Adult Chest Surgery

Chapter 10. Overview 

 

Esophageal cancer is among the 10 most frequent cancers in the world. The annual incidence reported in Western countries is 3 per 100,000, compared with 140 per 100,000 in Linxian Province in central China.1 Esophageal cancer remains one of the most lethal of all malignancies. Once a diagnosis is established, the prognosis is poor, with a 5-year survival rate of less than 10%. The results of single-modality treatment have been poor, with the exception of surgery for early esophageal cancer. Recently, neoadjuvant chemotherapy, radiotherapy, and combined chemoradiation therapy have been added as treatment modalities to enhance local control, increase resectability rates, and improve disease-free survival.2 The initial results of these multimodality treatments have been encouraging. Since management of esophageal cancer and survival of patients is stage-dependent, accuracy of clinical staging is vital. Recent advances in CT, MRI, and PET of the esophagus, as well as endoscopic ultrasound (EUS) and minimally invasive thoracoscopic/laparoscopic staging (Ts/Ls) offer new hope for reliable preoperative diagnosis and staging of patients with esophageal cancer.

ANATOMY

The boundaries of the esophagus are the inferior cricopharyngeal constrictor proximally and the esophagogastric junction distally. The esophagus is composed of four layers: mucosa, submucosa or lamina propria, muscularis propria, and adventitia (Fig. 10-1). The esophagus has no serosa, providing a teleologic explanation for the ease of spread of esophageal cancer.

Figure 10-1.

 

The four layers of the esophagus: mucosa, submucosa or lamina propria, muscularis propria, and adventitia.

 

Anatomically, the normal adult esophagus is approximately 35 cm in length and 2.5 cm in diameter, although it is not uniform throughout its course. The course of the esophagus begins in the midline in the upper neck at the level of the sixth cervical vertebra, which corresponds roughly to the level of the cricoid cartilage, and then deviates to the left in the lower neck and upper thorax. At the level of the tracheal bifurcation (24 cm from the incisors by endoscopic measurement), the esophagus again returns to the midline only to deviate to the left once again in the lower thorax, where it enters the abdomen through the diaphragmatic hiatus (40 cm from the incisors). Clinically, the esophagus is divided into three segments, the cervical, middle, and distal segments. The cervical segment ranges from the cricoid cartilage to the thoracic inlet (10–18 cm from the incisors). The middle esophageal segment ranges from the thoracic inlet to the midpoint between the tracheal bifurcation and the esophagogastric junction (19–34 cm). The distal esophageal segment extends from the midpoint between the tracheal bifurcation and the esophagogastric junction (35–44 cm). Three distinct narrowings are present in the esophagus. The first narrowing is formed by the cricopharyngeus muscle and is the narrowest segment of the gastrointestinal tract, located 12–15 cm from the incisors in the adult. The second narrowing is caused by the tracheal bifurcation and aortic arch at approximately 24–26 cm from the incisors. The last narrowing is located at the lower esophageal sphincter, approximately 40–44 cm from the incisors.3

The arterial blood supply of the esophagus is segmental (Fig. 10-2). The upper esophagus is supplied by branches from the inferior thyroid and subclavian arteries. The midesophagus receives blood from the bronchial arteries and direct branches from the thoracic aorta. The lower esophagus is supplied by branches of the inferior phrenic and gastric vessels. Venous drainage of the esophagus is segmental as well. The upper esophagus drains via the inferior thyroid veins. The midesophagus drains into the bronchial and azygos or hemiazygos veins. The lower esophagus drains into the coronary vein. As with the arterial network, the rich plexus of veins in the submucosa makes venous congestion unlikely.

Figure 10-2.

 

Arterial blood supply of the esophagus.

 

Lymphatic drainage of the esophagus consists of two longitudinal interconnecting networks, the lymph channels and the lymph nodes. The intraesophageal or mucosal network of lymph channels is connected to the submucosa through transverse interconnections (Fig. 10-3). These collecting lymph channels merge, forming larger channels that feed into the extraesophageal lymph nodes (Fig. 10-4). It is estimated that the longitudinal flow is significant, which also may explain the frequency of spread of tumor. Flow proceeds in either direction freely and can be influenced by intrathoracic pressure differences and/or obstruction of lymphatic channels. The typical drainage pattern, however, is as follows: Cervical lymphatics drain into the internal jugular and supraclavicular nodes, the midesophagus drains into the paraesophageal and periesophageal nodes, and the inferior esophagus drains below the diaphragm to the region of the cardia, left gastric vessels, lesser curve of the stomach, and celiac axis.4

Figure 10-3.

 

Two longitudinal networks of intraesophageal lymph channels traverse the muscularis feeding into the regional extraesophageal lymph node network.

 

Figure 10-4.

 

Longitudinal extraesophageal lymph node network.

