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NCI/PDQ^® Health professionals: Esophageal Cancer Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 30 de noviembre del 2012

TABLE OF CONTENTS

• General Information About Esophageal Cancer
  • Incidence and Mortality
  • Related Summaries

• Cellular Classification of Esophageal Cancer

• Stage Information for Esophageal Cancer
  • Definitions of TNM

• Treatment Option Overview
  • Preoperative Chemoradiation Therapy
  • Preoperative Chemotherapy Alone

• Stage 0 Esophageal Cancer
  • Current Clinical Trials

• Stage I Esophageal Cancer
  • Current Clinical Trials

• Stage II Esophageal Cancer
  • Current Clinical Trials

• Stage III Esophageal Cancer
  • Current Clinical Trials

• Stage IV Esophageal Cancer
  • Current Clinical Trials

• Recurrent Esophageal Cancer
  • Current Clinical Trials

• Changes to This Summary (11/30/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Esophageal Cancer

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Incidence and Mortality

Estimated new cases and deaths from esophageal cancer in the United States in 2012: 1

• New cases: 17,460.
• Deaths: 15,070.

The incidence of esophageal cancer has risen in recent decades, coinciding with a shift in histologic type and primary tumor location. 2 3 Adenocarcinoma of the esophagus is now more prevalent than squamous cell carcinoma in the United States and western Europe, with most tumors located in the distal esophagus. The cause for the rising incidence and demographic alterations is unknown.

While risk factors for squamous cell carcinoma of the esophagus have been identified (e.g., tobacco, alcohol, diet), the risk factors associated with esophageal adenocarcinoma are less clear. 3 The presence of Barrett esophagus is associated with an increased risk of developing adenocarcinoma of the esophagus, and chronic reflux is considered the predominant cause of Barrett metaplasia. The results of a population-based, case-controlled study from Sweden strongly suggest that symptomatic gastroesophageal reflux is a risk factor for esophageal adenocarcinoma. The frequency, severity, and duration of reflux symptoms were positively correlated with increased risk of esophageal adenocarcinoma. 4

Esophageal cancer is a treatable disease, but it is rarely curable. The overall 5-year survival rate in patients amenable to definitive treatment ranges from 5% to 30%. The occasional patient with very early disease has a better chance of survival. Patients with severe dysplasia in distal esophageal Barrett mucosa often have in situ or even invasive cancer within the dysplastic area. Following resection, these patients usually have excellent prognoses.

Primary treatment modalities include surgery alone or chemotherapy with radiation therapy. Combined modality therapy (i.e., chemotherapy plus surgery, or chemotherapy and radiation therapy plus surgery) is under clinical evaluation. Effective palliation may be obtained in individual cases with various combinations of surgery, chemotherapy, radiation therapy, stents, 5 photodynamic therapy, 6 7 8 and endoscopic therapy with Nd:YAG laser. 9

One of the major difficulties in allocating and comparing treatment modalities for patients with esophageal cancer is the lack of precise preoperative staging. Standard noninvasive staging modalities include computed tomography (CT) of the chest and abdomen and endoscopic ultrasound (EUS). The overall tumor depth staging accuracy of EUS is 85% to 90%, as compared with 50% to 80% for CT; the accuracy of regional nodal staging is 70% to 80% for EUS and 50% to 70% for CT. 10 11 EUS-guided fine-needle aspiration (FNA) for lymph node staging is under prospective evaluation; one retrospective series reported a 93% sensitivity and 100% specificity of regional nodal staging with EUS-FNA. 12 Thoracoscopy and laparoscopy have been used in esophageal cancer staging at some surgical centers. 13 14 15 An intergroup trial reported an increase in positive lymph node detection to 56% of 107 evaluable patients using thoracoscopy/laparoscopy, from 41% (using noninvasive staging tests, e.g., CT, magnetic resonance imaging, EUS) with no major complications or deaths. 16 Noninvasive positron emission tomography using the radiolabeled glucose analog 18-F-fluorodeoxy-D-glucose for preoperative staging of esophageal cancer is under clinical evaluation and may be useful in detecting stage IV disease. 17 18 19 20

Gastrointestinal stromal tumors can occur in the esophagus and are usually benign. (Refer to the PDQ® summary on Gastrointestinal Stromal Tumors Treatment for more information.)

