factor bij het slokdarmcarcinoom. SUV analyse zou bepaald moeten worden omdat een hoge SUV gerelateerd is aan een vergevorderd tumor stadium, irresectabiliteit en daarom aan prognose. Echter, SUV is niet geschikt als een onafhankelijke voorspeller van de overleving in patiënten met slokdarmkanker. Omdat een slokdarmresectie de beste curatieve optie is, is de overleving sterk gerelateerd aan de geschiktheid voor chirurgie. In hoofdstuk 9 is de nieuwe tracer 18F-fluorothymidine (FLT) onderzocht in een pilot study. Momenteel is FDG de tracer van eerste keus voor de stadiëring van het slokdarmcarcinoom. FLT is tumor specifieker vergeleken met FDG. Ondanks het lager aantal fout-positieve resultaten met FLT neemt het aantal fout-negatieve resultaten toe bij het gebruik van FLT, hetgeen een groot nadeel is bij de stadiëring van slokdarmkanker.

DANKWOORD

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DANKWOORDHet is zover. Het proefschrift is af. Een leuke periode van onderzoek doen en schrijven is afgesloten. Ik ben iedereen die op een of andere manier betrokken is geweest bij de totstandkoming van mijn proefschrift zeer dankbaar. Een aantal personen wil ik in het bijzonder bedanken:

Mijn promotor, Prof dr T Wiggers. Beste Theo, dank voor de vrijheid en het vertrouwen om dit onderzoek binnen de afdeling heelkunde uit te voeren. Dankzij jouw relativerende en pragmatische suggesties tijdens onze voortgangsgesprekken heeft de structuur van dit proefschrift spoedig gestalte gekregen.

Prof dr JJB van Lanschot. Beste Jan, tijdens de diverse besprekingen in Amsterdam en Groningen ben ik onder de indruk geraakt van je expertise op het gebied van de slokdarmchirurgie. Jouw bijdrage bij diverse publicaties van dit proefschrift was dan ook onmisbaar. Dank voor de bereidwilligheid mijn tweede promotor te zijn.

Dr JThM Plukker. Beste John, jou ben ik als mijn directe begeleider en initiator van dit onderzoek veel dank verschuldigd. Jouw nimmer aflatende enthousiasme heeft mijn ‘motortje’ draaiende gehouden. Dank voor de goede harmonie waarin we samen hebben gewerkt. Je deur stond altijd voor me open wat ik zeer gewaardeerd heb. Dat je de tocht naar het ‘verre’ TRIADE-gebouw zeer regelmatig maakte karakteriseert jouw wijze van begeleiden. Ik kijk terug op een waardevolle samenwerking!

Dr HM van Dullemen. Beste Hendrik, dankzij jouw verdiensten hebben we de inclusie in recordtijd gehaald. Je nam voor elke patiënt de tijd om de formulieren in te vullen, gevolgd door het bekende telefoontje: ‘Hee met Hendrik, handel’. Dank voor je bereidheid mijn copromotor te zijn.

Dr PL Jager. Beste Piet, dankzij jouw nuchtere wijze van beoordelen is het aantal fout-positieve bevindingen beperkt gebleven! Jouw scherpzinnige commentaar op de manuscripten was van omineus belang. Dankzij jouw vertrouwen heb ik binnen de PET afdeling in alle vrijheid het onderzoek kunnen uitvoeren. Jouw rol als copromotor is dan ook vanzelfsprekend. Dank!

Dr H Groen. Beste Henk, de basis van dit proefschrift is mede door jouw medewerking tot stand gekomen. Statistiek, kostenanalyse, manuscripten, alle problemen waren opgelost met een bezoek aan jou. Dank voor je tijd, inzet en punctualiteit!

Dr EJ van der Jagt. Beste Eric, vele CT’s hebben we op een rustig plekje binnen jouw afdeling met een bak koffie bekeken. Jouw uitleg hierbij was bijzonder leerzaam. Dank voor de snelle verwerking van alle aanvragen.

