Simon K. Cheng • Bhupesh Parashar • Zhongxing Liao
Esophageal Cancer – Highlights
Key Recent Clinical Studies
Lin et al. (IJROBP 2012) reported in a large series of 676 esophageal cancer patients that the use of IMRT improved overall survival, locoregional control, and noncancer-related deaths compared to 3DCRT. (PMID 22867894)
Van Hagen et al. (NEJM 2012) reported the CROSS study, a randomized trial of neoadjuvant chemoradiotherapy and surgery compared to surgery alone, and found improved median survival benefit of 49.4 months to 24 months in favor of trimodality treatment. (PMID 22646630)
Patel et al. (IJROBP 2009) evaluated esophageal tumor motion using 4D CT scans and found adequate coverage with superior–inferior margins of 2.25 cm, anterior–posterior margins of 1.0 cm, and left–right margins of 0.75 cm. (PMID 19362248)
New Target Delineation Contours
FIGURE 14-9. An axial image of a 9-field IMRT isodose distribution for an esophageal carcinoma.
1.1. Anatomical Course
• The esophagus begins in the neck at the cricoid cartilage at the level of vertebra C7, passes through the thorax in the posterior mediastinum, and extends for several centimeters past the diaphragm to its junction with the stomach, which is near the lower border of vertebra T11. The average length is 25 cm.
• The cervical esophagus is posterior to the trachea and bounded on both sides by the recurrent laryngeal nerve and the carotid sheath. The thoracic esophagus continues posterior to the trachea to the level of bifurcation, then courses posteriorly to the left atrium, with the azygous veins ascending on either side of the thoracic segment.
• The esophagus is divided into five regions (Fig. 14-1):
º Cervical esophagus: extends from the lower edge of the cricoid cartilage to the thoracic inlet, approximately 20 cm from the incisors.
• For classification and staging, the American Joint Committee on Cancer (AJCC)1 has sub-divided the thoracic region into four locations:
º Upper thoracic esophagus: extends from the thoracic inlet to the tracheal bifurcation, 20 to 25 cm from the incisors.
º Middle thoracic esophagus: part of intrathoracic esophagus, >25 to 30 cm from the incisors.
º Lower thoracic: part of lower intrathoracic esophagus, >30 to 40 cm from the incisors.
º Esophagogastric junction: includes tumors in the intra-abdominal esophagus, esophagogastric junction, or within the proximal 5 cm of the stomach that extends into the esophagogastric junction.
• The esophagus has four layers: the mucosa, submucosa, muscularis propria, and adventitia or serosa (Fig. 14-2).
• The mucosa consists of a nonkeratinizing, stratified, squamous epithelium, the lamina propria, and the muscularis mucosa (T1a).
FIGURE 14-1. Basic anatomy of the esophagus. Note the lengths of the various segments of the esophagus from the upper central incisors and the AJCC classification scheme for subdividing the esophagus. (Adapted from Chao KSC, Perez CA, Brady LW. Radiation Oncology Management Decisions, 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2011:358.)
• The submucosa comprises the loose connective tissue containing vessels, nerve fibers, lymphatics, and submucosal glands (T1b).
• The muscularis propria is composed of the inner circular and outer longitudinal muscle layers (T2).
• The thoracic esophagus bounded by the outermost connective tissue is called adventitia (T3). The serosa lines the short segment of the lower thoracic and intra-abdominal esophagus.2
1.4. Lymphatic Drainage
• The esophagus has a rich longitudinal interconnecting system of lymphatics in the lamina propria, and submucosa connects with the lymphatics in the muscularis propria and adventitia. Because of this longitudinal arrangement, extensive intramucosal and submucosal spread beyond a grossly visible tumor is common. Micrometastasis within the lymph fluid can travel the entire length before draining into the lymph nodes, which commonly represents “skip areas”(See Fig. 14-2A).
• The lymphatic network of the esophagus drains into three areas: the upper, middle, and lower lymphatic trunks. All three groups of lymphatics drain into the paraesophageal lymph nodes located immediately adjacent to the esophagus. The cervical esophagus drains into the internal jugular and upper tracheal lymph node groups. The thoracic esophagus drains into the superior, middle, lower mediastinal lymph node groups, and into the abdominal segment (which includes superior gastric artery, celiac axis, common hepatic artery, and splenic artery lymph nodes). However, extensive communication among the lymphatics results in a varied and unpredictable nodal involvement pattern.2
• Figure 14-3 shows the positive lymph node distribution according to the location of the primary esophageal tumor.
