The effort to improve outcomes in esophageal cancer has included attempts at improving staging and patient selection. 2-Deoxy-2-[ 18 F]fluoro-Dglucose positron emission tomography (FDG-PET) has been extensively studied in this context and has been widely accepted as a staging tool. Its role in restaging or assessing therapeutic response is investigational and promising. Laparoscopy has also been studied as a means for improving staging, but its role may be limited in the era of PET. This article discusses the literature assessing these modalities, particularly with regard to the practical management of the patient in the clinic.
Prognostically, esophageal cancer is characterized by high rates of local or distant recurrence following primary therapy, with death occurring soon after. Further darkening this grim prognosis is the observation that patients may spend their final months enduring and trying to recover from primary therapy, which often includes a potentially toxic combination of chemotherapy, radiation, and surgery.
The high failure rate is partly due to inadequacies in staging, which ideally would distinguish curable from incurable disease at the outset. Ideal staging selects patients for therapy according to the likelihood of clinical benefit—patients with local or locally advanced disease could receive local or multimodality therapy, whereas those with distant metastases could be spared aggressive and futile interventions.
For years, CT was the first-line method to detect distant metastases; however, major US trials enrolling patients thought to have resectable disease after CT with or without endoscopic ultrasonography (EUS) yielded noncurative resections in as many as 15% to 30% of patients and 1-year disease-free and overall survival rates of only 30% to 48% and 58% to 72%, respectively. In recent years, CT has been reported to have a sensitivity and specificity for detecting distant metastases of 41% to 81% and 82% to 83%, respectively.
When EUS was introduced, it became the most reliable method for determining T stage and identifying cancerous regional lymph nodes. EUS with fine-needle aspiration (FNA) enabled selective aspiration of echographically suspicious nodes, including those at the celiac axis; however, even when combined with CT, EUS has a reported sensitivity for detecting involved lymph nodes of only 11% to 54% and a specificity of 90% to 95%. Moreover, EUS is limited in esophageal obstruction, which impedes adequate passage of the endoscope and accurate detection of the depth of invasion and metastatic disease.
While tremendous attention has focused on developing effective therapies in all stages of disease, another line of investigation has been to improve initial staging. Modalities that have received attention or become standard at some institutions include 2-deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomography (FDG-PET) scanning, staging laparoscopy, and EUS.
PET has emerged as an important, increasingly common staging tool, particularly for the detection of distant metastases. Its routine use is recommended by the National Comprehensive Cancer Network in staging patients lacking M1 disease on CT and EUS. PET has also been studied to assess therapeutic response and to prognosticate, a role that is still investigational. Meanwhile, staging laparoscopy has been evaluated for the detection of peritoneal disease, particularly in patients with disease involving the gastroesophageal junction. Its acceptance has been less widespread. The role of EUS is discussed in detail elsewhere in this issue.
This article primarily reviews the data on the role of PET in staging and restaging esophageal cancer and in assessing the response to therapy. It also discusses the potential role of laparoscopy as a staging tool. Because of the dominance of adenocarcinoma in the United States and other Western countries, and because it appears to be a distinct clinical entity from squamous cell carcinoma, this discussion of the current literature draws attention to studies focusing on this histologic subtype.
Positron emission tomography in initial staging
CT and EUS provide anatomic visualization, whereas PET measures metabolic processes. PET can potentially determine quantitative information on blood flow, receptor status, and metabolic processes, depending on the radiopharmaceutical selected. Many of the early studies of PET in esophageal cancer were performed with “PET only” imaging. The advent of PET scanners with integrated CT scanners in recent years has allowed for direct comparison of metabolic information with anatomy with the added benefit of shorter imaging times for patients. This integration has led to an improvement in diagnostic accuracy from PET imaging; therefore, all state-of-the-art PET imaging is currently performed with integrated CT (PET/CT). The FDG is a glucose analogue that emits positron radiotracer. It is transported intracellularly and phosphorylated to FDG-6-phosphate via the same pathways as glucose. Because it is highly polarized, it is trapped in the cell. FDG-6-phosphate accumulates in tumors following injection and provides a signal of high glycolytic tissue activity in the body. Malignant tumors in most organ systems, except the brain and urinary tract, are frequently detected by FDG-PET.