Drs M Westerterp. Beste Marinke, samen hebben we de kar getrokken. Ik vond het ontzettend leuk en gezellig om met je samen te werken. Honderden telefoontjes en emails hebben de

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afstand Amsterdam-Groningen tot een minimum beperkt. Dankzij onze prima samenwerking is het allemaal vlotjes verlopen en waren we opgewassen tegen de kleine ‘dipjes’ die horen bij de onderzoekswereld! Nog even en voor jou is het ook zover. Tot ziens in regio II!

Prof dr RAJO Dierckx, Prof dr JH Kleibeuker en Prof dr M Oudkerk dank ik voor het beoordelen van dit proefschrift.

Drs CJ Verhoogt. Beste Carolien, dank voor jouw zeer nauwkeurige administratie en het bepalen van de vele SUV-jes.

Beste Riëtte, veel dank voor de nauwkeurige verwerking van de case record forms. Ongeacht de grootte van de stapel ‘gele mapjes’ was de klus door jou snel geklaard!

Beste Arja en Erna, super bedankt voor het snel plannen van de vele aanvragen. Geweldig!

Beste Hansje, jij als poortwachter wist me altijd vroegtijdig te informeren over de patiënten. Dankzij de ‘korte lijntjes’ hebben we de diverse onderzoeken en polibezoeken mooi kunnen stroomlijnen. Bedankt!

Collega onderzoekers, Esther Bastiaannet, Carlijn Buis, Lukas Been, Tjeerd Boelstra, David Cobben, Anne Brecht Francken, Ciska Jorna, Marten Kapma, Kirsten Kuizenga, Hugo Maathuis, Annemarie Nijboer, Martin Stenekes, het was een supergezellige tijd. Veel dank voor de gezelligheid, uitjes, etentjes, en taart! Het is een wonder dat het ondanks jullie toch gelukt is. Ik denk toch dat de vroege lunch (11.40 uur) het geheim is voor succesvol onderzoek!

Beste Astrid Heinstra, dank voor alle secretariële ondersteuning die onmisbaar was alvorens deze dag aanbrak.

Chirurgen en collega-assistenten van de Isala klinieken te Zwolle. De prima sfeer in de kliniek heeft de overstap van onderzoek naar de kliniek probleemloos later verlopen.

Ing F van Dam. Beste Frans, ik had niet kunnen denken toen we elkaar voor het eerst ontmoetten dat jij dit proefschrift zou lay-outen. Jouw creativiteit heeft weer tot iets moois geleid. Ontzettend bedankt.

Drs A van den Ham. Beste Arco, na een jarenlange vriendschap weet ik zeker dat jij als paranimf voor een fantastische dag zult zorgen.Drs G van ’t Hof. Beste Gerhard, onze carrière is gelijktijdig van start gegaan en we gaan nog steeds gelijk op! Dank dat je mijn paranimf wilt zijn.

Heit en mem, vrienden en vriendinnen, dank voor jullie interesse in mijn destijds ‘vage’ functie als arts-onderzoeker. Leuk dat jullie het feest mee willen vieren!

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Mijn ouders. Lieve pa en ma, een aantal ingrediënten uit jullie opvoeding hebben absoluut bijgedragen aan het voltooien van mijn proefschrift: ‘Benut de kansen die je krijgt’ en ‘Als je ergens aan begint maak je het gewoon af’. Dank voor deze onmisbare nuchterheid.

Allerliefste Andrea, jij was degene die me motiveerde om toch maar te reageren op de Groningse advertentie. We zijn elkaars beste maatjes en realiseren ons iedere keer weer hoe mooi we het samen hebben. Dank je wel voor alles!