NATURAL HISTORY

Epidemiology

Esophageal cancer is a disease primarily of men (3:1 male: female ratio) that occurs in the sixth and seventh decades of life with a median age of 67 years. In Western countries, the incidence is roughly 3 per 100,000 population, whereas in China it may be as high as 140 per 100,000 population. In addition, Russia, Japan, Scotland, and the Scandinavian countries have a higher incidence than the United States or western Europe. In the United States, the incidence of adenocarcinoma of the esophagus is increasing dramatically across all socioeconomic boundaries. The incidence of adenocarcinoma in white men is roughly three times that in black men, whereas the incidence of squamous cell carcinoma of the esophagus is six times higher in blacks. Several environmental factors have been implicated in its etiology, but none has been proved scientifically. Tobacco has been shown to increase the risk of esophageal cancer approximately 10-fold, whereas alcohol abuse increases the risk from 20 to 50-fold. Furthermore, the combination of tobacco and alcohol use may increase the risk 100-fold. Adenocarcinoma has a stronger association with tobacco use, whereas squamous cell carcinoma is more closely linked to alcohol use. In addition, diets high in nitrosamines and foods contaminated with molds (Fusarium) and fungus (Geotrichum candidum) also have been implicated, as well as diets in which hot liquids are consumed. Nutritional deficiencies also have been implicated. Diets low in beta-carotene, vitamins B and C, magnesium, and zinc all have been implicated. Environmental exposure to asbestos, perchloroethylene, and radiation also has been shown to contribute to increased incidence.5

Cancer of the esophagus is among the orphan malignancies identified by the National Cancer Institutes for priority research. Incidence rates vary by geographic region in the United States. Recent data from the Department of Health and Mental Hygiene of Maryland Cancer Statistics report, for example, show an overall cancer incidence rate of 486 per 100,000 population, significantly higher than the national average of 473 per 100,000 population. Despite the decline in cancer death rate by 2% per year over the last 5 years, the rates for esophageal cancer continue to be worrisome. The overall rate of esophageal cancer mortality in Maryland was 4.4% in 1996, much higher than the national average. Of interest, certain counties, including Anne Arundel, Carroll, Harford, St. Mary's, Somerset, and Washington counties, had rates even higher than the state or national average. Specifically, St. Mary's County and Baltimore City had almost double the state and national averages for esophageal cancer mortality. The data from the 2000 Maryland Cancer Registry seem to continue this trend both for esophageal cancer incidence and mortality. Black males have the highest incidence of esophageal cancer. The age-adjusted overall cancer incidence in men of 585 per 100,000 is significantly higher than the national average of 560 per 100,000. Black males also have the highest age-adjusted overall cancer incidence throughout the state (626 per 100,000). The overall risk of squamous cell carcinoma of the esophagus is higher than for white males, although this incidence is decreasing in both racial subgroups. The risk of adenocarcinoma is increased fourfold in white men in comparison with African Americans. These racial differences may be related in part to socioeconomic status, access to care, bias by health care workers, and other issues. Barrett's esophagus, the precursor lesion to most esophageal adenocarcinoma, is significantly less common in black patients. The overall incidence of esophageal cancer in Maryland is higher in men than in women with a ratio of 7:1.6

Pathophysiology

Several premalignant conditions have been shown to predispose to esophageal carcinoma. Achalasia causes esophageal irritation and is associated with a 5–10% incidence in squamous cell carcinoma over 15–25 years. This tumor tends to occur in younger individuals and carries a poor prognosis. Gastroesophageal reflux disease causing distal esophageal metaplasia (Barrett's esophagus) appears to be related to the increased incidence of adenocarcinoma in white males. It is noteworthy that these patients also have a high incidence of hiatal hernia and duodenal ulcer disease. Finally, obesity now has been shown to increase the incidence of adenocarcinoma perhaps threefold. Recent data from the United States and China suggest that esophageal cancer may be associated with human immunodeficiency virus (HIV) infection.

HISTOLOGY

The majority of esophageal carcinomas are either squamous cell carcinomas or adenocarcinomas. Squamous cell carcinoma most commonly arises in the midportion of the esophagus, whereas adenocarcinoma usually arises in the lower third, close to the gastroesophageal junction. Although squamous cell carcinoma remains the dominant histology worldwide, the incidence of adenocarcinoma is rising dramatically in the West. There is a geographic heterogeneity in the distribution of these two histologic entities. In the United States, squamous cell carcinoma accounted for roughly 90% of esophageal cancers in the 1960s. However, recent data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database indicate that the incidence of adenocarcinoma actually has surpassed that of squamous cell carcinoma. Based on correlative data, this is unlikely to be the result of the reclassification of squamous cell carcinoma or adjacent gastric adenocarcinoma or as an overdiagnosis of adenocarcinoma. The reason for this shift is still unclear, although increased prevalence of certain risk factors such as gastroesophageal reflux disease, increased body mass index, and low fruit and vegetable intake may contribute to the development of cancer.

