Nuclear Oncology, 1 Ed.

CHAPTER 5

ESOPHAGEAL CARCINOMA

Mark Dunphy • Heiko Schöder

INTRODUCTION

Esophageal cancer includes cancers involving the esophagus, including the cervical and the thoracic esophagus, as well as cancers involving the gastroesophageal junction (GEJ). In the current (seventh edition) American Joint Committee on Cancer (AJCC) guidelines, cancers with an epicenter in the stomach that is less than 5 cm from the GEJ with extension of this lesion to involve the GEJ are considered esophageal carcinoma.1 If a tumor is located within 5 cm distal to the GEJ but does not extend into it, this is considered gastric cancer. Other guidelines, for instance those of the National Comprehensive Cancer Network (NCCN), do not include the proximal 5 cm of the stomach.2 Esophageal cancer includes two major histologic subtypes: Adenocarcinoma (AC) and squamous cell carcinoma (SCC), both arising from the inner lining of the esophagus, the mucosa. Some tumors demonstrate a mixed histopathologic type, containing AC and SCC; these are considered essentially SCC because of their poorer prognosis. The Siewert classification of AC of the GEJ (AEG) defines AEG as a tumor whose center is within 5 cm proximal of, or distal to, the anatomical gastric cardia, including tumors with a center within the distal esophagus and margins that may infiltrate the GEJ (AEG type I); tumors arising at the GEJ and gastric cardiac epithelium (AEG type II); and tumors centered in the stomach beyond the gastric cardia, infiltrating the GEJ and distal esophagus “from below.”3

In 2013, in the United States, esophageal cancer claimed the lives of about 15,000 people, and an estimated 17,000 people were newly diagnosed with this disease.4 Worldwide, SCC is the most common form of esophageal cancer, particularly in eastern countries. However, in western countries the incidence of esophageal SCC has been declining over the past decades; AC is now the most common form of esophageal cancer in the United States.4,5 Overall, esophageal cancer incidence and mortality in the United States have declined progressively since the late 1980s, with differences among demographic groups.4,6 Risk factors for the development of esophageal cancer include columnar metaplasia of the distal esophagus (Barrett esophagus),7 obesity, cigarette smoking, and various autoimmune diseases such as celiac disease, reactive arthritis, or systemic sclerosis; and polycyclic aromatic hydrocarbon exposure.79 Interestingly, use of aspirin and other NSAIDs appears associated with a reduced incidence of esophageal AC.10 Worse clinical outcomes have been associated with a variety of clinical and biologic factors, including several inflammatory genes and microRNA biomarkers.

Patient survival depends upon whether and how far the disease has spread. Analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with esophageal cancer—either SCC or AC—between 2001 and 2007, revealed 5-year survival rates of 37% for patients with localized disease limited to the esophagus; 18% for patients with regional spread to lymph nodes or adjacent tissues, and 3% for patients with distant spread.11 Despite some progress in earlier detection, more than one-half of esophageal cancer patients present with incurable locally advanced or metastatic disease. Detection of early disease is rare because small primaries are usually asymptomatic and even small tumors have often already metastasized. The prognosis of these patients remains poor overall, and the optimal treatment strategy remains the subject of debate and research.12Approximately 15% of patients can achieve complete clinical remission after multimodality therapy.

Multimodality radiologic imaging plays an essential role in the initial staging of esophageal cancer, and in evaluating response to therapy. It also offers prognostic information in the pre- and posttreatment settings. Imaging procedures with accepted clinical roles in esophageal cancer management include x-ray fluoroscopy (barium swallowing study), endoscopic ultrasound (EUS), computed tomography (CT), and 18FDG PET/CT; MRI has no standard role at the present time. Although a barium swallowing study may provide some useful information, upper gastrointestinal endoscopy with biopsy is the primary modality leading to cancer diagnosis.13 Bone scintigraphy, previously used for the detection of osseous metastases, has been effectively supplanted by 18FDG PET/CT in most major cancer centers.14 This chapter focuses on the role of 18FDG PET/CT.2

STAGING OF ESOPHAGEAL CANCER

The seventh edition of the AJCC and the International Union Against Cancer (UICC) staging system classify the disease based on disease biology, prognosis, and therapeutic regimens. For instance, this new classification recognizes that in the absence of nodal metastases, prognosis depends only on T-stage, histology (SCC versus AC), tumor grade, and, for SCC, also on the location of the primary tumor within the esophagus.15 Some important changes compared to earlier classifications include the following.

• SCC and AC have separate staging schemes (Tables 5.1 and 5.2).

• Tumors arising in the GEJ and proximal 5 cm of stomach are included (previously considered primary gastric cancer16).

• Tumor grade is now a component of the stage groupings (previously TNM, now TNMG).

• Tumor location is a new component in patients with SCC.

• Tis has been redefined and T4 subclassified.

• N-stage is no longer simply divided into N0 (absence) or N1 (presence of metastasis), but as N0, N1, N2, or N3 according to the number of regional lymph node metastases and the definition of “regional” lymph nodes is changed.

• M-stage has been simplified into M0 or M1 (previously, M1 was subclassified).