PUBLICATIONS

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Publications

PUBLICATIONSPapersHL van Westreenen, LS de Vries, RH Gooskens, PG Nikkels, P Stoutenbeek, EJ MeijboomAneurysm of the v. magna cerebri (vein of Galen), a cause of congestive heart failure in five neonates.Ned Tijdschr Geneeskd 2001;145:1602-1605

HL van Westreenen, PA Heeren, PL Jager, HM van Dullemen, H Groen, JTh PlukkerPitfalls of positive findings in staging esophageal cancer with F-18-fluorodeoxyglucose positron emission tomography.Ann Surg Oncol 2003;10:1100-1105

HL van Westreenen, M Westerterp, PM Bossuyt, J Pruim, GW Sloof, JJ van Lanschot, H Groen, JT PlukkerSystematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer.J Clin Oncol 2004:22;3805-3812

PA Heeren, HL van Westreenen, GJ Geersing, HM van Dullemen, JT PlukkerInfluence of tumor characteristics on the accuracy of endoscopic ultrasonography in staging cancer of the esophagus and esophagogastric junction.Endoscopy 2004;36:966-971

HL van Westreenen, PA Heeren, HM van Dullemen, EJ van der Jagt, PL Jager, H Groen, JT PlukkerPositron emission tomography with F-18-fluorodeoxyglucose in a combined staging strategy of esophageal cancer prevents unnecessary surgical explorations.J Gastrointest Surg 2005;9:54-61

HL van Westreenen, DC Cobben, PL Jager, HM van Dullemen, J Wesseling, PH Elsinga, JT PlukkerComparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer.J Nucl Med 2005;46:400-404

PA Heeren, W Kelder, I Blondeel, HL van Westreenen, H Hollema, JT PlukkerPrognostic value of nodal micrometastases in patients with cancer of the gastro-oesophageal junction.Eur J Surg Oncol 2005;31:270-276

HL van Westreenen, JT Plukker, DC Cobben, CJ Verhoogt, H Groen, PL JagerPrognostic value of the standardized uptake value in esophageal cancer.Am J Roentgenol 2005;185:436-440

HL van Westreenen, M Westerterp, PL Jager, HM van Dullemen, GW Sloof, EF Comans, JJ van

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Publications

Lanschot, T Wiggers, JT PlukkerSynchronous primary neoplasms detected on 18F-FDG PET in staging of patients with esophageal cancer.J Nucl Med 2005;46:1321-1325

M Westerterp, HL van Westreenen, JB Reitsma, OS Hoekstra, J Stoker, P Fockens, PL Jager, BL van Eck-Smit, JT Plukker, JJ van Lanschot, GW SloofEsophageal cancer: CT, endoscopic ultrasound, and FDG PET for assessment of response to neoadjuvant therapy - systematic review.Radiology 2005;236:841-851

Oral presentationsHL van Westreenen, PAM Heeren, PL Jager, JThM PlukkerPitfalls of positive findings in staging esophageal cancer with positron emission tomography.Symposium Experimenteel Onderzoek Heelkundige Specialismen, Rotterdam 2002

HL van Westreenen, PAM Heeren, PL Jager, JThM PlukkerPitfalls of positive findings in staging esophageal cancer with positron emission tomography.Society of Surgical Oncology, Los Angeles 2003

HL van Westreenen, HM van Dullemen, EJ van der Jagt, PL Jager, H Groen, JThM PlukkerExtent of preoperative staging of esophageal cancer to prevent futile explorative surgery. World Organization for Specialized Studies on Diseases of the Esophagus 7th World Congress, Paris 2003

HL van Westreenen, PAM Heeren, HM van Dullemen, JThM PlukkerInvloed van tumor gerelateerde factoren op de betrouwbaarheid van de EUS bij het slokdarmcarcinoom.Chirurgendagen Nederlandse Vereniging voor Heelkunde, Veldhoven 2004

HL van Westreenen, JThM Plukker, HM van Dullemen, PL Jager, EJ van der JagtStaging of esophageal cancer with multidetector computed tomography. European Society of Gastrointestinal and Abdominal Radiology, Genève 2004