2. NATURAL HISTORY
• In the past 20 years, there has been a dramatic change in the epidemiology in North America and most western countries characterized by a very rapid rise in the incidence rate of 5% to 10% increase per year, and a shift of histology from squamous cell carcinoma occurring mostly in the middle and lower esophagus to adenocarcinoma arising at the distal esophagus and gastroesophageal junction.2Adenocarcinomas now comprise of 70% of all new cases compared with 10% to 15% about 10 years ago.
FIGURE 14-2. (A) Patterns of spread, thoracic esophagus. Left, coronal view. Right, sagittal view. T-stages indicated by colored arrows: T1, green; T2, blue; T3, purple; and T4, red.
FIGURE 14-2. (B) Patterns of spread, esophagogastric junction. Left, junction magnified; Right, junction spread in chest. T-stages indicated by colored arrows: Tis (carcinoma in situ of mucosa), yellow; T1 (T1a—invades lamina propria, T1b—invades submucosa), green; T2 (penetrates the muscularis propia), blue; T3 (reaches the adventitia), purple; and T4 (invades through adventitia into neighboring organs), red. (Reprinted from Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:227,255. Modified from Agur AMR, Dalley AF, eds. Grant’s Atlas of Anatomy, 12th edition. Philadelphia: Lippincott Williams & Wilkins, 2009.)
• Predisposing factors for squamous cell carcinoma include high alcohol intake, heavy smoking, and nutritional deficiencies of minerals and vitamins.
• Predisposing factors for adenocarcinoma are acid reflux and Barrett esophagus.
FIGURE 14-3. Positive lymph node distribution according to the location of the primary tumor. (Modified from Akiyama H, Tsurumaru M, Kawamura T, et al. Principles of surgical treatment for carcinoma of the esophagus: analysis of lymph node involvement. Ann Surg 1981;194:438; and Dormans E. Das Oesophaguscarcinom. Ergebnisse der unter mitarbeit von 39 pathologischen instituten Deutschlands durchgeführten Erhebung über das oesophaguscarcinom (1925–1933). Z Krebforsch 1939;49:86; with permission.)
2.1. Mucosal Spread
• Esophageal cancer, regardless of its histopathology features, may extend over wide areas of the mucosal surface.
• Squamous cell carcinoma often arises as multifocal tumors, presumably as a result of field cancerization. The mean microscopic proximal spread beyond the gross tumor is 10.5 ± 13.5 mm and distal spread is 10.6 ± 8.5 mm, with 94% of patients having all tumor encompassed within 30-mm margin.3
• Adenocarcinomas may have varying lengths of mucosal and submucosal disease, particularly in patients with the long segment of Barrett esophagus. Proximal mean microscopic proximal spread beyond the gross tumor is 10.3 ± 7.2 mm and distal spread is 18.3 ± 16.3 mm, with 94% of patients having all tumor encompassed within 50-mm margin.3
2.2. Patterns of Lymph Node Metastasis
• Lymph node metastasis occurs both upward and downward at a very early stage (Fig. 14-3). The incidence of lymph node metastasis is directly correlated with the depth of tumor invasion (Table 14-1).4
• Furthermore, larger tumors are more likely to present with locoregional nodal metastasis (Table 14-2).
3. DIAGNOSIS AND STAGING SYSTEM
3.1. Signs and Symptoms
• Early symptoms include those related to acid reflux and Barrett esophagus.
• Odynophagia as a result of esophageal ulceration.
• Progressive dysphagia and weight loss are the most common clinical symptoms for all lesions as a result of tumor obstruction of the esophageal lumen and deep invasion of the esophageal wall. Both are indications of locally advanced disease.
• Pretreatment evaluation of esophageal cancer typically includes a combination of esophagogram, endoscopic examination with biopsy, endoscopic ultrasound examination, computed tomography (CT) of the chest, magnetic resonance imaging (MRI), and positron emission tomography (PET).
• The accuracy of staging by esophagography, esophagoscopy, endoscopic ultrasonography, and CT scan for T staging was 80% and for N staging 72% with a sensitivity of 78%, specificity of 60%, and positive predictive value of 78%. The overall accuracy of stage group was 56%.
• Esophagograms provide good assessment of the structure of the esophageal lumen and mucosal surface. Mucosal irregularity, an intraluminal filling defect, and stricture seen on a barium esophagogram are suggestive of an esophageal malignancy (Fig. 14-4A).
• Although the length of a tumor can be estimated from a barium esophagogram, a noticeable discrepancy exists when it is compared with the length measured from CT, esophagastroduodenoscopy, and histopathology.