TABLE 5.1

SQUAMOUS CELL CARCINOMA, AMERICAN JOINT COMMITTEE ON CANCER (AJCC)/UNION FOR INTERNATIONAL CANCER CONTROL (UICC) STAGING

TABLE 5.2

ADENOCARCINOMA, AMERICAN JOINT COMMITTEE ON CANCER (AJCC)/UNION FOR INTERNATIONAL CANCER CONTROL (UICC) STAGING

Accurate staging is vital for appropriate therapeutic management. If patients have potentially resectable disease, their median survival strongly correlates with disease stage. For instance, resection alone is considered sufficient treatment for superficial cancers without metastatic disease (T1N0M0) and may also be appropriate for (true) T2N0M0 disease. Apart from gross extraesophageal infiltration, the depth of primary tumor penetration within the layers of the esophageal wall cannot be determined with CT or PET/CT, and small lymph nodes, especially when located near the primary, may not be recognized. Instead, EUS has a pre-eminent role in evaluating the primary tumor (size and depth of invasion) and locoregional lymph nodes. It is superior to CT, MRI, or 18FDG PET/CT for this purpose.1719 CT and 18FDG PET/CT are especially useful to detect metastatic disease.2,2022 This may spare patients the morbidity of surgery and/or toxicity of other therapeutic regimens that only benefit patients of lesser stage disease. It also appears to be cost-effective.23,24 However, to avoid “overstaging,” suspicious findings that could potentially alter the patient management should be confirmed by biopsy. The addition of 18FDG PET/CT to other tests changes the disease stage in about 40% of patients, leading to changes in patient management in 10% to 40% of patients.2529 Changes in management may involve a change in therapeutic intent (about one-half of cases, usually will be reclassified from curative to palliative intent) with changes in treatment modalities or methods of treatment delivery. When 18FDG PET/CT detects heretofore unknown distant disease, it is usually found in supraclavicular or abdominal lymph nodes (Fig. 5.1), as well as liver and bone.28 In a recent study in 139 patients with esophageal cancer,26PET/CT correctly changed the stage group in 40% of patients (e.g., upstaged from group I-IIA to stage group IIB-III or stage group IV, reflecting differences in therapeutic approach) and changed the management in 34% of patients (26% high impact change, 8% medium impact change).

In patients with GEJ tumors, diagnostic laparoscopy may be pursued in search of intraperitoneal disease but this is not considered mandatory, particularly if no metastatic disease is evident elsewhere.2

FIGURE 5.1. A 68-year-old man with poorly differentiated adenocarcinoma of the distal esophagus. Staging CT scan of the chest, including supraclavicular regions, showed no evidence of metastatic disease. Staging FDG PET/CT revealed abnormal hypermetabolic activity in a subcentimeter left supraclavicular lymph node. The subcentimeter node was below CT-size criteria for abnormality. Shown are corresponding companion CT (upper) and fusion PET-CT (lower) transaxial images showing the small hypermetabolic lymph node (arrows ). Ultrasound-guided biopsy found the sonographic appearance of the lymph node abnormal; biopsy pathology confirmed metastatic adenocarcinoma. FDG PET/CT improved disease staging.

CHARACTERIZATION OF THE PRIMARY TUMOR: TUMOR LOCATION

Esophageal SCC is found in the midregion of the thoracic esophagus more often than elsewhere (Fig. 5.2). SCC primary tumors in the GEJ are more favorable, associated with lower disease stage (Table 5.1).

The SCC staging classification categorizes primary esophageal tumor location as upper, middle, or lower. “Upper” includes the upper thoracic esophagus, which is between thoracic inlet and the lower border of the arch of the azygos vein (i.e., its arch over the right mainstem bronchus), and the cervical esophagus, which is between the thoracic inlet and the upper esophageal sphincter (UES). The UES can sometimes be visualized on CT as a small mass-like contraction of the esophagus musculature posteriorly to the cricoid cartilage and on 18FDG PET as a site of focally prominent 18FDG uptake. The UES is an important landmark because it also defines resectability: Cervical or “cervicothoracic” (thoracic esophagus but <5 cm from the UES) primary tumors are usually unresectable and, therefore, preferentially treated with definitive chemoradiotherapy.2

FIGURE 5.2. Anatomy of esophageal cancer primary site, including typical endoscopic measurements of each region measured from the incisors. Exact measurements are dependent on body size and height. (Reprinted with permission from Springer-Verlag New York Inc., Publisher of American Joint Committee on Cancer (AJCC). AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.) GEJ, gastroesophageal junction; UES, upper esophageal sphincter.

“Middle” is defined as the region between the transaxial levels of the azygos vein arch and the inferior pulmonary veins, and “lower” is defined as the region below the inferior pulmonary veins, including the GEJ. The lower esophagus normally has an intra-abdominal portion, passing through the diaphragm before connecting to the stomach, but this can be absent because of hiatal hernia. Like the UES, the contracted lower esophageal sphincter (LES) can appear “mass-like” and intensely 18FDG avid on PET/CT; in the presence of hiatal hernia, a contracted LES can mimic an 18FDG-avid tumor of the lower thoracic esophagus.

STAGING AND GRADING

In contrast to many other malignancies, T-stage is not defined by size, but by depth of tumor penetration through the layers of the esophageal wall and involvement of extraesophageal tissues (Table 5.3 and Fig. 5.3). Nevertheless, T3 and T4 tumors are usually larger than T1 and T2 tumors.30 On CT, a thoracic esophageal wall may be considered abnormally thick if it measures >5 mm when contracted or nondistended3134 or >3 mm if adequately distended.31,34The normal wall of the nondistended intra-abdominal portion of the esophagus may be up to 6 mm in thickness. Noncancerous esophageal disease can cause wall thickening that may confuse CT-delineation of primary tumor extent—notably Barrett esophagus and esophagitis.33 Barrett esophagus and esophagitis, caused by reflux disease or prior irradiation, can also be 18FDG avid3537 and interfere with the evaluation of the primary tumor.

TABLE 5.3

T-STAGE CRITERIA, AMERICAN JOINT COMMITTEE ON CANCER (AJCC)/UNION FOR INTERNATIONAL CANCER CONTROL (UICC) STAGING SYSTEM FOR ESOPHAGEAL CARCINOMA

The esophageal wall includes three layers: Mucosa (Tis and T1a), submucosa (T1b), and muscularis propria (T2). The mucosa is further divided into three sublayers: Epithelium (m1), lamina propria (m2), and muscularis mucosae(m3). Table 5.3 describes the depth of invasion into these layers and extraesophageal structures that define each T-stage. The submucosa has no internal anatomic separations, but pathologists often measure invasion of the submucosa according to thirds of its depth: Inner third (sm1), middle third (sm2), and outer third (sm3). These histologic layers and sublayers are far below the spatial resolution of PET but are often discussed in the PET literature when correlating imaging and histopathology findings. The muscularis propria has inner circular and outer longitudinal muscle layers. Extraesophageal invasion begins with the connective tissues enveloping the esophagus, the adventitia(T3). The esophagus has no serosa.