HL van Westreenen, HM van Dullemen, PL Jager, Th Wiggers, JThM PlukkerDetection of unexpected primary neoplasms on FDG-PET in staging of patients with esophageal cancer.Najaarsvergadering Nederlandse Vereniging voor Gastroenterologie, Veldhoven 2004

HL van Westreenen, HM van Dullemen, JThM Plukker, DCP Cobben, H Groen, PL JagerClinical relevance of the standardized uptake value in staging esophageal cancer with FDG-PET.Najaarsvergadering Nederlandse Vereniging voor Gastroenterologie, Veldhoven 2004

144

Publications

HL van Westreenen, HM van Dullemen, JThM Plukker, DCP Cobben, H Groen, PL JagerClinical relevance of the standardized uptake value in staging esophageal cancer with FDG-PET.19th World Congress of International Society for Digestive Surgery, Yokohama 2004

HL van Westreenen, DCP Cobben, PL Jager, HM van Dullemen, J Wesseling, PH Elsinga, JThM PlukkerComparison of FLT-PET and FDG-PET in the visualization, staging and proliferation of esophageal cancer.19th World Congress of International Society for Digestive Surgery, Yokohama 2004

Poster presentationsHL van Westreenen, PAM Heeren, PL Jager, JThM PlukkerPitfalls of positive findings in staging esophageal cancer with positron emission tomography.4th International From Gene to Cure Congress, Amsterdam 2002

HL van Westreenen, HM van Dullemen, EJ van der Jagt, PL Jager, H Groen, JThM PlukkerPreoperative staging of esophageal cancer with FDG-PET to prevent futile explorative surgery.ASCO Gastrointestinal Cancers Symposium, San Francisco 2004

HL van Westreenen, PAM Heeren, HM van Dullemen, JThM PlukkerTumor-related factors influencing the accuracy of endoscopic ultrasound in cancer of the esophagus and the gastro-esophageal junction.ASCO Gastrointestinal Cancers Symposium, San Francisco 2004

HL van Westreenen, HM van Dullemen, EJ van der Jagt, PL Jager, H Groen, JThM PlukkerPreoperative staging of esophageal cancer with FDG-PET to prevent futile explorative surgery.Digestive Disease Week, New Orleans 2004

HL van Westreenen, PAM Heeren, HM van Dullemen, JThM PlukkerTumor-related factors influencing the accuracy of endoscopic ultrasound in cancer of the esophagus and the gastro-esophageal junction.Digestive Disease Week, New Orleans 2004

HL van Westreenen, BB Pultrum, JThM PlukkerOutcome in patients with stage IV esophageal cancer detected during explorative surgery.European Society of Surgical Oncology, Budapest 2004

CURRICULUM VITAE

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Curriculum Vitae

CURRICULUM VITAEHenderik Leendert van Westreenen werd geboren op 21 augustus 1977 te IJzendoorn (gemeente Echteld). In 1989 ging hij naar het Ichthus college te Veenendaal, waar hij het VWO-diploma behaalde in 1995. Aansluitend startte hij de studie Medische Biologie aan de Universiteit te Utrecht waarvan de propaedeuse werd behaald in 1996. Datzelfde jaar begon hij met de studie Geneeskunde. Na een stage van 3 maanden in Parbatipur, Bangladesh, werd het artsexamen behaald in 2002. Vanaf augustus 2002 zette hij zijn loopbaan voort als arts-onderzoeker op de afdeling chirurgie van het Universitair Medisch Centrum te Groningen onder leiding van prof dr T Wiggers en dr JThM Plukker. Dit onderzoek naar de rol van positron emissie tomografie bij de stadiëring van het slokdarmcarcinoom heeft geresulteerd in deze dissertatie. Sedert januari 2005 is hij in opleiding tot chirurg in de Isala klinieken te Zwolle (dr D van Geldere). Hij zal deze opleiding voortzetten in het Academisch Medisch Centrum te Amsterdam (prof dr JJB van Lanschot).