Related Summaries

Other PDQ® summaries containing information related to esophageal cancer include the following:

• Esophageal Cancer Prevention
• Esophageal Cancer Screening

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. Devesa SS, Blot WJ, Fraumeni JF Jr: Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83 (10): 2049-53, 1998. [PUBMED Abstract]
3. Blot WJ, McLaughlin JK: The changing epidemiology of esophageal cancer. Semin Oncol 26 (5 Suppl 15): 2-8, 1999. [PUBMED Abstract]
4. Lagergren J, Bergstrím R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340 (11): 825-31, 1999. [PUBMED Abstract]
5. Tietjen TG, Pasricha PJ, Kalloo AN: Management of malignant esophageal stricture with esophageal dilation and esophageal stents. Gastrointest Endosc Clin N Am 4 (4): 851-62, 1994. [PUBMED Abstract]
6. Lightdale CJ, Heier SK, Marcon NE, et al.: Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 42 (6): 507-12, 1995. [PUBMED Abstract]
7. Kubba AK: Role of photodynamic therapy in the management of gastrointestinal cancer. Digestion 60 (1): 1-10, 1999 Jan-Feb. [PUBMED Abstract]
8. Heier SK, Heier LM: Tissue sensitizers. Gastrointest Endosc Clin N Am 4 (2): 327-52, 1994. [PUBMED Abstract]
9. Bourke MJ, Hope RL, Chu G, et al.: Laser palliation of inoperable malignant dysphagia: initial and at death. Gastrointest Endosc 43 (1): 29-32, 1996. [PUBMED Abstract]
10. Ziegler K, Sanft C, Zeitz M, et al.: Evaluation of endosonography in TN staging of oesophageal cancer. Gut 32 (1): 16-20, 1991. [PUBMED Abstract]
11. Tio TL, Coene PP, den Hartog Jager FC, et al.: Preoperative TNM classification of esophageal carcinoma by endosonography. Hepatogastroenterology 37 (4): 376-81, 1990. [PUBMED Abstract]
12. Vazquez-Sequeiros E, Norton ID, Clain JE, et al.: Impact of EUS-guided fine-needle aspiration on lymph node staging in patients with esophageal carcinoma. Gastrointest Endosc 53 (7): 751-7, 2001. [PUBMED Abstract]
13. Bonavina L, Incarbone R, Lattuada E, et al.: Preoperative laparoscopy in management of patients with carcinoma of the esophagus and of the esophagogastric junction. J Surg Oncol 65 (3): 171-4, 1997. [PUBMED Abstract]
14. Sugarbaker DJ, Jaklitsch MT, Liptay MJ: Thoracoscopic staging and surgical therapy for esophageal cancer. Chest 107 (6 Suppl): 218S-223S, 1995. [PUBMED Abstract]
15. Luketich JD, Schauer P, Landreneau R, et al.: Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer. J Thorac Cardiovasc Surg 114 (5): 817-21; discussion 821-3, 1997. [PUBMED Abstract]
16. Krasna MJ, Reed CE, Nedzwiecki D, et al.: CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer. Ann Thorac Surg 71 (4): 1073-9, 2001. [PUBMED Abstract]
17. Flamen P, Lerut A, Van Cutsem E, et al.: Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 18 (18): 3202-10, 2000. [PUBMED Abstract]
18. Flamen P, Van Cutsem E, Lerut A, et al.: Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol 13 (3): 361-8, 2002. [PUBMED Abstract]
19. Weber WA, Ott K, Becker K, et al.: Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 19 (12): 3058-65, 2001. [PUBMED Abstract]
20. van Westreenen HL, Westerterp M, Bossuyt PM, et al.: Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 22 (18): 3805-12, 2004. [PUBMED Abstract]

Cellular Classification of Esophageal Cancer

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Fewer than 50% of esophageal cancers are squamous cell carcinomas. Adenocarcinomas, typically arising in Barrett esophagus, account for at least 50% of malignant lesions, and the incidence of this histology appears to be rising. Barrett esophagus contains glandular epithelium cephalad to the esophagogastric junction.