FIGURE 5.3. T, N, and M classifications, American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. Primary tumor (T) is classified by depth of tumor invasion. Regional lymph node classifications are determined by metastatic burden. Distant metastatic sites are designated M1. (Reprinted with permission from Springer-Verlag New York Inc., Publisher of American Joint Committee on Cancer (AJCC). AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010).

Higher T-stages are associated with higher risks of metastatic disease and worse overall survival. T1 to T2 tumors may undergo primary surgical resection if no metastatic disease is evident. T3 or T4 tumors may receive neoadjuvant therapy, followed by resection, or definitive treatment by a nonsurgical approach with combined modality (chemoradio-) therapy. Unresectable (T4b) tumors include those involving heart, great vessels, trachea, liver, pancreas, lung and/or spleen. Tumors involving pericardium, pleura, or diaphragm alone are usually resectable (T4a).

Although EUS is the primary modality for detailed evaluation of the primary tumor, CT findings may suggest T4 disease or the absence of T4 disease. Invasion may be obvious, such as gross extension into adjacent organs, or more subtle, such as a loss of fat planes between primary and other mediastinal structures. For aortic involvement (T4b), loss of fat planes is considered more specific for invasion if the tumor is inseparable from ≥90 degree of the aortic circumference38 or if the small triangular region between the esophagus, aorta, and spine (normally occupied by fat) is occupied by tumor.39 Displacement of the tracheobronchial airways or heart/pericardium by an abutting tumor, especially if associated with focal impingement/deformity, is suspicious for T4b disease.38,40 Pericardial effusion, thickening, and loss of pericardial fat are other suspicious signs.41 If distinct fat planes exist between the esophageal tumor and other mediastinal structures, an absence of T4 findings can be reported, and EUS can be used to distinguish among T1- to T3-stages.

EUS is the imaging modality of choice for primary tumor delineation, because it can visualize the depth of tumor penetration within the esophageal wall. The overall accuracy for T-stage is 70% to 90%, with lesser accuracies in tiny superficial lesions and tumors associated with esophageal stenosis.42,43 For histologic grading (G), tumor differentiation is scored from G1, for well-differentiated tumors, to G4, for undifferentiated tumors.

Of note, even small tumors with only mucosal or submucosal involvement (T1a-b) can present with extensive nodal or even distant metastatic disease. Therefore, 18FDG PET/CT may be useful even for staging of very small primaries.

PRIMARY TUMOR 18FDG AVIDITY AND 18FDG PET IMAGING OF THE NORMAL ESOPHAGUS

Both AC and SCC of the esophagus usually demonstrate intense 18FDG uptake.25 18FDG PET/CT fusion imaging has markedly superior diagnostic accuracy compared to PET alone and also in comparison to the sum of information gained from interpretation of separately acquired PET and CT data.4446 When the PET/CT is performed with intravenous contrast, artifacts from high-concentration contrast material in mediastinal vessels can rarely be seen and should not be confused with 18FDG uptake in metastatic lymph nodes. This question is easily addressed by careful review of CT and PET data sets as well as review of nonattenuation corrected PET images. 18FDG avidity appears independent of the primary location within the esophagus.47 Sometimes focal prominence of 18FDG uptake can be seen in the retrocardiac (mid-) region of the thoracic esophagus as a normal variant. Mild diffuse 18FDG uptake along the course of the entire esophagus may be related to increased peristalsis/spasm or esophagitis. Many T1 tumors are not detectable on PET—probably because of their small volume and the partial volume effects on PET.48,49

Some (but not all) studies have shown that the intensity of 18FDG uptake correlates with dedifferentiation,47,50 presence of nodal metastases,47,51 vascular invasion,47 as well as GLUT-1 and hexokinase II expression.47,52Moreover, the SUV of the primary esophageal tumor correlates weakly with T-stage.50 Higher primary tumor SUV has been associated with advanced disease stage.50,51

Nodal Involvement (N-Stage)

The presence or absence of nodal (or other) metastatic disease is the most important prognostic factor in esophageal cancer.11,53 N-stage is defined by the number of regional lymph nodes involved (Table 5.4), based upon data suggesting the prognostic importance of the number of involved locoregional lymph nodes.5459 The detection of 18FDG-avid locoregional lymph nodes on PET/CT is associated with worse survival in both AC (76) and SCC (77). Of note, even microscopic nodal metastatic disease, invisible to CT and often undetectable on FDG PET, is an adverse prognostic factor.60

TABLE 5.4

NODAL STAGING, AMERICAN JOINT COMMITTEE ON CANCER (AJCC)/UNION FOR INTERNATIONAL CANCER CONTROL (UICC) STAGING SYSTEM, FOR ESOPHAGEAL CARCINOMA

EUS is the single most accurate imaging modality for detection of nodal metastases, but it is imperfect. Hence, oncologists often rely upon the combined sensitivity of EUS, CT, and sometimes 18FDG PET/CT to avoid understaging. Several small early studies of 18FDG PET (not PET/CT), reported a highly variable sensitivity for the detection of nodal involvement (22% to 93%).48,49,61,62 These numbers are probably no longer applicable in the current era. Combined PET/CT provides better detection of nodal metastases than PET alone (because of accurate localization of mediastinal 18FDG activity). Table 5.5summarizes the sensitivity and specificity of 18FDG PET for detection of lymph node metastases from various published studies.19,29,48,6169

