Editor(s): John D. Urschel, M.D., FACS, FRCSEd Reviewers: Frank C. Detterbeck, M.D., Mark K. Ferguson, M.D., and Brian P Whooley, M.D

Current Controversies

1. Treatment of patients with high-grade dysplasia in Barrett's esophagus 2. Extent of resection for esophageal cancer (radicality of resection and lymph node dissection) 3. Operative approach for esophageal resection (thoracotomy, transhiatal, and minimally invasive) 4. Surgery as a component of multimodality treatment (induction therapy and surgery; surgery and adjuvant therapy) 5. Chemoradiotherapy without surgery, or with surgery reserved as a "salvage" strategy only

Epidemiology of Esophageal Cancer

Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104:510-3.

This is a classic paper on the changing epidemiology of esophageal cancer.

Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31.

There is a strong relationship (probably causal) between reflux and adenocarcinoma of the esophagus.

Columnar-lined Esophagus

SSAT, AGA, ASGE Panel. Consensus statement on Barrett's esophagus. J Gastrointest Surg 2000:4:115-134.

A series of concise consensus reviews on all aspects of Barrett's esophagus.

Staging

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 2000;18:3202-10.

A recent report showing the value of PET scanning for staging.

Surgical Therapy

Roder JD, Busch R, Stein HJ, Fink U, Siewert JR. Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the esophagus. Br J Surg 1994;81:410-3.

This paper emphasizes the lymph node ratio as a prognostic factor. The lymph node ratio is also a surgical quality indicator. It is the lymphatic equivalent of a resection margin.

Nigro JJ, DeMeester SR, Hagen JA, et al. Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy. J Thorac Cardiovasc Surg 1999;117:960-8.

This North American group advocates en bloc style resection. Complete (R0) resection is emphasized. The lymph node ratio is important prognostically.

Siewert JR, Stein HJ. Lymph-node dissection in squamous cell esophageal cancer - who benefits? Langenbecks Arch Surg 1999;384:141-8.

An excellent review of the lymphadenectomy controversy.

Orringer MB, Marshall B, Iannettoni MD. Transhiatal esophagectomy: clinical experience and refinements. Ann Surg 1999;230:392-403.

The definitive reference for this operative approach.

Hulscher JB, van Sandick JW, Tijssen JG, Obertop H, van Lanschot JJ. The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg 2000;191:143-8.

Local-regional cancer recurrences occur in approximately 40% of patients undergoing seemingly complete resection by transhiatal esophagectomy. This is concerning.

Rindani R, Martin CJ, Cox MR. Transhiatal versus Ivor-Lewis oesophagectomy: is there a difference? Aust N Z J Surg 1999;69:187-94.

A collective review of randomized trials and retrospective studies shows little difference in operative morbidity or cancer survival.

Luketich JD, Schauer PR, Christie NA, et al. Minimally invasive esophagectomy. Ann Thorac Surg 2000;70:906-12.

The technique is technically demanding but feasible. Its value in esophageal cancer surgery is not yet known.

Whooley BP, Law S, Murthy SC, et al. Analysis of reduced death and complication rates after esophageal resection. Ann Surg 2001;233:338-44.

With experience, and efforts to prevent postoperative pulmonary complications, transthoracic esophagectomy can be done with an extremely low mortality.

Pathology

Izbicki JR, Hosch SB, Pichlmeier U, et al. Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer. N Engl J Med 1997;337:1188-94.

Occult lymph node metastases (not detectable by routine histologic examination) are prognostically significant. This highlights the shortcomings of our current cancer staging systems.

Cancer of the Cardia

Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998;85:1457-9.

The most commonly used classification scheme for tumors near the cardia. Operative approaches are outlined. The authors down play the usefulness of a left thoracoabdominal esophagogastrectomy for these tumors.

Wijnhoven BP, Siersema PD, Hop WC, van Dekken H, Tilanus HW. Adenocarcinomas of the distal oesophagus and gastric cardia are one clinical entity. Br J Surg 1999;86:529-35.

A surgical view contrary to that reported by Siewert's group.

Complications of Esophagectomy

Bains MS. Complications of abdominal right-thoracic (Ivor Lewis) esophagectomy. Chest Surg Clin N Am 1997;7:587-99.

An excellent review of prevention and treatment of complications.

Iannettoni MD, Whyte RI, Orringer MB. Catastrophic complications of the cervical esophagogastric anastomosis. J Thorac Cardiovasc Surg 1995;110:1493-501.

Cervical esophagogastric anastomotic leaks are generally less morbid than intrathoracic leaks, but it is a mistake to underestimate their lethal potential.