Three different types of glandular epithelium can be seen:
• Metaplastic columnar epithelium.
• Metaplastic parietal cell glandular epithelium within the esophageal wall.
• Metaplastic intestinal epithelium with typical goblet cells.

Dysplasia is particularly likely to develop in the intestinal type mucosa.

Gastrointestinal stromal tumors can occur in the esophagus and are usually benign. (Refer to the PDQ® summary on Gastrointestinal Stromal Tumors Treatment for more information.)

Stage Information for Esophageal Cancer

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The stage determines whether the intent of the therapeutic approach will be curative or palliative. The AJCC has designated staging by TNM classification to define cancer of the esophagus and esophagogastric junction. 1

Definitions of TNM

The AJCC has designated staging by TNM classification to define cancer of the esophagus and esophagogastric junction. 1

Table 1. Primary Tumor (T)^a,b

^aReprinted with permission from AJCC: Esophageal and esophagogastric junction. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 103-15.^b(1) At least maximal dimension of the tumor must be recorded, and (2) multiple tumors require the T(m) suffix.^cHigh-grade dysplasia includes all noninvasive neoplastic epithelia that was formerly called carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the gastrointestinal tract.

TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	High-grade dysplasia.c
T1	Tumor invades lamina propria, muscularis mucosae, or submucosa.
T1a	Tumor invades lamina propria or muscularis mucosae.
T1b	Tumor invades submucosa.
T2	Tumor invades muscularis propria.
T3	Tumor invades adventitia.
T4	Tumor invades adjacent structures.
T4a	Resectable tumor invading pleura, pericardium, or diaphragm.
T4b	Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.

Table 2. Regional Lymph Nodes (N)^a,b

^aReprinted with permission from AJCC: Esophageal and esophagogastric junction. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 103-15.^bNumber must be recorded for total number of regional nodes sampled and total number of reported nodes with metastasis.

NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.
N1	Metastases in 12 regional lymph nodes.
N2	Metastases in 36 regional lymph nodes.
N3	Metastases in 7 regional lymph nodes.

Table 3. Distant Metastasis (M)^a

^aReprinted with permission from AJCC: Esophageal and esophagogastric junction. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 103-15.

M0	No distant metastasis.
M1	Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groups^a

^aReprinted with permission from AJCC: Esophageal and esophagogastric junction. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 103-15.^bOr mixed histology, including a squamous component or not otherwise specified.^cLocation of the primary cancer site is defined by the position of the upper (proximal) edge of the tumor in the esophagus.

Squamous Cell Carcinomab
Stage	T	N	M	Grade	Tumor Locationc
0	Tis (HGD)	N0	M0	1, X	Any
IA	T1	N0	M0	1, X	Any
IB	T1	N0	M0	23	Any
	T23	N0	M0	1, X	Lower, X
IIA	T23	N0	M0	1, X	Upper, middle
	T23	N0	M0	23	Lower, X
IIB	T23	N0	M0	23	Upper, middle
	T12	N1	M0	Any	Any
IIIA	T12	N2	M0	Any	Any
	T3	N1	M0	Any	Any
	T4a	N0	M0	Any	Any
IIIB	T3	N2	M0	Any	Any
IIIC	T4a	N12	M0	Any	Any
	T4b	Any	M0	Any	Any
	Any	N3	M0	Any	Any
IV	Any	Any	M1	Any	Any
Adenocarcinoma
Stage	T	N	M	Grade
0	Tis (HGD)	N0	M0	1, X
IA	T1	N0	M0	12, X
IB	T1	N0	M0	3
	T2	N0	M0	12, X
IIA	T2	N0	M0	3
IIB	T3	N0	M0	Any
	T12	N1	M0	Any
IIIA	T12	N2	M0	Any
	T3	N1	M0	Any
	T4a	N0	M0	Any
IIIB	T3	N2	M0	Any
IIIC	T4a	N12	M0	Any
	T4b	Any	M0	Any
	Any	N3	M0	Any
IV	Any	Any	M1	Any
HGD = high-grade dysplasia.