PRESENTING SIGNS AND SYMPTOMS

Esophageal cancer often presents in an insidious and nonspecific manner, with indigestion, retrosternal discomfort, and transient dysphagia comprising the leading complaints. Often patients may present late because they have been able to compensate subconsciously for symptoms of dysphagia by eating softer foods or chewing their food more thoroughly. Dysphagia is the most common presenting symptom of esophageal carcinoma. It can progress to odynophagia and eventually to complete obstruction. Pain may be transient, associated with swallowing, or constant. It may be retrosternal or epigastric in location. Weight loss may be due to dietary changes, starvation, or tumor anorexia. Patients may experience regurgitation of undigested food, that is, food that has not been tainted with acidic gastric secretions. Patients also may develop respiratory sequelae primarily from aspiration but also from other causes such as direct invasion of tumor into the tracheobronchial tree or even a tracheoesophageal fistula, usually involving the left main stem bronchus. Symptoms may include cough, dyspnea, and pleuritic pain. Hoarseness can result from direct involvement of the recurrent laryngeal nerve, a poor prognostic sign. Also, in advanced cases of near-complete or complete esophageal obstruction, patients may become severely dehydrated, even hypokalemic, because of their inability to swallow potassium-rich saliva.

DIAGNOSTIC TECHNIQUES

The most commonly used diagnostic and staging modalities are the barium swallow study, chest radiography, esophagoscopy, bronchoscopy, CT, MRI, and EUS. More recent innovations include EUS-guided fine-needle aspiration (FNA), thoracoscopic and laparoscopic staging, and PET scan. Usually, the first diagnostic method is a barium swallow, followed by endoscopy with biopsy. After a histologic diagnosis of carcinoma is confirmed, a CT scan of the thorax and abdomen should be obtained for the purpose of staging, paying particular attention to tumor extension, lymphadenopathy, and distant metastases. In some countries, abdominal ultrasound is often performed instead of CT to diagnose liver or celiac lymphatic metastasis.

Chest radiography has a minimal role in the modern diagnosis and staging of esophageal cancer, although it can reveal an abnormal finding in almost half of patients with esophageal cancer. However, in some countries it is still used routinely to identify hilar or mediastinal adenopathy, evidence of pulmonary metastases, secondary pulmonary infiltrates caused by aspiration, and pleural effusion.7 Bronchoscopy is helpful in determining involvement of the tracheobronchial tree for patients with middle- and upper-third disease.8,9 Gallium scanning can be useful for the detection of bony metastases but generally has been replaced by PET scan in the United States. Endoscopy remains the method of choice for the confirmation of esophageal cancer. Its ability to detect early lesions is improved with the use of staining techniques.

Although the role of CT in evaluating esophageal cancer has been studied thoroughly, questions regarding its utility still remain. While CT is highly effective in the assessment of mediastinal esophageal carcinomas, it is less helpful in the staging of cervical or gastroesophageal junction carcinomas. It plays a key role in assessing initial tumor bulk for radiation therapy planning and is also useful in monitoring tumor response to the cytoreductive therapy. CT is also helpful in depicting extraesophageal tumor spread to contiguous structures and distant metastases. CT evaluation is performed from the thoracic inlet through the liver to include the upper abdominal lymph node groups. Either thin barium or water-soluble oral contrast agents are administered routinely. Adequate distention of the gastroesophageal junction is essential to exclude tumor involvement of this anatomic segment. Intravenous contrast material should be administered by the dynamic bolus technique to ensure optimal opacification of the heart, mediastinal vessels, and liver. Measurements of esophageal wall thickness greater than 5 mm are abnormal regardless of the degree of distention. Intraluminal air is seen in 60% of normal patients. CT staging of esophageal cancer includes assessment of (1) the extent of involvement of the esophageal wall by tumor, (2) tumor invasion of the periesophageal fat and adjacent structures, and (3) metastases to regional lymph nodes or distant organs. The two key prognostic features of esophageal cancer are (1) the depth of tumor infiltration into or through the esophageal wall and (2) the presence or absence of visceral metastasis. Although the thickness of the esophageal wall often can be determined by CT, the individual layers of the esophageal wall cannot.10 T1 and T2 lesions generally show an esophageal mass thickness between 5 and 15 mm, and T3 lesions show a thickness greater than 15 mm. T4 lesions show invasion of contiguous structures on CT. Specific findings of tracheobronchial invasion include demonstration of a tracheobronchial fistula or extension of tumor into the airway lumen. If an esophageal tumor indents or displaces the adjacent airway, luminal invasion is likely. Thickening of the wall of the tracheobronchial tree also suggests invasion. On CT, pericardial invasion is suggested by pericardial thickening adjacent to tumor, pericardial effusion, or inward deformity of the heart with loss of the intervening fat plane at the level of the tumor but with preservation of the fat plane at levels immediately above and below. Although CT is useful in determining the extent of local disease, it is not as accurate in the staging of lymph node involvement; it is limited in differentiating between small normal nodes and nodes invaded by tumor but small in size. It has been suggested that mediastinal nodes greater than 10 mm in diameter in the short axis should be classified as pathologic and that subdiaphragmatic nodes greater than 8 mm in diameter should be considered abnormal. The accuracy of CT in predicting lymph node involvement ranges from 83% to 87% for abdominal lymph nodes but only from 51% to 70% for mediastinal nodes.