Urschel JD. Esophagogastrostomy anastomotic leaks complicating esophagectomy: a review. Am J Surg 1995;169:634-40.

The etiology, prevention and treatment of leaks are reviewed. Surgical experience and perfusion of the gastric conduit are key factors for successful anastomotic healing.

Beitler AL, Urschel JD. Comparison of stapled and hand-sewn esophagogastric anastomoses. Am J Surg 1998;175:337-40.

This collective review of randomized controlled trials shows that both techniques are acceptable.

Whooley BP, Law S, Alexandrou A, et al. Critical appraisal of the significance of intrathoracic anastomotic leakage after esophagectomy for cancer. Am J Surg 2001;181:198-203.

A detailed report from John Wong's group on the prevention and contemporary management of intrathoracic anastomotic leaks.

Surgery and Multimodality Treatment

Stein HJ, Sendler A, Fink U, Siewert JR. Multidisciplinary approach to esophageal and gastric cancer. Surg Clin North Am 2000;80:659-82

An excellent overview of the issues.

Arnott SJ, Duncan W, Gignoux M, et al. Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group). Int J Radiat Oncol Biol Phys 1998;41:579-83.

Several randomized trials of preoperative radiotherapy show no survival benefit. This meta-analysis of those trials shows little if any benefit for preoperative radiotherapy. Preoperative radiotherapy (alone) is not recommended and this induction strategy is no longer the subject of trials.

Fok M, Sham JS, Choy D, Cheng SW, Wong J. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 1993;113:138-47.

One of several randomized trials of postoperative radiotherapy. Postoperative radiotherapy does not improve survival. This trial, and one other, showed a reduction in local recurrences. Postoperative radiotherapy causes morbidity. It should be reserved for specific indications (residual disease, positive margins).

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;339:1979-84.

This is the most recently published (in full article form) randomized trial of induction chemotherapy followed by surgery. Although phase II studies were very promising, almost all the published randomized trials have failed to show a survival advantage for this treatment strategy. Poor response rate to chemotherapy is largely responsible. In some of the trials the chemotherapy "responders" benefited at the expense of the "non-responders" (ie. responders faired better than controls, but non-responders had shorter survival than controls). After Kelsen's report interest in this induction strategy (vs. chemoradiotherapy induction) waned in North America. However, a recently presented UK trial (see abstracts below) showed a benefit for induction chemotherapy.

Ando N, Iizuka T, Kakegawa T, et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg 1997;114:205-9.

This is the only major randomized trial of adjuvant (postoperative) chemotherapy. There was no benefit. It is difficult to give adjuvant chemotherapy after esophagectomy (contrast with breast and colon cancers). Patients are too frail and they do not complete the treatment (hence the interest in induction or neoadjuvant treatment).

Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462-7.

This randomized trial of chemoradiotherapy and surgery vs. surgery alone showed a benefit for multimodality treatment. Response rates with induction chemoradiotherapy are superior to those seen with induction chemotherapy. The concurrent (vs. sequential) administration of chemotherapy and radiotherapy appears to be important for a good treatment response. A major US intergroup trial was similar to this Irish trial, but it closed in April 2000 due to poor accrual.

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 1997;337:161-7.

In contrast to the Walsh study, this randomized trial showed no overall survival benefit for induction chemoradiotherapy. However, improved cancer survival in the multimodality arm was offset by increased postoperative mortality. Postoperative deaths were pulmonary in nature and may be related to the radiation treatment. The radiation schedule (split course) is now known to be suboptimal for cancer treatment and the fractionation (large fractions) predisposes to postoperative ARDS. Despite the "negative" overall outcome of the trial, it does provide some support for chemoradiotherapy followed by surgery (improved disease-free survival).

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 2001;19:305-13.

One hundred patients were randomized to transhiatal esophagectomy alone or chemoradiotherapy followed by transhiatal esophagectomy. Median survival was similar (17 months). 3-year survival was 16% after surgery alone and 30% after trimodality therapy (p=0.15). Once again, the results differ from the Irish trial.

Chemoradiotherapy

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 1999;281:1623-7.

Some oncologists believe that chemoradiotherapy is the most important treatment for esophageal cancer, and that esophageal resection adds very little. No randomized trial addresses this issue. Cooper's paper is the long-term follow up of an RTOG trial originally reported by Herskovic. That trial, along with others, established chemoradiotherapy as the standard non-operative treatment of esophageal cancer (vs. radiotherapy alone). Surgeons would argue that the high rate of persistent and recurrent local disease with chemoradiotherapy (~45%) is justification for esophageal resection.

Wilson KS, Lim JT. Primary chemo-radiotherapy and selective oesophagectomy for oesophageal cancer: goal of cure with organ preservation. Radiother Oncol 2000;54:129-34.