3.2.2. Esophagastroduodenoscopic Examination
• Esophagastroduodenoscopic (EGD) examination with biopsy is the procedure of choice for diagnosing esophageal cancer. The lesion seen at the endoscope examination must be brushed and then biopsied. The accuracy of brushing cytology plus biopsy is 98.8% compared with 93.9% with biopsy alone and 87.9% with brushing cytology alone.
• EGD allows for an excellent structural examination of the esophageal lumen and determining the extent of mucosal spread, although EGD alone cannot assess the extraluminal extension of the disease or nodal status.
3.2.3. Endoscopic Ultrasonography
• Endoscopic ultrasonography (EUS) is an ideal modality for determining clinical tumor and nodal stage according to the TNM staging system. Because it can distinguish wall layers of the esophagus, EUS provides a more accurate determination of the depth of tumor invasion, which is the basis of tumor staging, than a CT scan.
• The reported accuracy of EUS in tumor staging ranges from 75% to 90% compared with pathological examination of the resected specimen.12–15 The accuracy of EUS in measuring tumor invasion ranges from 76% to 89%, compared with 49% to 59% for CT.13–16 EUS is also more accurate than CT in staging regional nodal metastasis. The accuracy of EUS ranges from 70% to 90%,17–20 compared with 46% to 58% for CT.13,16
• Although EUS is the most powerful procedure for accurately staging tumors of the esophagus, its role in target delineation is limited by the fact that EUS defines no spatial relationship between the tumor and adjacent structure and that the examination sometimes cannot be completed because of severe stricture.
3.2.4. CT Scan
• For preclinical evaluation and target delineation of esophageal cancer, CT is the most commonly used diagnostic modality (Fig. 14-4B).
• The normal esophageal wall thickness seen on a CT scan is 3 mm or less; a wall thickness of more than 5 mm is considered abnormal.21 Evident thickening of the esophageal wall and proximal lumen dilatation caused by obstruction characterize an esophageal malignancy. An asymmetric thickening of the esophageal wall is the principal, but nonspecific CT finding of an esophageal carcinoma.
• Although CT does not define the layers of the esophagus, the lack of a fat plane between a tumor mass and an adjacent structure seen on CT scan indicates a T4 tumor.
• The proximal extent of the tumor often can be identified by its interface with a dilated air- or fluid-filled proximal esophageal lumen; whereas, the distal tumor margin may be difficult to delineate using CT. CT scan can underestimate tumor length up to 3 cm, compared with a barium-swallow test.22
FIGURE 14-4. (A) Esophagogram showing a distal stricture characteristic of esophageal cancer. (B) Chest CT scan of the same lesion. (C) PET scan showing hypermetabolism in the distal esophagus. Arrows indicate the lesion.
• Regional lymph nodes are readily visualized in paraesophageal and retroperitoneal fat. Enlarged lymph nodes or clusters of multiple lymph nodes are abnormal. A short axis that is longer than 1 cm in the intrathoracic and intra-abdominal region is enlarged. Supraclavicular lymph nodes with a short axis longer than 0.5 cm and retrocrural lymph nodes longer than 0.6 cm are pathologic.21
• Normal-sized nodes may contain metastatic deposits, and not all the enlarged lymph nodes may be malignant. Accuracy of 61% to 90%, sensitivity of 8% to 75%, and specificity of 60% to 98% were reported for cervical, mediastinal, and abdominal nodes.21,22
3.2.5. PET Scan
• PET scan can detect hypermetabolism in 92% to 100% of esophageal cancers.23,24 The specificity for regional and distant lymph nodes is 98% with a sensitivity of 43% compared to the combined use of EUS and CT scan (Fig. 14-4C).25
• Fluorodeoxyglucose (FDG)-PET can make the identification of microscopic disease possible. Whole-body fused PET/CT scanning enables the areas of hypermetabolism to be correlated with anatomic sites of disease.21
• PET scan is a powerful complementary tool to CT for delineating the target volume especially the proximal and distal extent of disease in esophageal cancer treatment planning (Fig. 14-4C).
3.3. Staging System
• The current staging system is the 7th edition of AJCC.26
• A regional lymph node has been redefined to include any paraesophageal node extending from cervical nodes to celiac nodes (Fig. 14-3). Further subdivision into the number of positive nodes N0 (0 nodes), N1 (3–6), and N3 (>−7) is now consistent with the gastric N classifications. The nonregional lymph node groups of M1a and M1b have been eliminated.