MRI offers an alternative to CT for the evaluation of esophageal cancer. Its application in esophageal carcinoma has received scant attention. Like CT, MRI is highly accurate for detecting distant metastases of esophageal cancer, especially to the liver, and for determining advanced local spread (T4). However, it is less reliable in defining early infiltration (T1-3). MRI appears to be as sensitive as CT in predicting mediastinal invasion. One advantage of MRI is the loss of signal in the vessels and the air-filled trachea and bronchi, which may provide a clear delineation between the tumor and the aorta and the tracheobronchial tree. Like CT, MRI is poor at detecting tumors restricted to mucosa or submucosa and also tends to understage the regional lymph nodes.11

EUS is one of the newer modalities used in the staging of esophageal cancer. EUS combines the technologies of flexible endoscopy and ultrasonic imaging. Tio and colleagues found that the accuracy of EUS for T1 and T2cancer was 85% versus 12% for CT.12 Stenosis is a definite limiting factor for EUS. Lymph nodes at a distance of more than 2 cm from the esophageal lumen cannot be imaged because of the very limited penetration depth of ultrasound. For patients with severe stenosis, a nonoptical, wire-guided echoendoscope can markedly reduce the occurrence of incomplete esophageal cancer staging and improve the detection of metastatic disease. EUS is also of help in the assessment of unresectability. The most important findings of unresectability are tumor invasion into the left atrium (with loss of smooth, flexible movement of the pericardium on real-time EUS), the wall of the descending aorta, the spinal body, the pulmonary vein or artery, or the tracheobronchial system. The latter should be confirmed with bronchoscopy with transbronchial FNA. It is also possible to perform ultrasound-guided needle biopsies through the EUS endoscope. The use of EUS-guided FNA was first reported in the diagnosis of esophageal cancer recurrence after distal esophageal resection in 1989.13 Curved-array echo endoscopes appear to be more suitable than radial scanning echoendoscopes because the needle can be visualized along its entire length sonographically during the procedure. At this time, EUS, especially when combined with FNA, is the most accurate imaging modality for locoregional staging of esophageal cancer.

Since multimodal neoadjuvant treatment for esophageal cancer has been used with increased frequency, tumor restaging remains fundamental in evaluating the response to therapy and in planning an operation. Many studies have evaluated the role of EUS in this setting. Although EUS is extremely accurate for staging untreated esophageal cancer, its accuracy in staging tumors after neoadjuvant chemoradiotherapy is relatively poor, with most errors owing to overstaging.14

While EUS is close to 90% accurate in predicting initial T stage, after neoadjuvant therapy, accuracy ranges from 27% to 82%. N stage is from 38% to 73% accurate after neoadjuvant therapy, whereas FNA can be expected to increase the accuracy further. Errors in posttherapy staging are likely due to the similar echogenic appearance of fibrosis and residual tumor. Interestingly, Agarwal and colleagues determined that T stage after neoadjuvant therapy is not a predictor of survival.14 Yet residual nodal disease is an ominous finding. EUS, when combined with FNA, is very useful in detecting residual cancer within the lymph nodes. Others have found that ultrasound evidence of tumor regression is predictive of pathologic response to neoadjuvant therapy.

The initial results in the application of [18F]fluoro-2-deoxy-D-glucose (FDG)–PET in the staging of esophageal cancer are also encouraging. The results show that PET improves staging and facilitates selection of patients for operation by detecting distant disease not identified by CT alone. PET and CT are effective in showing the primary tumor and are equally sensitive in the demonstration of periesophageal nodes, although PET is probably more sensitive than CT for the detection of distant metastases. PET has a higher sensitivity for nodal and distant metastases and a higher accuracy for determining resectability than CT.15 These results suggest that PET may improve the ability to detect distant metastases missed by conventional noninvasive staging of esophageal cancer; however, small locoregional nodal metastases cannot be identified by current PET technology. Another potential use of PET in esophageal cancer is for the detection of responses to chemotherapy and radiotherapy. Historically, clinicians have used tumor shrinkage to assess efficacy. FDG–PET imaging can identify changes in glucose uptake, which may prove to be a better indicator of a favorable response to treatment. PET has been shown to be helpful in classifying responses to chemotherapy and in predicting survival in patients with lung cancer and head and neck cancer.

PATHOLOGY/STAGING

The Manual for Staging of Cancer of the American Joint Committee on Cancer is applicable to clinical as well as pathologic criteria and will improve the ability to provide meaningful prognostication. The TNM system takes into account the extent of tumor invasion (T stage), the presence and level of nodal involvement (N stage), and the presence of distant metastatic disease (M stage). Recently, modifications have been proposed to improve the classification of esophageal cancer based on nodal status16 (Table 10-1). The importance of staging esophageal carcinoma lies in the fact that individuals with stage I tumors have a 60% 5-year survival, whereas those with higher-stage tumors have minimal 5-year survival. By accurately diagnosing and staging these tumors, patients can be treated appropriately. Those with low-stage tumors are offered curative resection, whereas those with higher-stage tumors are grouped into palliative surgical treatment and/or chemotherapy and radiation protocols.