The extensive lymphatic network of the esophagus facilitates the spread of metastatic disease even from primary tumors limited to the mucosa of the esophageal wall.70 Lymphatic channels are found in highest concentration in the submucosa, frequently draining directly into the thoracic duct, facilitating the spread of systemic metastatic disease. Lymphatic channels are also present, to a lesser degree, in the lamina propria of the mucosa, allowing the potential lymphatic spread of T1a tumors. Therefore, occasionally 18FDG PET/CT may detect nodal metastases even in patients with small T1 primaries. The submucosal lymphatics are oriented along the same longitudinal axis as the overall esophagus, and lymph may flow from the region of the primary esophageal tumor to a “local” lymph node that is not on an adjacent transaxial plane. Hence, for esophageal cancer, “local” lymph node involvement is defined as metastatic lymphadenopathy found anywhere from the cervical periesophageal region to the celiac nodal basin.70 If nodal involvement is found outside these anatomic regions, it is considered distant metastatic (M) disease. Although celiac adenopathy was previously considered distant metastatic disease, the seventh edition of the AJJ staging criteria now considers this locoregional disease and, hence, not necessarily an indication of unresectable disease. Nevertheless, the presence of celiac adenopathy is still considered an adverse prognostic factor71 and merits special mention in the 18FDG PET report. For GEJ tumors, the lymphatic drainage pattern depends on the exact location: Tumor of the distal esophagus may drain into the mediastinum and along the celiac axis, whereas tumors of the gastric cardia and below drain to nodes in the celiac axis, splenic hilum, and para-aortic region.72

The main reason for a false-negative 18FDG PET/CT in nodal staging is probably the small size of metastatic deposits in some nodes; when PET/CT shows no evidence of nodal involvement, up to half of such patients may actually harbor nodal metastases (pN+).69 In one series, 38% of PET-N0 patients harbored pN1 disease and 8% harbored pN2 disease; pN3 disease was not observed.69 Yasuda et al.69 studied the PET detection rates of metastatic disease within a particular nodal station and showed a sensitivity and specificity of 34.8% and 99.9%, respectively. They measured the area (mm2) occupied by the “nest” of cancer cells within each node and the cancer cell density (cells/mm2). Metastatic disease in lymph nodes with false-negative PET/CT contained smaller tumor cell nests than PET-positive nodes (median of <2 mm2 versus 85 mm2). The density of metastatic cells was similar in both true-positive and false-negative PET groups. In a small surgical series of 39 patients with AC,46 PET/CT identified 70% (55 out of 79) of the nodal groups harboring metastatic disease. The 24 lymph node groups with false-negative PET/CT were randomly distributed and contained lymph nodes with mean diameters of 4 to 5 mm. Despite these limitations, patients with PET-N0 disease have better relapse free survival, better overall survival, and lower postoperative recurrence rates than patents with PET-N+ disease; this probably reflects the metastatic disease volume.69

There are many potential reasons for false-positive lymph nodes on a staging 18FDG PET/CT scan. Therefore, suspicious lymph nodes on 18FDG PET/CT are usually confirmed by tissue sampling. For instance, false-positive FDG uptake may occur because of nodal inflammation associated with reactive or granulomatous adenopathy (e.g., sarcoidosis),46 in particular when occurring symmetrically in the pulmonary hila where PET specificity is much lower (hilar specificity only 29% as compared to 93% in mediastinal nodes in one study).63 Of note, sarcoid adenopathy classically demonstrates a fairly symmetrical pattern of mediastinal and particularly hilar/perihilar 18FDG-avid uptake (“too symmetrical” for nodal metastatic disease). False-positive 18FDG uptake can also be seen in brown adipose tissue in the neck, various areas of the mediastinum, and upper abdomen (perihepatic, perinephric). This can sometimes obscure true-positive 18FDG uptake in lymph nodes.

TABLE 5.5

CLINICAL STUDIES COMPARING THE ACCURACY OF POSITRON EMISSION TOMOGRAPHY (PET) OR FUSION PET-CT WITH COMPUTED TOMOGRAPHY (WITHOUT PET) AND/OR ENDOULTRASONOGRAPHY FOR THE DETECTION OF LYMPH NODE METASTASES

Distant Metastases (M-Stage)

Current AJCC classification defines patients according to the absence (M0) or presence (M1) of distant metastases. Common sites of distant metastases in esophageal cancer patients are liver, lungs, bone, and adrenal glands.27,73 AC, especially of the GEJ, more frequently metastasizes to intra-abdominal sites—notably liver and peritoneum. SCC metastases are usually intrathoracic. Preoperative 18FDG PET changes clinical management in up to 20% of such esophageal cancer patients—usually by revealing metastatic disease that aborts fruitless surgery and/or prompts induction therapy.18,24,7376 In the prospective Z0060 trial by the American College of Surgeons Oncology Group, 18FDG PET-only (not PET/CT) after standard clinical staging for esophageal carcinoma identified confirmed M1b disease in only 5% of patients.74 In an additional 9% of patients, PET suggested distant disease, but this was not confirmed by biopsy; assuming up to 50% false positives, the true rate of unexpected PET-detected metastases may thus have been 5% to 10%. Of note, these data from the PET-only era may have limited applicability at the present time. In patients with GEJ tumors staged M0, by imaging, diagnostic laparoscopy may be performed because CT and PET are poor at detecting small peritoneal metastases.77,78

PROGNOSTIC VALUE OF PRETREATMENT FDG PET/CT

Primary esophageal tumor SUV has been variably reported as prognostic for survival in SCC50 and AC.79 In studies that exclusively or predominantly enrolled SCC patients, SUV and other parameters quantifying the 18FDG avidity of the primary tumor was often shown to be prognostic, with higher 18FDG avidity portending a worse outcome.50,51,80,81