The current staging system for esophageal cancer is based largely on retrospective data from the Japanese Committee for Registration of Esophageal Carcinoma. It is most applicable to patients with squamous cell carcinomas of the upper third and middle third of the esophagus, as opposed to the increasingly common distal esophageal and gastroesophageal junction adenocarcinomas. 2 In particular, the classification of involved abdominal lymph nodes as M1 disease has been criticized. The presence of positive abdominal lymph nodes does not appear to carry as grave a prognosis as metastases to distant organs. 3 Patients with regional and/or celiac axis lymphadenopathy should not necessarily be considered to have unresectable disease caused by metastases. Complete resection of the primary tumor and appropriate lymphadenectomy should be attempted when possible.

References:

1. Esophagus and esophagogastric junction. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 103-11. [PUBMED Abstract]
2. Iizuka T, Isono K, Kakegawa T, et al.: Parameters linked to ten-year survival in Japan of resected esophageal carcinoma. Japanese Committee for Registration of Esophageal Carcinoma Cases. Chest 96 (5): 1005-11, 1989. [PUBMED Abstract]
3. Korst RJ, Rusch VW, Venkatraman E, et al.: Proposed revision of the staging classification for esophageal cancer. J Thorac Cardiovasc Surg 115 (3): 660-69; discussion 669-70, 1998. [PUBMED Abstract]

Treatment Option Overview

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The prevalence of Barrett metaplasia in adenocarcinoma of the esophagus suggests that Barrett esophagus is a premalignant condition. Strong consideration should be given to resection in patients with high-grade dysplasia in the setting of Barrett metaplasia. Endoscopic surveillance of patients with Barrett metaplasia may detect adenocarcinoma at an earlier stage more amenable to curative resection. 1 The survival rate of patients with esophageal cancer is poor. Asymptomatic small tumors confined to the esophageal mucosa or submucosa are detected only by chance. Surgery is the treatment of choice for these small tumors. Once symptoms are present (e.g., dysphagia, in most cases), esophageal cancers have usually invaded the muscularis propria or beyond and may have metastasized to lymph nodes or other organs.

In the presence of complete esophageal obstruction without clinical evidence of systemic metastasis, surgical excision of the tumor with mobilization of the stomach to replace the esophagus has been the traditional means of relieving the dysphagia. In the United States, the median age of patients who present with esophageal cancer is 67 years. 2 The results of a retrospective review of 505 consecutive patients who were operated on by a single surgical team over 17 years found no difference in the perioperative mortality, median survival, or palliative benefit of esophagectomy on dysphagia when the group of patients older than 70 years were compared to their younger peers. 3[Levels of evidence: 3iiA and 3iiB] All of the patients in this series were selected for surgery on the basis of potential operative risk. Age alone should not determine therapy for patients with potentially resectable disease.

The optimal surgical procedure is controversial. One approach advocates transhiatal esophagectomy with anastomosis of the stomach to the cervical esophagus. A second approach advocates abdominal mobilization of the stomach and transthoracic excision of the esophagus with anastomosis of the stomach to the upper thoracic esophagus or the cervical esophagus. One study concluded that transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy; however, median overall disease-free and quality-adjusted survival did not differ significantly. 4 Similarly, no differences in long-term quality of life (QOL) using validated QOL instruments have been reported. 5 In patients with partial esophageal obstruction, dysphagia may, at times, be relieved by placement of an expandable metallic stent 6 or by radiation therapy if the patient has disseminated disease or is not a candidate for surgery. Alternative methods of relieving dysphagia have been reported, including laser therapy and electrocoagulation to destroy intraluminal tumor. 7 8 9 10