Table 10-1. American Joint Committee on Cancer Staging System for Esophageal Cancer

Current (pTNM)

Primary tumor (T)

  Tx

Primary tumor cannot be assessed

  Tis

Carcinoma in situ

  T1

Tumor invades lamina propria or submucosa

  T2

Tumor invades muscularis propria

  T3

Tumor invades adventitia

  T4

Tumor invades adjacent structures

Regional lymph nodes (N)

  Nx

Regional nodes cannot be assessed

  N0

No regional node metastasis

  N1

Regional node metastasis

Distant metastasis (M)

  Mx

Presence of distant metastasis cannot be assessed

  M0

No distant metastasis

  M1a

Celiac node metastasis for tumors of the lower esophagus/gastroesophageal junction, supraclavicular node metastasis for tumors of the upper esophagus

  M1b

Nonregional nodal metastasis or distant metastasis

Proposed Modifications to Staging System (pTNM)

Primary tumor (T)

  Tx

Primary tumor cannot be assessed

  T0

No evidence of primary tumor

  Tis

Carcinoma in situ

  T1

Tumor invades lamina propria or submucosa

  T2

Tumor invades muscularis propria

  T3

Tumor invades adventitia

  T4

Tumor invades adjacent structures

Regional lymph nodes (N)

  Nx

Regional nodes cannot be assessed

  N0

0 regional node metastasis

  N1

1–3 regional lymph node metastases, including nodes previously labeled as M1a

  N2

>3 regional lymph node metastases, including nodes previously labeled as M1a

  N3

Nonregional lymph node metastasis

Distant metastasis (M)

  Mx

Presence of metastasis cannot be assessed

  M0

No distant metastasis

  M1

Distant metastasis

 

AJCC Stage Groupings: Stage 0 = Tis, N0, M0; Stage I = T1, N0, M0; Stage IIA = T2, N0, M0 and T3, N0, M0; Stage IIB = T1, N1, M0 and T2, N1, M0; Stage III = T3, N1, M0 and T4, any N, M0; Stage IV = Any T, any N, M1; Stage IVA = Any T, any N, M1a; Stage IVB = Any T, any N, M1b

Many surgical studies show a significant stratification of survival after resection of esophageal cancer based on accurate pathologic staging. Multimodality treatment of this disease has been introduced; however, it is difficult to compare different treatment modalities because of the lack of precise preoperative staging. Preoperative minimally invasive surgical staging in esophageal cancer may solve this problem, just as the successful use of mediastinoscopy in preoperative staging has solved this problem for lung cancer. Such staging in esophageal cancer may separate advanced disease from early local disease. Prognostication in patients with esophageal cancer may allow more appropriate allocation of chemotherapy and/or radiation therapy, thus reducing the morbidity and mortality associated with esophageal cancer treatment. Murray and associates first reported their experience with minimally invasive surgical staging for esophageal cancer in 1977.17 They used mediastinoscopy and minilaparotomy prospectively in 30 esophageal cancer patients. Seven were found to have positive lymph nodes by mediastinoscopy, and 16 had celiac lymph nodes identified. Dagnini and coworkers did routine laparoscopy in 369 esophageal cancer patients, and they noted intraabdominal metastases in 14% and celiac lymph node metastases in 9.7%. All these patients with metastasis avoided unnecessary resection.18 Diagnostic laparoscopy with laparoscopic ultrasound revealed previously unknown findings, particularly in patients with locally advanced adenocarcinoma of the distal esophagus or cardia (hepatic metastases in 22% and peritoneal tumor spread or free tumor cells in the abdominal cavity in 25%), whereas the diagnostic gain was low in patients with squamous cell esophageal cancer.19 With the advances in thoracoscopic (Ts) and laparoscopic (Ls) techniques, Ts/Ls has been used for staging esophageal cancer in some centers. Recent reports show that Ts/Ls staging can correctly predict nodal metastasis for esophageal cancer, as mediastinoscopy does for lung cancer. Krasna and McLaughlin first described the efficacy of thoracoscopic lymph node staging in esophageal cancer.20 They further reported their successful experience with combined Ts/Ls for staging disease in the chest and abdomen in a follow-up series from three institutions of the Cancer and Leukemia Group B with an accuracy of over 90%.21 A more recent report of 65 patients showed a 94% accuracy with laparoscopy and 91% accuracy with thoracoscopy in esophageal cancer staging.22 When compared with EUS, Ts/Ls staging is superior in detecting lymph node metastases. The study also demonstrated that clinical stage evaluation based on noninvasive diagnostic methods including CT, MRI, and EUS may be used to guide surgeons to focus on the suspicious areas for the most high-yield biopsy targets when doing Ts/Ls staging.23 The main advantage of Ts/Ls staging is that it provides greater accuracy in evaluation of regional and celiac lymph nodes. Such information is very important in patient stratification and selection of therapy, especially in the setting of new treatment protocols. Furthermore, the histologic status of mediastinal and abdominal lymph nodes is critical for design of the field for irradiation. It permits one to maximize the dose delivery to areas of known disease while minimizing dose to surrounding sensitive, normal tissue. Minimally invasive surgical techniques in combination with new molecular diagnostic techniques may improve the ability to stage cancer patients. Reverse transcriptase-polymerase chain reaction of carcinoembryonic antigen mRNA has been used to increase the detection of micrometastases in lymph nodes from esophageal cancer patients with minimally invasive staging.24 Krasna and associates found that immunohistochemistry study of the molecular marker of p53 also can be used for this purpose; immunohistochemistry study of cytokeratin, an antibody to epithelial cells, also can be used to detect occult micrometastasis in Ts/Ls lymph nodes, and patients with positive cytokeratin findings tend to have poor survival.25