In cancer studies that exclusively or predominantly enrolled AC patients, quantitative 18FDG-avidity parameters again have frequently proven prognostic.79,82 However, other studies did not confirm this.8385 For instance, Rizk et al.79 studied AC patients and found that baseline 18FDG SUV predicted outcome for resectable early stage disease, independent of clinical and pathologic stages; but it did not predict the survival of patients with locally advanced disease receiving preoperative chemoradiotherapy.86 In fact, these authors found that tumors with higher18FDG avidity were more likely to demonstrate a pathologic response to neoadjuvant therapy, which may have acted as an equalizing factor among patient groups with otherwise different prognosis.86 Along the same lines, a small study in 31 patients noted that the subgroup of patients with SCC and high baseline SUV responded better to trimodality therapy than those with lower SUV but this trend was not seen when considering all histologies.87 This may reflect the different tumor biology of SCC versus AC and highlights the need to study AC and SCC histologies separately.

In some studies, parameters of tumor 18FDG avidity, besides SUV, were found to be prognostic even when SUV was not.8082,88 More recently, the metabolic tumor volume (MTV) of the primary tumor was found to be a better predictor of overall survival than was SUV.80

A proper assessment of data from studies regarding the prognostic significance of FDG uptake in esophageal cancer is complicated by several methodologic issues: For example, some studies used a variety of PET scanners, and many combined all patients regardless of histology and treatment modalities into one analysis.89 Finally, most studies only examined 18FDG uptake in the primary tumor as a prognostic biomarker, but disease response to neoadjuvant therapy may vary between the primary tumor and lymph nodes.

EVALUATING TUMOR RESPONSE TO CANCER TREATMENT

The optimal therapeutic approach to advanced esophageal cancer remains a subject of debate. Current NCCN guidelines discuss multiple therapeutic options for a particular esophageal cancer stage with no definitive recommendation regarding what constitutes the optimal treatment.2 There is general agreement2 that surgery is unsuitable for patients with a cervical esophageal cancer or “cervicothoracic” primary (<5 cm from the UES). For tumors in other locations, chemoradiotherapy without surgical resection is associated with a high local failure rate. Trimodality therapy (i.e., chemotherapy + radiotherapy + surgical resection) offers some survival benefit over chemoradiotherapy alone,90 even though postsurgical mortality may be as high as 13%.91 A recently published multicenter trial indicates that preoperative chemotherapy plus resection offers an improved survival for esophageal cancer patients (n = 366; predominantly AC histology) compared to surgery alone.92 One rationale for neoadjuvant (or induction) therapy is to downsize the primary tumor in hope of making it more resectable, because a complete primary resection (R0) is associated with more favorable clinical outcome than incomplete (R1, R2) resections.93 Yet neoadjuvant chemotherapy benefits only a subgroup of patients, while potentially exposing nonresponders to significant toxicity.93,94

There is a clear need to identify those patients who are not benefiting from induction chemotherapy as quickly as possible, both to avoid unnecessary delay in surgery that may be beneficial (possibly curative) or to switch those “metabolic nonresponders” from the ineffective and potentially toxic neoadjuvant treatment to an alternative salvage drug regimen. For these purposes, researchers have tested the efficacy of imaging as a surrogate biomarker of tumor response. Moreover, if resection is not performed, and pathologic response therefore not quantifiable, measurement of clinical tumor response by imaging becomes a crucial response parameter. The ultimate “gold standard” of response is improved patient survival, but tumor response on imaging studies can also be correlated with other surrogate markers, such as time to disease progression or primary tumor pathologic response. When pathologic response serves as the gold standard, the Mandard tumor regression grading (TRG) system95 or similar systems are commonly used. In essence, the pathologic response is scored by the percentage of tumor cells that remain viable under the microscope: Nonresponders show >10% tumor cells viable; partial responders 0% to 10%; and complete responders 0% viable tumor cells. A “major” pathologic response is often defined as ≤10% viable tumor cells, grouping together the pPR and pCR categories.

Changes in tumor extent, measured by EUS and/or CT, have a poor accuracy for predicting pathologic complete response at the time of subsequent surgery.9699 A randomized study of 162 patients with locally advanced SCC compared overall survival in patients receiving chemoradiotherapy with or without surgery. With a median follow-up of 6 years, the outcome of patients receiving chemoradiotherapy alone was similar to that in patients who underwent subsequent surgical resection. Because pathologic response data were not available in the nonsurgical cohort, clinical tumor response was found to be the single independent prognostic factor for overall survival (hazard ratio, 0.30; 95% CI, 0.19 to 0.47)—with clinical response defined as improved dysphagia, CT tumor shrinkage by >50%, and a 50% reduction in esophageal lumen encroachment by barium swallow. However, in other trials of locally advanced SCC, CT could not predict pathologic or clinical response to neoadjuvant therapy.100102 For instance, in a study of 51 patients with locally advanced disease, 18FDG PET response using PET response criteria in solid tumors (PERCIST) criteria102 predicted disease-free and overall survival, whereas CT tumor response using conventional response evaluation criteria in solid tumors (RECIST) criteria102 did not (CT often underestimated tumor response, and the CT response could not be evaluated in 10% of patients). CT volume measurements and changes in tumor volume over time have been proposed as better response parameters than simple assessment of tumor length or diameter. However, in one small trial, CT volume changes after 2 weeks of induction therapy did not predict histopathologic response to chemoradiation.103

18FDG PET for Response Assessment

Data regarding the predictive value of 18FDG PET for response assessment (Table 5.6) need to be interpreted considering several major variables, such as tumor histology (AC versus SCC), disease stage, therapeutic regimen (chemotherapy with various drug combinations versus chemoradiotherapy), and the time of imaging (e.g., during or at the end of neoadjuvant therapy).27,87,101,104121 Of note, the published studies on this subject have been rather heterogeneous; readers are encouraged to review the methodology in each study carefully before accepting conclusions. This difficulty in interpreting PET-response studies in esophageal cancer was also highlighted in a recent meta-analysis.89