PET images are analyzed qualitatively and quantitatively. The intensity of FDG uptake characterized as a standardized uptake value (SUV) within specific lesions is calculated as follows:
SUV = mean activity in the region of interest ( mCi / mL ) injected dose of FDG ( mCi ) / body wt ( g )
Assessing T Stage
PET/CT has limited use in T staging, although tumor invasion into adjacent organs (T4) can sometimes be detected. Signs of invasion into adjacent organs include blurring of periesophageal fat, loss of intervening fat planes, and a large concave interface. After neoadjuvant radiotherapy, loss of normal tissue planes due to radiation-induced fibrosis and necrosis makes repeat evaluation of the T classification difficult with all imaging modalities, and local organ invasion may not be detected until esophagectomy.
Key studies evaluating PET in the initial staging of patients with adenocarcinoma of the esophagus or gastroesophageal junction are shown in Table 1 . The sensitivity of PET for detecting primary esophageal tumors has been reported in prospective studies to be 91% to 95%. In one study of 75 esophageal cancer patients, PET correctly assessed T status in 43% of cases, understaged status in 29%, and overstaged status in 29%. Given the limited spatial resolution of PET imaging devices (about 5–8 mm), it is generally believed that lesions smaller than 1 cm, particularly early stage cancers, may not be detected.
| Study | Institute | Design | Number of Patients | Other Modalities | AC/SCC (%) | T (%) a | N | M | PCM (%) | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Sensitivity (%) | Specificity (%) | Sensitivity (%) | Specificity (%) | ||||||||
| Block 1997 | Washington University | Unclear | 58 | CT | 59/40 | — b | — | — | — | — | 15 |
| Luketich 1997 | University of Pittsburgh | Retro | 35 | EUS, bscan, CT, Ls or Ts | 71/26 | 97 | 45 | 100 | 88 c | 93 c | 20 |
| Lowe 2005 | Mayo | Prosp | 75 | CT, EUS | 90/10 | — | 82 | 60 | 81 | 91 | 4 |
| Flamen 2000 | Gathuisberg, Belgium | Prosp | 74 | CT, EUS | 72/28 | 95 | 39 | 97 | 74 | 90 | — |
| Meyers 2007 | ACOSOG | Prosp | 189 | CT | NR | 91 | — | — | 5%–10% Upstaged to M1b 3% Falsely upstaged to M1b | ||
| Heeren 2004 | Groningen, Netherlands | Prosp | 74 | CT, EUS | 84/16 | 95 | 55 | 71 | 78 | 98 | 7 |
a Sensitivity for identifying primary tumor. Specificity for detecting tumor was not assessed in most studies because inclusion criteria required the presence of primary esophageal tumor.
b Dash denotes results reported in a way that did not permit simple cross-study comparison.
Assessing N Stage
Locoregional lymph nodes (eg, gastrohepatic ligament) are generally considered resectable (N1), whereas the resectability of celiac axis nodes is more controversial (M1a). Most studies indicate that PET, with or without CT, has limited use in assessing locoregional lymph node status (see Table 1 ). FDG uptake within periesophageal nodes close to the primary tumor is difficult to differentiate from uptake within the esophageal tumor itself due to the limited spatial resolution of PET. Further limiting the interpretation of nodes is the observation that FDG uptake can occur in benign disease such as granulomatous inflammation (eg, sarcoidosis), aspiration pneumonitis, or other inflammatory/infectious conditions.
A meta-analysis of 12 studies (n = 490) that examined the diagnostic accuracy of PET in preoperative staging of esophageal cancer reported sensitivity and specificity for detecting locoregional node involvement of 51% and 84%, respectively. The studies in the meta-analysis were heterogeneous in methodologic quality, in whether preoperative EUS was incorporated, and in whether PET images were fused with images from CT.
A Belgian study included in the meta-analysis reported the accuracy of PET in detecting local versus regional-distant nodal involvement (n = 74) and found accuracy rates to be similar between nodal regions. Local nodes were defined as those located within 3 cm from the primary tumor. Regional and distant nodes comprised all other nodes, including those in mediastinal, supraclavicular, and retroperitoneal areas. The sensitivity and specificity of PET were similar in the two nodal groups: 33% and 89% for local nodes and 46% and 90% for regional-distant nodes, respectively.
Subsequent to the meta-analysis, the authors reported the results of a prospective study at their institution comparing the accuracy of PET, CT, and EUS in the initial staging of patients with esophageal cancer (n = 75). In contrast to other data, the sensitivity of PET was found to be higher and the specificity of PET lower for detecting nodal metastases, that is, 82% and 60%, respectively.