Meunier B, Raoul J, Le Prise E, Lakehal M, Launois B. Salvage esophagectomy after unsuccessful curative chemoradiotherapy for squamous cell cancer of the esophagus. Dig Surg 1998;15:224-6.

These two papers are not "classics", but they report a strategy of definitive chemoradiotherapy with "salvage" esophagectomy reserved for local treatment failures. This treatment approach is fundamentally different than "planned" esophagectomy after induction chemoradiotherapy. The surgery is more difficult and postoperative morbidity is high. This therapeutic strategy is gaining momentum and it will likely be tested in a randomized trial.

Endoscopic Palliation

Reed CE. Pitfalls and complications of esophageal prosthesis, laser therapy, and dilation. Chest Surg Clin N Am 1997;7:623-36.

An excellent review of endoscopic palliative methods and their shortcomings.

Selected Abstracts - 2000 - 2001

The 2000 SSO, STS, AATS, and ASCO meetings did not include any phase III studies on surgery for esophageal cancer. However, the ASCO meeting featured an important gastric cancer phase III study and some studies with non-operative themes; we should be aware of these developments.

Clark PI, et al. Surgical resection with or without pre-operative chemotherapy in oesophageal cancer: an updated analysis of a randomised controlled trial conducted by the UK Medical Research Council upper GI tract group. ASCO Proc 2001;20:126a.

802 patients were randomized to surgery alone or two cycles of platinum-5FU followed by surgery. Operative mortality and complications were similar in the treatment groups. Median survival was 17 months for chemo-surgery vs. 13 months for surgery alone. Overall survival was also better (odds ratio for death 0.78, 95%CI 0.66-0.92, p=0.003). This UK MRC trial is the largest ever conducted on induction chemotherapy followed by surgery. Unlike many previous trials, it was designed with adequate power to detect small differences in survival. The trial was similar in design to the North American trial reported by Kelsen. However, the results were very different. It will cause considerable rethinking of the issues around the world. Chemotherapy is generally safer and better tolerated than chemo-radiotherapy as an induction treatment.

Macdonald JS, et al. Postoperative combined radiation and chemotherapy improves disease-free and overall survival in resected adenocarcinoma of the stomach and GE junction. Results of intergroup study INT-0116 (SWOG-9008). ASCO Proc 2000;19:1a.

This is the first randomized controlled trial to show a benefit for postoperative chemoradiotherapy in gastric cancer. This strategy could be beneficial for esophageal cancers as well, but there hasn't been much enthusiasm to this point (as opposed to preoperative therapy). There are several reasons for this. Neoadjuvant treatment has the advantages (some theoretical) of early treatment of micrometastatic disease, increased resectability from tumor downstaging, ability to assess treatment response, and better tolerance of aggressive chemoradiotherapy. Most postoperative esophageal cancer patients have a difficult time getting through an aggressive protocol of chemoradiotherapy. Kelsen has written a good commentary on this trial. He touches on related surgical quality issues (Kelsen DP. Postoperative adjuvant chemoradiation therapy for patients with resected gastric cancer: intergroup 116. J Clin Oncol 2000;18(21 Suppl):32S-4S.)

3. Swisher SG, et al. Is surgical salvage indicated for recurrent esophageal tumors following definitive chemoradiation? AATS 2001 meeting (http://aats.e-studiolive.net/Session/general/general.php3).

Surgical salvage is a morbid undertaking. Patient selection is critical. An RTOG phase II trial is being planned

Clinical trials

CALGB 9781 (CLOSED, poor accrual)- Phase III study of trimodality (chemotherapy, radiotherapy, surgery) therapy versus surgery alone for esophageal cancer (Intergroup Esophageal Cancer Trial, ICE-T).

This trial randomized patients with resectable (local-regional disease) squamous or adenocarcinoma of the esophagus to esophagectomy alone or induction chemoradiotherapy (5-FU, cisplatin, 50.4Gy) followed by surgery. It was similar conceptually to the study published by Walsh. It closed in April 2000 because of poor accrual. Its failure to accrue is noteworthy. There is a perception in the community that surgery alone is no longer valid as a control arm.

ACOSOG-Z0060 - Diagnostic study of PET imaging in staging of patients with potentially operable carcinoma of the thoracic esophagus or gastroesophageal junction.

A study to determine the usefulness of PET staging in esophageal cancer.

NCI-P00-0145 - Chemoprevention study of celecoxib in patients with Barrett's esophagus. Patients are randomized to celecoxib or placebo for one to two years. They are followed for development of toxicity or adenocarcinoma.