THERAPEUTIC OPTIONS

Esophageal cancer can metastasize to virtually any organ in the body. Widespread distant metastases are almost always present at the time of death. The extensive lymphatic drainage pathways in the esophagus and the long time interval during which tumors typically remain asymptomatic may contribute to the high incidence of lymph node metastases. As many as 30% of patients with early (T1) lesions may have lymph node metastases. For this reason, neoadjuvant regimens have been designed to achieve better survival in this disease.

The rationale for using preoperative radiotherapy is to reduce marginally resectable tumors to a more resectable size, to reduce the risk of tumor spread during surgical manipulation, and to treat extension of tumor beyond the surgical specimen. Surgery then removes the central, more radioresistant tumor mass. It does not appear that preoperative radiotherapy has an adverse effect on resectability or surgical morbidity.

Preoperative radiation doses of 30–45 Gy have been reported to result in a complete pathologic response rate of 15–30%. It is important to note that precise reporting of the rates of tumor sterilization is not possible, because not all patients who are irradiated undergo surgery and not all those operated on are resectable. Some clinical trials have suggested that survival after preoperative radiotherapy is correlated with the extent of tumor destruction seen in the resected specimen. A multicenter randomized controlled trial conducted by the European Organization for Research and Treatment of Cancer involved the administration of 33 Gy in 10 fractions in the treatment arm, followed by esophagectomy within 8 days. There were no significant differences in resectability or operative mortality between the study arms. Locoregional failure was decreased significantly in the radiotherapy arm from 67% to 46%. This was not associated with a survival benefit.26

Neoadjuvant chemotherapy in patients with esophageal cancer who appear to have locoregional disease may diminish the incidence of unrecognized systemic metastases. The potential benefits of preoperative chemotherapy include downstaging the disease to facilitate surgical resection, improvement of local control, and eradication of micrometastatic disease. Surgical resection subsequently provides an opportunity to assess the tumor response to chemotherapy and to evaluate the patient for possible postoperative adjuvant therapy. In patients with localized, resectable tumors, chemotherapy-related toxicity occasionally can result in prolonged delay or even cancellation of planned surgical resection, risking further spread of disease. The resulting need for careful patient selection for participation in clinical trials of preoperative chemotherapy can bias treatment results. An American multi-institutional randomized trial of 440 patients compared surgery alone versus neoadjuvant chemotherapy followed by surgery. Preoperative chemotherapy consisted of three cycles of 5-fluorouracil and cisplatin. Surgical resection followed 2–4 weeks later. Patients received two additional cycles of chemotherapy postoperatively. There was no significant difference in perioperative morbidity and mortality between the two groups. There was no significant difference in 1-year survival (60%), 2-year survival (35%), or local or distant recurrence rates. Survival did not differ between patients with squamous cell carcinoma and adenocarcinoma. Median survival time was 15–16 months in both treatment arms.27

A British randomized controlled trial of 802 patients also studied the use of preoperative 5-fluorouracil and cisplatin. The rate of microscopically complete resection was significantly higher for patients undergoing preoperative chemotherapy than for those undergoing surgery alone (60% versus 54%). Postoperative complication rates were similar in both groups (41% versus 42%). Patients undergoing preoperative chemotherapy achieved significantly improved median survival (16.8 versus 13.3 months) and 2-year survival (43% versus 34%).28 The results of this trial, however, are potentially confounded by the fact that clinicians were allowed the option of giving preoperative radiotherapy to their patients irrespective of randomization. There are data to suggest that survival benefit from preoperative chemotherapy for esophageal cancer might depend on the achievement of a complete pathologic response. The use of neoadjuvant chemotherapy still must be considered investigational at this time.