Surgical treatment of resectable esophageal cancers results in 5-year survival rates of 5% to 30%, with higher survival rates in patients with early-stage cancers. This is associated with a less than 10% operative mortality rate. 11 In an attempt to avoid this perioperative mortality and to relieve dysphagia, definitive radiation therapy in combination with chemotherapy has been studied. A Radiation Therapy Oncology Group randomized trial (RTOG-8501) of chemotherapy and radiation therapy versus radiation therapy alone resulted in an improvement in 5-year survival for the combined modality group (27% vs. 0%). 12[Level of evidence: 1iiA] An eight-year follow-up of this trial demonstrated an overall survival (OS) rate of 22% for patients receiving chemoradiation therapy. 12 An Eastern Cooperative Oncology Group trial (EST-1282) of 135 patients showed that chemotherapy plus radiation provided a better 2-year survival rate than radiation therapy alone, 13 which was similar to that shown in the Intergroup trial. 12[Level of evidence: 1iiA] In an attempt to improve upon the results of RTOG-8501, Intergroup-0123 (RTOG-9405) randomly assigned 236 patients with localized esophageal tumors to chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of fluorouracil (5-FU) and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule. 14 Although originally designed to accrue 298 patients, this trial was closed in 1999 after a planned interim analysis showed that it was statistically unlikely that there would be any advantage to using high-dose radiation. At 2 years' median follow-up, no statistical differences were observed between the high-dose and conventional-dose radiation therapy arms in median survival (13 months vs. 18 months), 2-year survival (31% vs. 40%), or local/regional failures (56% vs. 52%). 14[Level of evidence: 1iiA]

Preoperative Chemoradiation Therapy

Chemoradiation followed by surgery is a standard treatment option for patients with stages IB, II, III, and IVA esophageal cancer, based on the results of several randomized trials.

The CROSS (NCT01498289) study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m² of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. 15[Level of evidence: 1iiA] The majority of the patients enrolled in the study had adenocarcinoma (75%).

With a median follow-up of 45 months, preoperative chemoradiation was found to improve median OS from 24 months in the surgery-alone group to 49.4 months (hazard ratio [HR], 0.657; 95% confidence interval [CI], 0.4950.871, P = .003). Additionally, preoperative chemoradiation improved the rate of R0 resections (R0 is defined as complete resection with no tumor within 1 mm of resection margins, 92% vs. 69%, P < .001). A complete pathologic response was achieved in 29% of patients who underwent resection after chemoradiation therapy. Postoperative complications and in-hospital mortality were equivalent in both groups. The most common hematologic side effects in the chemoradiation group were leukopenia (6%) and neutropenia (2%). The most common nonhematologic side effects were anorexia (5%) and fatigue (3%). 15

Other phase III trials have compared preoperative concurrent chemoradiation therapy to surgery alone for patients with esophageal cancer. 15 16 17 18 19[Level of evidence: 1iiA] A multicenter prospective randomized trial in which preoperative combined chemotherapy (i.e., cisplatin) and radiation therapy (37 Gy in 3.7 Gy fractions) followed by surgery was compared to surgery alone in patients with squamous cell carcinoma showed no improvement in OS and a significantly higher postoperative mortality (12% vs. 4%) in the combined modality arm. 16 In patients with adenocarcinoma of the esophagus, a single-institution phase III trial demonstrated a modest survival benefit (16 months vs. 11 months) for patients treated with induction chemoradiation therapy consisting of 5-FU, cisplatin, and 40 Gy (2.67 Gy fractions) plus surgery over resection alone. 17 A subsequent single-institution trial randomly assigned patients (75% with adenocarcinoma) to 5-FU, cisplatin, vinblastine, and radiation therapy (1.5 Gy twice daily to a total of 45 Gy) plus resection versus esophagectomy alone. 18 At a median follow-up of more than 8 years, there was no significant difference between the surgery alone and combined modality therapy with respect to median survival (17.6 months vs. 16.9 months), OS (16% vs. 30% at 3 years), or disease-free survival (16% vs. 28% at 3 years). An Intergroup trial (CALGB-9781) planned to randomly assign 475 patients with resectable squamous cell or adenocarcinoma of the thoracic esophagus to treatment with preoperative chemoradiation therapy (5-FU, cisplatin, and 50.4 Gy) followed by esophagectomy and nodal dissection or surgery alone. 19[Level of evidence: 1iiA] The trial was closed as a result of poor patient accrual; however, the results of the 56 enrolled patients, with a median follow-up of 6 years, were reported. The median survival was 4.48 years (95% CI, 2.4 years to not estimable) for trimodality therapy versus 1.79 years (95% CI, 1.412.59 years) for surgery alone (P = .002), with 5-year OS of 39% (95% CI, 21%57%) versus 16% (95% CI, 5%33%) for trimodality therapy versus surgery alone.