In general, a greater decline in 18FDG SUV during therapy correlates with better histopathologic response and better clinical outcome but this is not a linear relationship. Lack of residual FDG uptake after completion of treatment (or minimal residual uptake) conferred prognostic information in some but not all trials. Other parameters of tumor 18FDG metabolism have been reported predictive of therapeutic response but these require further validation and are not clearly superior to standard SUV analysis.88,104 In most clinical studies, investigators used changes in 18FDG tumor SUV under therapy to segregate patients into two groups: Metabolic responders versus metabolic nonresponders. This was done by retrospective analysis, either dichotomizing the data set or using ROC analysis to find the percentage change in SUV that best separates metabolic responders from nonresponders, using histopathology of the tumor specimen or clinical outcome as the gold standard. These studies show considerable overlap in the ranges of SUV changes between these two patient groups. The most stringent PET criterion to diagnose a complete pathologic response (pCR) is the complete lack of any residual abnormal 18FDG uptake at the previously visualized tumor site. However, even using this stringent criterion, McLoughlin et al.122 reported poor negative predictive value (35%) and poor specificity (44%) to exclude residual viable tumor cells. In fact, this is not entirely surprising because small volume (microscopic) tumor deposits are not detectable by PET imaging. Similarly, persistent increased activity at the tumor site after treatment also has suboptimal specificity as a marker of residual disease (slightly better when residual activity is focal rather than diffuse113) because inflammation can cause false-positive 18FDG uptake.

TABLE 5.6

Selected Published Clinical Trial Data Regarding The Efficacy of FDG PET for Predicting the Histopathologic and/or Clinical Response of Esophageal Cancer to Various Therapeutic Regimens

The potential clinical implications of PET-response studies vary with the time when imaging is performed. Studies performed during neoadjuvant therapy provide an insight into the kinetics of tumor cell kill in response to therapy; early changes in 18FDG uptake during therapy are used as a predictor of ultimate response at the completion of such therapy. Patients identified as metabolic nonresponders at an early time point can possibly be switched to a different induction regimen (noncross resistant therapy or combined chemoradiotherapy instead of chemotherapy alone), or proceed straight to surgery. The latter approach avoids potential toxicity and tumor progression during ineffective neoadjuvant therapy. In contrast, studies obtained at the end of induction therapy serve two aims: Restaging of distant disease and prediction of pathologic response at the primary site. These end-of-treatment studies should be obtained at least 5 to 6 weeks after the last therapy dose in order to avoid false-positive PET findings secondary to treatment-induced inflammation.2,112

PET STUDIES IN ADENOCARCINOMA

Early Response Evaluation

The role of 18FDG PET early during neoadjuvant chemotherapy (without radiation) in locally-advanced AC of the esophagogastric junction (AEG) has been addressed in a series of studies by investigators in Munich (Germany). In early studies, they performed 18FDG PET pretreatment and after 2 weeks into a 3-month preoperative chemotherapy regimen. A favorable histopathologic and clinical response was best defined as an SUV decrease of ≥35%.107 Poor response (defined as SUV decrease <35%) was associated with a lack of histopathologic response at the time of subsequent surgery, increased risk for tumor recurrence, and worse overall survival.107,111 These investigators subsequently tested the hypothesis that patients with AC who were metabolic nonresponders to induction therapy at 2 weeks might benefit from a change in therapeutic strategy. In this prospective, nonrandomized MUNICON-I trial,108 PET metabolic nonresponders underwent early tumor resection, whereas PET responders received a full course (up to 12 weeks) of preoperative therapy. In the surgical specimen, 58% of patients with favorable PET response also had a favorable pathologic response (<10% viable tumor tissue at resection), whereas 0% of patients with an unfavorable 18FDG PET response had a pathologic response.

The use of “early” PET to predict AC tumor pathologic response to neoadjuvant combined chemotherapy plus radiation therapy (CRT) has been studied by van Heijl et al.106 at 2 weeks into treatment (same time point as in the Munich trials of neoadjuvant chemotherapy alone). In this study, 100 patients underwent potentially curative esophagectomy and 2 PET scans. Among the 64 pathologic responders, the mean decline in 18FDG SUV was 30% (range -17% to -51%); among the 36 pathologic nonresponders, the mean decline in SUV was 2% (range -36% to +17%). PET predicted response better in AC than in SCC. 76 patients were classified as metabolic responders (initially defined as any decline in 18FDG SUV > 0%), and this was correct in 58. Overall, the accuracy and in particular negative predictive value in this trial remained suboptimal, even when other cutoffs for % decline in SUV were applied. Interestingly, six of the 24 metabolic “nonresponders” actually showed a clinically significant pathologic response, raising concern that potentially effective therapy might be abandoned mistakenly based on a false negative PET scan. Two other trials also reported that pathologic nonresponders to CRT can demonstrate significant decreases in SUV of up to 26% to 47% at the same time point.112,113 In one trial, the SUV decreases were in fact quite similar in pathologic responders and nonresponders112; moreover, in both trials SUV decreases were not associated with prognosis.

Other studies also investigated the utility of 18FDG PET early during combined CRT, but they included both SCC and AC patients in near-equal proportions. Because SCC and AC are different diseases—different in radiosensitivity, natural history, and other important clinical–biologic features — this pooling of patients makes the interpretation of study results difficult. Another group of investigators combined neoadjuvant chemoradiotherapy with hyperthermia (believed to enhance tumor response105); again these data are difficult to compare to standard treatment regimens. Overall, published clinical trial data regarding the utility of “early” 18FDG PET for predicting esophageal AC response suggest: (1) An early (∼2 weeks) favorable 18FDG PET response to induction chemotherapy (without radiation) indicates that the primary tumor will show a significant pathologic response at resection (about 50-50 chance); and (2) a primary tumor failing to demonstrate an early PET response to induction chemotherapy is very unlikely to exhibit a significant pathologic response. However, the same conclusions do not necessarily apply to patients treated with induction chemoradiotherapy.