Both chemotherapy and radiotherapy have been reported to improve survival in patients with esophageal cancer when administered preoperatively. The notion of downstaging esophageal cancer before surgical resection is appealing. In an attempt to improve resectability and survival in esophageal cancer, chemotherapy has been combined with radiotherapy in the neoadjuvant setting. Most reports of so-called trimodality therapy for esophageal carcinoma describe concurrent neoadjuvant chemoradiation using combinations of cisplatin and 5-fluorouracil while administering 30–45 Gy of radiation. Some studies have used additional postoperative chemotherapy. The results appear comparable at most experienced centers. In an Irish study of 113 patients who had esophageal adenocarcinoma, patients were randomly allocated to surgery alone versus trimodality therapy with neoadjuvant chemoradiation.29 Patients randomized to the trimodality arm received two cycles of 5-fluoruracil and cisplatin given concurrently with 40 Gy of radiation, followed by surgery. Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 25%. Trimodality therapy was associated with significantly increased median survival (16 versus 11 months) and 3-year survival (32% versus 6%).30 It should be noted that the incidence of lymph node involvement was significantly higher in the group undergoing surgery alone. Survival with surgery alone was lower than that reported in most other series. A French randomized trial of 282 patients compared surgery alone with two cycles of cisplatin chemotherapy and concurrent radiotherapy (total 37 Gy) followed 2–4 weeks later by surgery.31 Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 26% but with significantly increased operative mortality (12.3% versus 3.6%). Despite a significantly increased rate of microscopically complete resection, longer local disease-free survival time, longer overall disease-free survival time, and fewer cancer-related deaths in the trimodality arm, overall survival time was 18.6 months in both treatment arms.

Meta-analyses of randomized trials of trimodality therapy versus surgery alone for esophageal carcinoma have revealed a trend toward increased treatment-related mortality and slightly increased overall survival. Among patients treated with trimodality therapy for esophageal carcinoma, the best predictor of survival appears to be the finding of a pathologic complete response at the time of surgical resection.32 Cancer and Leukemia Group B 9781 was a prospective, randomized intergroup trial of trimodality therapy versus surgery alone for the treatment of stages I–III esophageal cancer.33 Patients were randomized to treatment with either surgery alone or cisplatin (100 mg/m2) and 5-fluorouracil (1000 mg/m2/d x 4 days) during weeks 1 and 5 concurrent with radiation therapy (50.4 Gy at 1.8 Gy/daily fraction over 5.6 weeks) followed by esophagectomy with lymph node dissection. A total of 56 patients were entered into the study between October 1997 and March 2000 when the trial was closed as a consequence of poor accrual. Thirty patients were randomized to trimodality therapy and 26 to surgery alone. An intent-to-treat analysis showed a median survival of 4.5 versus 1.8 years in favor of trimodality therapy (log rank p = 0.02). A log-rank test with stratifications by N stage, staging approach, and histology demonstrated a p value of 0.005. The 5-year survival was 39% (95% confidence interval 21–57%) versus 16% (95% confidence interval 5–33%) in favor of trimodality therapy. To date, there is no completely reliable preoperative method for identifying a pathologic complete response after neoadjuvant chemoradiation.

Radiotherapy is commonly considered postoperatively to "sterilize" residual microscopic disease and to control gross residual locoregional tumor. As an advantage, reserving radiotherapy for postoperative use avoids the necessity of subjecting all patients with completely resectable disease to the damaging effects of radiation. As a disadvantage, the use of postoperative radiation in patients who have undergone gastric pull-up or colonic interposition exposes large volumes of normal tissue to harm and is a potential cause of late morbidity. A French randomized trial of 221 patients with squamous cell carcinoma arising in the distal two-thirds of the esophagus compared surgical resection alone versus surgery followed by postoperative radiotherapy doses of 45–55 Gy in daily fractions of 1.8 Gy. Among patients with negative lymph nodes, local recurrence rates were lower in the group that received postoperative radiotherapy. There was no significant difference in survival between the two groups.34 A randomized trial from Hong Kong studied 130 patients undergoing either palliative or curative resection for esophageal cancer. Patients randomized to the postoperative radiotherapy arm of the study received doses of 49-52.5 Gy in daily fractions of 3.5 Gy. The very high daily radiation dose used in this study was associated with a significantly decreased median survival compared with surgery alone (8.7 versus 15.2 months). In patients undergoing curative resection, postoperative radiotherapy was not associated with any improvement in local control. Although postoperative radiotherapy was associated with improved local control in patients undergoing palliative resection with gross residual disease, there was no survival benefit.35 A prospective Chinese study of 495 patients who had undergone surgical resection of esophageal cancer randomized patients to a postoperative radiotherapy group or a control group. A midplane dose of 50–60 Gy was administered in daily fractions of 2 Gy. A trend toward improved 5-year survival in patients who received postoperative radiotherapy (41.3% versus 31.7%) was not statistically significant. This trend was somewhat stronger in patients with positive lymph nodes (29.2% versus 14.7%, p = 0.07). Postoperative radiotherapy was associated with a statistically significant improvement in 5-year survival only among patients with stage III disease (35.1% versus 13.1%).36

Adjuvant chemotherapy also has been studied. A multi-institutional Japanese randomized controlled trial of 242 patients who had undergone complete surgical resection for esophageal squamous cell carcinoma studied the effects of adjuvant chemotherapy with two cycles of cisplatin and 5-fluorouracil. Adjuvant chemotherapy was associated with significantly improved 5-year disease-free survival in patients with lymph node involvement (52% versus 38%). Despite improved disease-free survival, there was no significant improvement in overall survival. Among node-negative patients receiving adjuvant chemotherapy, a trend toward improved 5-year disease-free survival (76% versus 70%) was not statistically significant.37

To date, there are no published North American data suggesting that postoperative chemotherapy in the absence of documented metastatic disease is associated with prolonged survival. Perhaps the most intriguing finding of these reports is the improved survival associated with the addition of surgical resection after chemoradiation.