A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus. 20[Level of evidence: 1iiA] OS was the primary outcome. The analysis of 172 eligible, randomly assigned patients showed that OS at 2 years was not statistically significantly different between the two treatment groups (arm A: 39.9%; 95% CI, 29.4%50.4%; arm B: 35.4%; 95% CI, 25.2%45.6%; log-rank test for equivalence with 0.15, P < .007). Local progression-free survival (PFS) was higher in the surgery group (2-year PFS, 64.3%; 95% CI, 52.1%76.5%) than in the chemoradiation therapy group (2-year PFS, 40.7%; 95% CI, 28.9%52.5%; HR for arm B vs. arm A, 2.1; 95% CI, 1.33.5; P < .003). Treatment-related mortality was higher in the surgery group compared with the chemoradiation therapy group (12.8% vs. 3.5%, respectively; P < .03).

Preoperative Chemotherapy Alone

The effects of preoperative chemotherapy are being evaluated in randomized trials, as was done in the NCT00525785 trial. 21 22[Level of evidence: 1iiA]. An Intergroup trial randomly assigned 440 patients with local and operable esophageal cancer of any cell type to three cycles of preoperative 5-fluorouracil (5-FU) and cisplatin followed by surgery and two additional cycles of chemotherapy versus surgery alone. After a median follow-up of 55 months, there were no significant differences between the chemotherapy/surgery and surgery-alone groups in median survival (14.9 months and 16.1 months, respectively) or 2-year survival (35% and 37%, respectively). The addition of chemotherapy did not increase the morbidity associated with surgery. The Medical Research Council Oesophageal Cancer Working Party randomly assigned 802 patients with resectable esophageal cancer also of any cell type to two cycles of preoperative 5-FU and cisplatin followed by surgery versus surgery alone. At a median follow-up of 37 months, median survival was significantly improved in the preoperative chemotherapy arm (16.8 months vs. 13.3 months with surgery alone; difference 3.5 months; 95% CI, 16.5 months), as was 2-year OS (43% and 34% respectively; difference 9%; 95% CI, 314 months). The interpretation of the results from both of these trials is challenging because T or N staging was not reported and prerandomization and radiation could be offered at the discretion of the treating oncologist.

The Japanese Clinical Oncology Group randomly assigned 330 patients with clinical stage II or III, excluding T4, squamous cell carcinomas to receive either two cycles of preoperative cisplatin and 5-FU (fluorouracil) followed by surgery versus surgery followed by postoperative chemotherapy of the same regimen. 23[Level of evidence: 1iiC] A planned interim analysis was conducted after patient accrual, and although the primary endpoint of PFS was not met, there was a significant benefit in OS among patients treated with preoperative chemotherapy (P = .01). As a result of these findings, the Data and Safety Monitoring Committee recommended early publication.

With a median follow-up of 61 months, the 5-year OS was 55% among patients treated with preoperative chemotherapy compared with 43% among patients treated with postoperative chemotherapy (P = .04). However, there was no significant difference between groups with respect to PFS (5-year PFS, 39% vs. 44%; P = .22). Additionally, there were no significant differences between the two groups with respect to postoperative complications or treatment-related toxicities. 23 Based on these results, preoperative chemotherapy without radiation therapy should still be considered under clinical evaluation.