• T4 has been subclassified as T4a resectable disease with invasion into adjacent structures such as pleura, pericardium, and diaphragm; and T4b unresectable disease with involvement of the aorta, vertebral body, and trachea.
4. GENERAL MANAGEMENT
4.1. Surgical Approach
4.1.1. Surgery Alone
• Esophagectomy continues to be a crucial component of therapy for patients with resectable tumors. However, only 30% to 40% of patients present with resectable disease, and only 20% undergo curation resection due to medical co-morbidities.
• The entire esophagus or at least 5 cm surgical margins has been the principle of esophagectomy. Transhiatal and transthoracic esophagectomies allow for different exposures depending on the location of tumor. However, there is no evidence to support that one approach is better than other in survival.
• Regional lymph nodes should be dissected during esophagectomy, and the number of lymph nodes removed is an independent predictor of survival.
• Distant metastatic disease is common (34% to 50%) and locoregional recurrence even after an R0 resection ranges from 21% to 39%.20,27–29 The 5-year overall survival is 20% to 25%. For T1N0, the 5-year overall survival is ~77%, whereas for stage III survival is 10% to 15%.
4.1.2. Neoadjuvant Therapy
• Neoadjuvant chemotherapy before surgery has not shown to improve outcomes measured by resectability, locoregional control, and overall survival (Fig. 14-5).30
• Neoadjuvant chemoradiation therapy has been shown to improve overall survival and R0 resection when compared to surgery alone. The most recent meta-analysis in 2007 showed a 2-year overall survival benefit of 13% for neoadjuvant chemoradiation over surgery alone.31 Results of individual neoadjuvant chemoradiation studies are shown in Table 14-3.
• The most recent CROSS study used concurrent weekly administration of carboplatin and paclitaxel32 with 41.4 Gy radiation in 23 fractions. The intergroup RTOG 1010 neoadjuvant protocol continues to use carboplatin and paclitaxel but with higher-radiation dose of 50.4 Gy in 28 fractions.
4.1.3. Adjuvant Therapy
• For tumors involving esophagogastric junction with extension in the gastric cardiac, these cancers can be considered of gastric origin and treated with postoperative chemoradiation as in intergroup INT-0116.39
4.2. Nonsurgical Approach
4.2.1. Radiation Therapy Alone
• No patients treated with radiation alone in the RTOG 85-01 trial survived at 3 years.40
• Radiation therapy alone as a single modality is reserved for palliation and for patients who are not candidates for chemotherapy.
4.2.2. Concurrent Chemoradiation
• Concurrent chemoradiation is the treatment of choice for patients who are not surgical candidates.
FIGURE 14-5. Outcome of neoadjuvant chemotherapy for esophageal cancer. (From Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979–1984.)
• Table 14-4 demonstrates the outcomes of randomized studies comparing radiation alone with concurrent chemoradiation. The long-term overall survival after chemoradiation is similar to that of surgery.
• An intergroup study (RTOG 94-05, INT 0123) compared different radiation doses with concurrent chemotherapy: 50.4 Gy versus 64.8 Gy.41 The higher-radiation dose did not lead to improved survival or locoregional control.42
5. INTENSITY-MODULATED RADIATION THERAPY IN ESOPHAGEAL CANCER
5.1. Gross Tumor Volume Determination
• Gross tumor volume (GTV) includes the primary tumor mass and enlarged lymph nodes determined by the combination of all available pretreatment evaluation modalities. Information from barium swallow, endoscopic examination, and PET/CT scan should be reviewed and incorporated in GTV contouring (Fig. 14-6).
• An esophageal wall thickness of more than 0.5 cm on CT scan is usually considered abnormal and should be included in the GTV.
• Fusion of diagnostic PET/CT scan to CT simulation and/or PET/CT simulation is highly recommended for target delineation, especially in determining the location and length of the primary tumor (Fig. 14-7).
5.2. Clinical Target Volume Delineation
• Esophageal cancer may be associated with multicentric disease or submucosal “skip” metastasis sometimes found at a considerable distance from the primary tumor.43 This tendency supports the use of generous proximal and distal margins for treating the primary tumor.
• For the primary esophageal tumor, the standard GTV to clinical target volume (CTV) expansions are 4 cm superiorly and inferiorly along the length of the esophagus and cardia and a 1.0-cm radial expansion. The 4-cm superior and inferior expansion should follow the contour of the esophagus and proximal stomach to cover submucosal spread (Fig. 14-6).