Based on the data mentioned above, two pertinent questions needed to be addressed: (1) Would the overall survival of metabolic nonresponders who proceeded straight to early tumor resection without continued ineffective chemotherapy be at least as good or better than the overall survival of a historical control group of PET nonresponders who completed the standard 3 months of preoperative chemotherapy123 and (2) could the outcome of metabolic nonresponders whose treatment regimen is escalated to combined CRT be improved compared to the historical control group receiving continued chemotherapy alone. The second question was addressed in 56 patients in the MUNICON-II trial.111 Twenty-three early nonresponders were switched to combined CRT. Their histopathologic tumor response rates were better than those of MUNICON-I nonresponders who had proceeded directly to surgery without further neoadjuvant treatment. However, the R0 resection rate, median time to progression of disease, and overall survival did not improve in MUNICON-II versus MUNICON-I nonresponders. A limitation in MUNICON-II was the lack of randomization, which would have required a much larger patient sample. Such prospective, randomized trials are now ongoing. For instance, in the United States, the multicenter CALGB 80803 trial (NCT01333033) is enrolling patients with GEJ cancer who will be randomized to either FOLFOX or carboplatin/paclitaxel therapy. Early PET nonresponders (SUV decrease <35% at 40 days) will be switched to the other drug regimen. Early PET responders continue to receive their initial drug regimen for several more weeks. Radiotherapy will be added to both arms after the early PET-response assessment. Patients will then undergo surgical resection. Study endpoints include the comparison of pathologic response rates, progression free and overall survival in both arms. In the ongoing prospective HICON trial (Heidelberg Imaging program in Cancer of the esophagogastric during Neoadjuvant treatment), patients with AEG type I and II AC who are early PET nonresponders to neoadjuvant chemotherapy will undergo salvage CRT. This trial will test whether sequential FDG PET studies can predict histopathologic response to salvage CRT.124 Although some of the initial data are promising, we recommend that clinical management decisions not be based on percentage changes in FDG SUV outside of clinical trials at this time.

FIGURE 5.4. A 68-year-old man with poorly differentiated adenocarcinoma of the distal esophagus. Shown are 3D maximum intensity projection FDG PET images, spanning neck, chest, and abdomen, from scans obtained before (LEFT) and 9 days after (RIGHT) five cycles of chemotherapy (oxaliplatin, leucovorin, and 5-fluorouracil [5-FU]). Hypermetabolic activity visualized by the pretreatment scan in the primary tumor (arrow ) and a biopsy-proven left supraclavicular nodal metastasis (arrowhead ) completely resolved, on the posttreatment scan.

End-of-Treatment Evaluation

The use of “late” 18FDG PET for evaluating AC tumor response after the completion of neoadjuvant therapy has been investigated in patients treated with induction chemotherapy only (Fig. 5.4) and in patients who underwent combined CRT. In patients treated with neoadjuvant chemotherapy only, a 67% decrease in SUVmax from baseline predicted complete or “subtotal” histopathologic response with 79% sensitivity and 75% specificity.125 In 55 patients treated with combined neoadjuvant CRT, Swisher et al.109 found that the changes in tumor SUV (either in the primary or at any metastatic site) did not separate responders from nonresponders; however, an SUV of ≥4 after completion of CRT could be used to identify patients lacking a major histopathologic response, with a sensitivity of 62% and a specificity of 84%. In multivariate analysis, tumor SUV <4 was an independent predictor of survival. As expected, a negative PET could not distinguish pathologic complete response from microscopic residual disease and could therefore not spare patients a potentially unnecessary esophagectomy.

As stated before, absolute SUV numbers or thresholds proposed in one trial must be validated prospectively and may not be applicable in other institutions with different PET protocol and equipment or in other patient groups with different clinical risk features and histologic profile. For instance, Monjazeb et al.110 defined PET complete response as residual SUV ≤3 rather than SUV <4 in the Swisher study after neoadjuvant CRT. Thirty-one percent of 105 evaluable patients in that retrospective study achieved such PET-CR, and their clinical outcome was better than the outcome in patients who did not. However, this difference in clinical outcome seemed limited to patients treated with CRT only (no additional surgery), suggesting that the end of induction SUV lost its prognostic value in patients who underwent subsequent esophagectomy because any residual disease was resected. However, this notion that radical surgery can overcome the negative prognostic value of residual abnormal 18FDG uptake after induction chemo- or chemoradiotherapy remains controversial. Another concern is the potentially high rate of false-positive PET scans in this setting. In the Swisher trial, the rate of false-positive PET scans was estimated at 34%. This would undermine the justification for additional neoadjuvant therapy in patients with positive end-of-treatment scan (lack of benefit but additional toxicity). A high rate of false-positive scans at the end of induction therapy could also explain the lack of prognostic value of PET in the surgical cohort (if the PET signal does not correlate with the presence and amount of residual disease, it could not possibly predict outcome after surgery).

PET STUDIES IN SQUAMOUS CELL CARCINOMA

Early Response Evaluation

In patients with esophageal SCC undergoing neoadjuvant combined CRT, an SUV decrease ≥30% at 2 weeks into treatment predicted histopathologic response with a 93% sensitivity and an 88% specificity.115 In a group of 61 patients, Yang et al.118 observed a more favorable 5-year progression-free survival in nonsurgical patients who showed a ≥51% decline in 18FDG SUV at 4 to 5 weeks into definitive CRT.