Two randomized trials have shown no significant OS benefit for postoperative radiation therapy over surgery alone. 24 25[Level of evidence: 1iiA] All newly diagnosed patients should be considered candidates for therapies and clinical trials comparing various treatment modalities.

Information about ongoing clinical trials is available from the NCI Web site.

Special attention to nutritional support is indicated in any patient undergoing treatment of esophageal cancer. (Refer to the PDQ® summary on Nutrition in Cancer Care for more information.)

References:

1. Lerut T, Coosemans W, Van Raemdonck D, et al.: Surgical treatment of Barrett's carcinoma. Correlations between morphologic findings and prognosis. J Thorac Cardiovasc Surg 107 (4): 1059-65; discussion 1065-6, 1994. [PUBMED Abstract]
2. Ginsberg RJ: Cancer treatment in the elderly. J Am Coll Surg 187 (4): 427-8, 1998. [PUBMED Abstract]
3. Ellis FH Jr, Williamson WA, Heatley GJ: Cancer of the esophagus and cardia: does age influence treatment selection and surgical outcomes? J Am Coll Surg 187 (4): 345-51, 1998. [PUBMED Abstract]
4. Hulscher JB, van Sandick JW, de Boer AG, et al.: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347 (21): 1662-9, 2002. [PUBMED Abstract]
5. de Boer AG, van Lanschot JJ, van Sandick JW, et al.: Quality of life after transhiatal compared with extended transthoracic resection for adenocarcinoma of the esophagus. J Clin Oncol 22 (20): 4202-8, 2004. [PUBMED Abstract]
6. Saxon RR, Morrison KE, Lakin PC, et al.: Malignant esophageal obstruction and esophagorespiratory fistula: palliation with a polyethylene-covered Z-stent. Radiology 202 (2): 349-54, 1997. [PUBMED Abstract]
7. Campbell WR Jr, Taylor SA, Pierce GE, et al.: Therapeutic alternatives in patients with esophageal cancer. Am J Surg 150 (6): 665-8, 1985. [PUBMED Abstract]
8. Mellow MH, Pinkas H: Endoscopic therapy for esophageal carcinoma with Nd:YAG laser: prospective evaluation of efficacy, complications, and survival. Gastrointest Endosc 30 (6): 334-9, 1984. [PUBMED Abstract]
9. Fleischer D, Sivak MV Jr: Endoscopic Nd:YAG laser therapy as palliation for esophagogastric cancer. Parameters affecting initial outcome. Gastroenterology 89 (4): 827-31, 1985. [PUBMED Abstract]
10. Karlin DA, Fisher RS, Krevsky B: Prolonged survival and effective palliation in patients with squamous cell carcinoma of the esophagus following endoscopic laser therapy. Cancer 59 (11): 1969-72, 1987. [PUBMED Abstract]
11. Kelsen DP, Bains M, Burt M: Neoadjuvant chemotherapy and surgery of cancer of the esophagus. Semin Surg Oncol 6 (5): 268-73, 1990. [PUBMED Abstract]
12. Cooper JS, Guo MD, Herskovic A, et al.: Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 281 (17): 1623-7, 1999. [PUBMED Abstract]
13. Smith TJ, Ryan LM, Douglass HO Jr, et al.: Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 42 (2): 269-76, 1998. [PUBMED Abstract]
14. Minsky BD, Pajak TF, Ginsberg RJ, et al.: INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 20 (5): 1167-74, 2002. [PUBMED Abstract]
15. van Hagen P, Hulshof MC, van Lanschot JJ, et al.: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366 (22): 2074-84, 2012. [PUBMED Abstract]
16. Bosset JF, Gignoux M, Triboulet JP, et al.: Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 337 (3): 161-7, 1997. [PUBMED Abstract]
17. Walsh TN, Noonan N, Hollywood D, et al.: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335 (7): 462-7, 1996. [PUBMED Abstract]
18. Urba SG, Orringer MB, Turrisi A, et al.: Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 19 (2): 305-13, 2001. [PUBMED Abstract]
19. Tepper J, Krasna MJ, Niedzwiecki D, et al.: Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26 (7): 1086-92, 2008. [PUBMED Abstract]
20. Stahl M, Stuschke M, Lehmann N, et al.: Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23 (10): 2310-7, 2005. [PUBMED Abstract]
21. Kelsen DP, Ginsberg R, Pajak TF, et al.: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339 (27): 1979-84, 1998. [PUBMED Abstract]
22. Medical Research Council Oesophageal Cancer Working Group.: Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 359 (9319): 1727-33, 2002. [PUBMED Abstract]
23. Ando N, Kato H, Igaki H, et al.: A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 19 (1): 68-74, 2012. [PUBMED Abstract]
24. Téniíre P, Hay JM, Fingerhut A, et al.: Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet 173 (2): 123-30, 1991. [PUBMED Abstract]
25. Fok M, Sham JS, Choy D, et al.: Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 113 (2): 138-47, 1993. [PUBMED Abstract]