Our reported specificity was probably lower because, unlike in other reports, EUS operators in the study were initially blinded to PET and CT results. After finishing TNM staging and sampling of visualized nodes, the EUS operator opened a sealed envelope to learn whether PET and CT had identified additional nodes or metastatic foci that could be assessed. If so, the operator sampled these areas, allowing histopathologic evaluation of all detected nodes in all modalities. Such pathologic confirmation could lead to a higher false-positivity rate (or lower specificity) attributed to PET or CT than reported elsewhere.
The sensitivity rate reported in our study was higher possibly because (1) we included both unresectable and resectable cases following CT evaluation, whereas other studies excluded unresectable cases, and (2) we performed PET with attenuation correction, which is known to improve sensitivity.
Changing Management: Evaluating Distant Disease (M Stage)
The crucial test for incorporating a diagnostic modality in staging work-up is the degree to which it rationally alters clinical management. In esophageal cancer, two anatomic-pathologic checkpoints can most affect clinical management. The first checkpoint is distinguishing T2 (submucosa) from T3 (serosa) lesions. T1-2 lesions may be cured with surgery alone, whereas T3 lesions are commonly managed with trimodality therapy. As discussed previously, PET contributes minimally in this regard. The second checkpoint is distinguishing potentially resectable, locally advanced disease (T3-4N0, N1, perhaps M1a) from distant disease (M1b, perhaps M1a). Patients properly diagnosed with distant disease would receive more accurate prognostic information and palliative chemotherapy and would be spared combined chemoradiation and esophagectomy. For these patients, PET may be most helpful.
In their discussion, the investigators of the meta-analysis observed that patient management was altered in 3% to 20% cases due to the addition of PET in the preoperative work-up. The large range is explained in part by differences in entry criteria, the rigor with which pathologic verification (gold standard) was obtained, the study design, and criteria for resectability.
In prospective studies with clear reporting and rigorous attempts at pathologic confirmation that distinguished between M1a and M1b disease, M1b disease was detected by PET and missed by CT (with or without EUS) in 5% to 7% of cases. The addition of preoperative PET would have spared these patients unnecessary surgery.
One study reported that PET indicated M1b disease in an additional 10% of patients, but pathologic confirmation was not obtained. The investigators clarified that these PET-avid M1b lesions were unlikely to be malignant, because many of the unconfirmed findings were noted in patients who subsequently underwent surgical resection and had no evidence of recurrence or progression at 6 months.
M1 disease of any type (M1a or M1b) was detected by PET and missed by CT (with or without EUS) in 6% to 15% of patients. The minimal contribution of PET in detecting M1 disease in our study (1%) is perhaps explained by the fact that EUS detected M1a and some adjacent hepatic lesions with substantially greater sensitivity than reported elsewhere.
Limitations and Risk of Positron Emission Tomography
A potential downside to the routine use of PET in staging is the burden imposed by false-positive findings. The specificity of PET for M1a or M1b disease has been reported consistently to be high (90%–98%). Nevertheless, as with any diagnostic modality, false-positive findings lead to futile, potentially harmful work-up.
This problem is most aptly illustrated in the ACOSOG trial, one of few studies that reported adverse events stemming from the use of PET. In that trial, 4% of patients had negative confirmatory procedures. One patient underwent an adrenalectomy for a false-positive PET suggesting an adrenal metastasis. In addition to requiring a surgical procedure, the patient also required subsequent therapy for adrenal insufficiency. Another patient experienced a grade 3 adverse event for a wound complication after a confirmatory procedure for a false-positive finding.
Repeat positron emission tomography during or after neoadjuvant therapy as a restaging tool and prognostic marker
Based on the cumulative evidence of several underpowered trials, one standard therapy for resectable, locally advanced esophageal cancer in the United States has evolved to include chemotherapy concurrent with radiation (before surgery). Likewise, some parts of Europe have adopted neoadjuvant chemotherapy alone (followed by surgery). Both preoperative approaches have improved outcomes modestly at best and with considerable toxicity; therefore, investigators have sought ways to improve the selection of patients for therapy.
In this context the value of obtaining a repeat PET scan during or after neoadjuvant therapy has been studied as a restaging tool and as a prognostic marker. Three clinical scenarios have received the most attention in their potential for PET to alter and improve patient management ( Table 2 ): (1) during neoadjuvant therapy for prognostication, (2) after neoadjuvant therapy and before surgery for restaging, and (3) after neoadjuvant therapy and before surgery for prognostication.
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Genetic Variations in Esophageal Cancer Risk and Prognosis
Traditional Chinese Medicinal Herbs in the Treatment of Patients with Esophageal Cancer: A Systematic Review
Future Developments in Esophageal Cancer Research
Screening, Surveillance, and Prevention for Esophageal Cancer
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