• For clinically involved lymph nodes, the standard GTV to CTV expansion is 1.0–1.5 cm in all directions. Esophageal cancer is characterized by a high rate of nodal involvement; thus, uninvolved high-risk regional lymph nodes should also be included in the CTV. If the primary tumor is above the carina (proximal esophagus), the supraclavicular nodes should be included in the CTV. For tumors of the lower two-thirds of the esophagus, the celiac nodes should be in the CTV. These guidelines are consistent with the current RTOG 10-10 study.
• Another critical consideration in determining target volume and treatment planning for esophageal cancer is tumor motion caused by respiration, cardiac motion, and esophageal peristalsis, especially in cases of esophagogastric junction tumors. Several studies have examined the dimensions of esophageal internal motion during radiation therapy (Table 14-5).44–46 The expansion from CTV to planning target volume (PTV) should be 0.5 to 1.5 cm and does not have to be uniform in all dimensions. The increased left-side margin is thought to be due to cardiac motion.
FIGURE 14-6. Delineation of GTV and CTV of mid-thoracic tumor in axial (A-D) and sagittal (E-F) view. GTV, green; CTV, red; spinal canal, orange; and esophagus mucosal extent, yellow (in sagittal sections).
FIGURE 14-7. Target delineation using PET/CT scanner on the same patient as in Figure 14-6.
• The use of four-dimensional CT (4D CT) scan and daily image-guided radiation therapy would allow for customization and reduction of PTV expansion.
5.3. Intensity-Modulated Radiation Therapy Results
• Intensity-modulated radiation therapy (IMRT) for esophageal cancer is advantageous in reducing total lung volume and dose that exceeds the tolerance of the normal lung tissue.
• Lee et al.47 reported higher rates of postoperative pulmonary complications of pneumonia and acute respiratory distress syndrome when higher volumes of lung received low doses of lung radiation in the preoperative setting. Specifically, when the volume of lung receiving >10 Gy (V10) was >40% versus <40%, the rates of pulmonary complication were 35% versus 8% (Table 14-6).
• In a study by Chandra et al.,48 10 patients with cancer of the distal esophagus and gastroesophageal junction were gathered for a treatment planning study.48 Three sets of IMRT plans each using 4, 7, and 9 fields were developed for each patient and compared to the 4-field three-dimensional conformal radiation therapy (3DCRT) plan used clinically. All IMRT plans significantly (P = 0.05) decreased the total lung V10, V20, Veff at 30 Gy, mean lung dose, and lung integral dose compared to the 3DCRT plans. For the total lung V10, V20, and mean lung dose parameters, the median absolute improvement of IMRT over 3DCRT plans was approximately 10%, 5%, and 2.5 Gy, respectively. The authors concluded that a clinical trial is warranted to further investigate the potential of lung toxicity reduction using IMRT for esophageal cancer.
• In a recent study by Lin et al.,49 esophageal cancer patients were analyzed for the long-term clinical outcomes comparing 3DCRT and IMRT in a nonrandomized large cohort of patients in a single institution. 3DCRT patients had a significantly greater risk of locoregional recurrence, but no differences were seen in cancer-specific mortality or distant metastasis. There was an increase in risk of dying in the 3DCRT patients that was attributed to increased noncancer-related deaths, in particular cardiac-related deaths but not pulmonary-related deaths.
• Figure 14-8 presents a sample dose-volume histogram (DVH) showing the DVH for 3DCRT and IMRT plans for PTV and total lung structures. The PTV is normalized to 95% coverage at prescription dose (50.4 Gy). The three IMRT plans show reduced total lung Vl0 and V20 compared to 3DCRT; the V5 for 9-field IMRT plans appeared to be increased compared to 3DCRT, but did not reach statistical significance (P = 0.139).
• Figure 14-9 illustrates images of 3DCRT and also 4-, 7- and 9-field IMRT of the thorax and gastroesophageal junction.
FIGURE 14-8. A sample dose–volume histogram (DVH) showing the 3DCRT and IMRT plans for PTV and total lung structures. The PTV is normalized to 95% coverage at prescription dose (50.4 Gy). The three IMRT plans show reduced total lung V10 and V20 compared to 3DCRT (P < 0.05 by Wilcoxon matched pairs signed-rank test). The V5 for 9-field IMRT plans appeared to be increased compared to 3DCRT, but did not reach statistical significance (P = 0.139).
FIGURE 14-9. A sample transverse image showing the sample IMRT isodose distributions in axial images at the level of the thorax (A) and gastroesophageal junction (B) Comparison of 3DCRT and 4-, 7-, and 9-field IMRT is shown.
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