Stage 0 Esophageal Cancer

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Stage 0 squamous esophageal cancer is rarely seen in the United States, but surgery has been used for this stage of cancer. 1 2

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Rusch VW, Levine DS, Haggitt R, et al.: The management of high grade dysplasia and early cancer in Barrett's esophagus. A multidisciplinary problem. Cancer 74 (4): 1225-9, 1994. [PUBMED Abstract]
2. Heitmiller RF, Redmond M, Hamilton SR: Barrett's esophagus with high-grade dysplasia. An indication for prophylactic esophagectomy. Ann Surg 224 (1): 66-71, 1996. [PUBMED Abstract]

Stage I Esophageal Cancer

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Standard treatment options:

• Chemoradiation with subsequent surgery.
• Surgery.

Treatment options under clinical evaluation:

• Clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage II Esophageal Cancer

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Standard treatment options:

1. Chemoradiation with subsequent surgery.
2. Chemoradiation alone.
3. Surgery alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage III Esophageal Cancer

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Standard treatment options:

1. Chemoradiation with subsequent surgery.
2. Chemoradiation alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage IV Esophageal Cancer

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At diagnosis, approximately 50% of patients with esophageal cancer will have metastatic disease and will be candidates for palliative therapy. 1

Standard treatment options:

1. Chemoradiation with subsequent surgery (for patients with stage IVA disease).
2. Endoscopic-placed stents to provide palliation of dysphagia. 2
3. Radiation therapy with or without intraluminal intubation and dilation.
4. Intraluminal brachytherapy to provide palliation of dysphagia. 3 4
5. Nd:YAG endoluminal tumor destruction or electrocoagulation. 5
6. Chemotherapy has provided partial responses for patients with metastatic distal esophageal adenocarcinomas. 6 7 8

Treatment options under clinical evaluation:

Many agents are active in esophageal cancer. Objective response rates of 30% to 60% and median survivals of less than 1 year are commonly reported with platinum-based combination regimens with fluorouracil, taxanes, topoisomerase inhibitors, hydroxyurea, or vinorelbine. 1 8 9

• Clinical trials evaluating single-agent or combination chemotherapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV esophageal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Enzinger PC, Ilson DH, Kelsen DP: Chemotherapy in esophageal cancer. Semin Oncol 26 (5 Suppl 15): 12-20, 1999. [PUBMED Abstract]
2. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001. [PUBMED Abstract]
3. Sur RK, Levin CV, Donde B, et al.: Prospective randomized trial of HDR brachytherapy as a sole modality in palliation of advanced esophageal carcinoma--an International Atomic Energy Agency study. Int J Radiat Oncol Biol Phys 53 (1): 127-33, 2002. [PUBMED Abstract]
4. Gaspar LE, Nag S, Herskovic A, et al.: American Brachytherapy Society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Clinical Research Committee, American Brachytherapy Society, Philadelphia, PA. Int J Radiat Oncol Biol Phys 38 (1): 127-32, 1997. [PUBMED Abstract]
5. Bourke MJ, Hope RL, Chu G, et al.: Laser palliation of inoperable malignant dysphagia: initial and at death.