The phase III randomized trials that have evaluated the role of trimodality therapy in this disease have yet to identify a clear and reproducible benefit compared with surgery alone.38 Despite this fact, it is clear from both the original and current patterns-of-care study surveys that this approach is increasing in popularity across the country. The data from these surveys emphasize the need to consider a national trial designed to compare definitive chemoradiation versus chemoradiation followed by surgical resection to appropriately determine a standard of care for the management of these patients.

Both chemotherapy and radiotherapy have been reported to improve survival in patients with esophageal cancer when administered preoperatively. Current data on trimodality therapy for esophageal carcinoma have revealed a trend toward increased treatment-related mortality with only slightly increased overall survival. The best predictor of survival after neoadjuvant chemoradiation is a complete pathologic response. To date, there is no completely reliable preoperative method to restage patients after neoadjuvant chemoradiation in order to identify a pathologic complete response. Novel restaging techniques, as well as further study of the risks and benefits of neoadjuvant chemoradiotherapy, are needed.

ROLE OF SURGERY

The success rate for treatment of esophageal cancer with surgery alone is related to the disease stage. If the depth of tumor invasion is limited to the submucosa without regional lymph node involvement or distant metastases (T1N0M0), most patients undergoing complete resection will survive 5 years. In most cases of esophageal cancer presenting with dysphagia, however, management is complicated by the prevalence of locally advanced disease (T3 or T4), involvement of regional lymph nodes (N1), or distant (often occult) metastases (M1). Curative treatment of esophageal cancer must address local control of the primary lesion as well as the control and/or prevention of metastases.

For most patients with localized esophageal cancer, surgical resection affords the best chance for local control and the best means of palliation of dysphagia. In all but the earliest stages of esophageal cancer (T1N0M0 or T2N0M0), however, both local and systemic recurrence of disease is common when surgical resection is performed as the sole treatment modality. For all but the earliest lesions, surgery alone with complete resection of all grossly apparent disease is associated with median survival ranging from 12–18 months in most centers and 5-year survival rarely exceeding 20%. Because of the low cure rates associated with the treatment of esophageal cancer by surgery alone, other modalities have been added to the treatment regimen.39,40

A large randomized trial initiated by the Radiation Therapy Oncology Group in the 1980s helped to establish the superiority of combination chemotherapy and radiation over standard radiation alone.41 Recently, a number of institutional experiences, including our own, have shown that induction chemotherapy and concurrent radiation followed by surgical resection have resulted in an improvement of both local control and survival compared with historical series of single-modality therapy.42 Despite these advances, the overall survival remains poor, with only 20% of patients achieving long-term cure. Many reasons have accounted for this poor outcome; however, the advanced nature of the primary disease at time of presentation and the frequency of regional lymph node involvement have been identified previously as important predictors of outcome.

A retrospective review of our group of 32 patients treated with trimodality therapy consisting of 50.4 Gy of conventionally fractionated radiotherapy, concurrent cisplatin 100 mg/m2 on day 1, and 5-fluorouracil 1000 mg/m2daily x 4 every 28 days for two cycles followed by Ivor Lewis esophagectomy resulted in a 40% 3-year survival. Of note, only 11 of 15 relapses were systemic. The implication of these data is that systemic control is the major hurdle to be overcome and that improved systemic therapy is indicated.25

TP53 is an important gene involved in DNA repair and in triggering apoptosis after cellular DNA is damaged. It has been suggested that it might play an important role during chemoradiation. In recent years, several investigators have found that the p53 tumor suppressor protein is one of the biomarkers that correlates well with prognosis of various kinds of cancer.43

Looking forward, correlation of clinicopathology and biologic markers (e.g., p53 and thymidine synthetase (TS)) and occult lymphatic metastasis with response, recurrence, and survival in esophageal carcinoma treated with trimodality treatment will be important to enhancing the treatment response in individual patients.

SUMMARY

Esophageal cancer is the fastest growing malignancy in terms of incidence in the North American and the Western nations. A multimodality approach generally is needed to treat this disease because it occurs in individuals of advanced age. With newer imaging and minimally invasive staging techniques, careful determination of pathologic TNM staging can be achieved before treatment. Patients can receive stage-specific treatment regimens, including chemotherapy, radiation therapy, and surgery, appropriate to their disease. With further advances in the identification of molecular markers, patients with esophageal cancer will be able to receive treatments based on a specific profile of genome expression, as is currently being done for patients with cancers of the breast and lung.

EDITOR'S COMMENT

The main message from this chapter is that esophageal cancer must be approached in a stage-specific fashion, just as one would approach any other solid organ malignancy. Using the revised TNM staging system, surgeons should carefully allocate treatment (resection, neoadjuvant and adjuvant therapy) as appropriate for each subgroup based on stage. Only in this way can we make significant differences in long-term survival.

–MJK

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