End-of-Treatment Evaluation

Studies in SCC are smaller and data more heterogeneous than in AC. For instance, metabolic response has been defined variably as lack of residual uptake after end of induction therapy, or a 50% to 70% decrease from baseline SUV. In a study that predominantly included patients with locally advanced SCCs (27 SCCs and 9 ACs)119 the complete disappearance of tumor 18FDG uptake at the end of induction therapy had a poor sensitivity for a pathologic complete response: Four out of six patients with pCR were correctly identified, the other two patients with pCR showed marked inflammation in the specimen, explaining the false-positive 18FDG uptake. Nevertheless, patients with a “major” PET response, defined as a disappearance of metastatic nodes and disappearance or near disappearance of primary tumor 18FDG uptake, had a better survival than PET nonresponders. Brücher et al.114 found that a 52% decrease in tumor uptake after completion of CRT identified patients with major histopathologic response (<10% viable cells) with 100% sensitivity and 55% specificity and predicted better survival. However, this study included only 27 patients and the 52% threshold was based on retrospective ROC analysis. In contrast, in a study by Higuchi et al.116 percentage changes in tumor SUV did not predict histologic or clinical response, but a lack of residual 18FDG uptake postchemotherapy (defined as SUV <2.5) identified patients with major histologic response and predicted better survival. This study included 35 patients undergoing chemotherapy and 15 patients undergoing CRT.

ROLE OF PET IN RADIOTHERAPY PLANNING

Radiotherapy planning requires the precise delineation of the primary tumor and all locoregional disease. Several studies have reported a favorable impact of 18FDG PET upon delineation of the target volume in radiotherapy planning. Target volumes based upon CT alone appear to both over- and underestimate the extent of disease in many patients compared to 18FDG PET,126128 with a predicted impact on normal tissue toxicity and antitumor efficacy.126 This is related, in part, to the greater accuracy of 18FDG PET/CT in identifying the presence and extent of locoregional disease. In addition, in many settings 18FDG PET/CT provides more reproducible measures of target volume compared to CT alone, and thus better inter- and/or intraobserver agreement.129 In a recent study, PET-based measurement of tumor length corresponded to the subsequent pathologic tumor length measurement with a mean difference of –0.05 cm (SD: 2.16 cm).130 Of note, tumor measurements may be affected by respiratory motion. Differences in tumor positions affected gross tumor volumes predominantly by associated changes in the tumor SUVmax—including a >20% change in SUVmax in 17% of the esophageal cancer cases.131 There is still a lack of data showing a potential benefit of 18FDG PET/CT-based radiotherapy planning with regard to locoregional control and survival.129 Clinical trials addressing this question are ongoing (e.g., NCT01156831).

ROLE OF PET IN DETECTING TUMOR RECURRENCE

Recurrences after R0 resection are most common in the mediastinum, bones, and lungs; metastatic disease in brain, pleura, and skin is rare.28 18FDG PET is a reliable test for detecting recurrent disease and for defining its extent (local, regional, and/or distant). Accordingly, 18FDG PET findings have a positive impact in the clinical diagnosis and management of recurrent disease in about 27% of cases.48 In SCC, 18FDG PET/CT is an excellent tool for detecting recurrence, either locoregional or at distant sites, with sensitivity typically reported as being ≥90% to 94%48,132,133; this is clearly superior to CT alone. An exception is subcentimeter pulmonary metastasis, which is better identified on dedicated CT. However, because patients with pulmonary metastases often also have concomitant recurrence in other organs, the overall PET sensitivity for disease recurrence on a per-patient basis remains excellent.133The specificity of 18FDG PET/CT for the detection of recurrent disease is not as high (typically ∼80% to 90%), but still generally superior to other modalities. False-positive 18FDG uptake occurs most commonly at the primary site48where specificity can be as low as 50%. Potential reasons for false-positive and false-negative 18FDG scans were already discussed above.

NOVEL IMAGING AGENTS

Several other radiotracers, beyond FDG, are under study in esophageal cancer. Of particular interest may be the proliferation marker Fluorine-18 fluorothymidine (18FLT). 18FLT uptake is considered a biomarker of thymidine kinase 1 activity (FLT is trapped intracellularly after phosphorylation by TK1) and tumor cell proliferation. 18FLT is not a suitable agent for tumor detection or staging because the intensity of uptake is generally lower than that of 18FDG. Instead, the primary application for 18FLT may lie in response assessment and possibly radiotherapy planning. For instance, Yue et al.134 reported a pilot clinical trial describing PET/CT findings in esophageal SCC patients undergoing both 18FDG PET/CT and 18FLT PET/CT scans during radiotherapy. 18FLT uptake in the primary tumor steadily diminished with cumulative delivery of radiation doses. In two patients, scans were obtained after 40 Gy to the tumor: 18FLT uptake had completely disappeared, whereas 18FDG uptake remained high. At histopathology, only soft tissue inflammation (no tumor) was present. These anecdotal findings—supplemented by other 18FLT PET literature135—suggest that 18FLT may offer the specificity that 18FDG lacks, for early response assessment; however, much more clinical validation is needed. Some ongoing studies are investigating the potential utility of 18FLT for radiotherapy dose painting (whereby higher doses would be delivered to areas of higher tumor cell proliferation). Other investigators are comparing histopathologic tumor length to PET-based gross tumor volumes (with 18FDG and 18FLT) and associated radiation doses to lungs and heart. One such study reported a potential dosimetric advantage for 18FLT PET/CT-based treatment planning, leading to lower radiation doses to lungs and heart as compared to 18FDG PET/CT-based planning.136

Another novel radiotracer with potential application in esophageal cancer is radiolabeled trastuzumab, which may potentially serve as a noninvasive imaging biomarker of HER2-neu overexpression. It is currently under investigation in early clinical trials.137 HER2-neu-targeted immunotherapy with trastuzumab is a potential treatment option in patients with HER2-positive metastatic disease.2,138

ACKNOWLEDGMENT

The authors gratefully acknowledge the assistance of Franklin Torres in the editing of this text.

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