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A. Epidemiologynavigator

  1. Includes esophageal and gastroesophageal junction cancers (esophageal ca)
  2. USA: 13,900 new cases annually, 13,000 deaths annually
  3. Lifetime risk of esophageal ca 0.8% for men, 0.3% for women
  4. Risk increases with age
  5. In USA, 7th leading cause of cancer death
  6. Worldwide 6th leading cause of cancer death
  7. Over 90% are either squamous cell or adeno-carcinomas

B. Types and Risk Factorsnavigator

  1. Squamous Cell Carcinoma
    1. Typical patient is man usually 60-70 years old
    2. Usually in upper 50% of esophagus
    3. Alcoholism and/or marked tobacco smoking history common
    4. Achalasia high risk
    5. Caustic injury to esophagus common
    6. Tylosis: nonepidermolytic palmoplantar keratoderma
    7. Plummer-Vinson Syndrome
  2. Adenocarcinoma
    1. Typical patient is 50-60 year old white or black man
    2. Usually due to Barrett's metaplasia of the distal esophagus
    3. Barrett's metaplasia is usually related to gastroesophageal reflux (GERD)
    4. Occurs lower 50% of esophagus
    5. Increasing in frequency relative to squamous cell and all other cancers
    6. Reasons for increasing incidence in industrialized countries are unknown
    7. May be linked to redistribution of H. pylori into gastric cardia and esophagus
    8. High-grade dysplasia may be treatable with photodynamic therapy without surgery
  3. Uncommon (<10% of total)
    1. Lymphomas - uncommon
    2. Rhabdomyosarcomas and Leimyosarcomas - uncommon
    3. Fibrosarcomas - very rare
    4. Melanomas - very rare
    5. Carcinoids - very rare

C. Risk Factors for Esophageal and/or Gastric Cardia Cancersnavigator

  1. Hiatal Hernia - ~4 fold increased risk
  2. GERD [3]
    1. Between 2.5 and 7 fold increased risk after 5 years
    2. With Barrett's esophagus, esophageal ca risk is ~5% per lifetime, or 1 case in 300 patient-years [4]
    3. Risk increased for adenocarcinoma, not for squamous cell carcinoma [3]
    4. Upper endoscopic screening is recommended for moderate to severe GERD, obesity, and probably any man with GERD [5]
    5. Drugs that reduce lower esophageal sphincter (LES) pressure increase risk (see below) [6]
  3. Esophageal Ulcer or Esophagitis - ~4 fold (4X) risk
  4. Difficulty Swallowing (Dysphagia) - ~2X risk
  5. Achalasia - >16X risk
  6. Radiation therapy for breast cancer - 4-5X increased risk [7]
  7. Drugs
    1. More than 4 prescriptions for H2-receptor antagonist have ~1.5X risk
    2. Anticholinergic agents for >5 years may increase risk (results conflicting)
    3. Long term (>5 years) use of LES pressure reducing drugs risk increased 3.8X [6]
    4. These drugs likely increase esophageal reflux
  8. Drugs Reducing LES Pressure [6]
    1. Nitroglycerin
    2. Aminophylline / Theophylline
    3. ß-Receptor Agonists
    4. Anticholinergics
    5. Benzodiazepines (very weak risk)
  9. Increased body mass index (BMI) or frank obesity are 2.3X or 4.3X risk factors [8]
  10. Human papilloma virus (HPV) infection is not a risk factor for esophageal cancer [9]

D. Symptoms [2]navigator

  1. Dysphagia (usually without initial odynophagia)
  2. Gastrogesophageal Reflux and regurgitation
  3. Weight Loss
  4. Tracheoesophageal and Other Fistula
    1. Life threatening complication of esophageal ca
    2. About 50% involve trachea, others involve left or right main bronchus
    3. Initial symptoms cough (56%), aspiration (37%), fever (25%)
    4. Pneumonia often develops

E. Diagnosisnavigator

  1. Barium Swallow
  2. Endoscopy with biopsy
  3. Staging
    1. CT scan to detect Lymph Node (LN) and other disease
    2. Endoscopic ultrasound to evaluate LN status
    3. Immunohistological detection of tumor in LN is better than standard pathology

F. Staging and Prognosisnavigator

  1. Very aggressive tumor with generally poor prognosis
  2. Prognostic Indicators
    1. Primary tumor size and presence of LN disease most important
    2. Grade of tumor but not histological type
  3. Survival correlates with presence of LN metastasis
    1. Usual histopathology fails to detect tumor in about 15-20% of LN
    2. Monoclonal antibody to Ber-EP4 can be used in immunohistopathology of LN
    3. Median survival for Ber-EP4+ nodes was 6-12 months, Ber-EP4- was > 4 years
    4. Four year survival was 25% for Ber-EP4+ versus 68% for Ber-EP4-
    5. Note that all tumors in this study were read as LN negative by standard pathology
    6. Immunohistochemical staining of LN is not currently standard of care, however
  4. Five Year Survival and Stage (Table 2, Ref [1])
    1. Standard T (Tumor), N (Lymph Node), M (Metastasis) staging system
    2. Stage 0: T in situ, N0, M0; >95% 5 year survival (5YS)
    3. Stage I: T1, N0, M0; ; ~65% 5YS
    4. Stage IIA: T2-3, N0, M0; ~35% 5YS
    5. Stage IIB: T1-2, N1 (regional LN), M0; ~20% 5YS
    6. Stage III: T3, N1, M0 OR T4, N0 or N1, M0; ~12% 5YS
    7. Stage IVA: any T or N, M1a (metastases to cervical nodes or celiac nodes); <5% 5YS
    8. Stage IVB: any T or N, M1b (other distant metastasis); <1% 5YS

G. Therapy [1] navigator

  1. Localized Esophageal Ca
    1. Resection and reanastamosis is mainstay of therapy
    2. Transhiatal esophagectomy has lower morbidity than open procedure [11]
    3. Total esophagectomy is often performed with extended en bloc lymphadenectomy
    4. Operation is complex with mortality 4-10%
    5. Perioperative complications ~35% (cardiopulmonary, infections, anastomotic leaks)
    6. Preoperative chemo- and/or radiotherapy probably of no benefit (see below) [1]
    7. Control of symptoms is critical
  2. Primary Radiotherapy
    1. May be alternative to surgery in squamous cell ca
    2. Total doses 5000-8000 cGy
    3. Avoids perioperative mortality and morbidity
    4. Likely not as effective for preventing dysphagia or odynophagia
  3. Dysphagia
    1. Chemotherapy, radiation therapy may be used for locally advanced unresectable tumor
    2. Endoscopy: Dilatation, laser, funnel tube (reduce tumor) [12]
    3. Photodynamic therapy directed by endoscopy is also effective
    4. Esophageal stenting - expandable metal stent usually placed endoscopically [13]
    5. Stenting is often effective in cases of tracheoesophageal fistula
  4. Esophageal - Airway (Tracheoesophageal) Fistula
    1. Pneumonia often develops and must be treated with broad spectrum agents
    2. Coated expandable metal stents are very effective
  5. Chemotherapy
    1. For advanced esophageal or gastric cancer, standard first line is combination of epirubicin + cisplatin + 5-fluorouracil (ECF)
    2. E+oxaliplatin+capecitabine (EOX) had longer survival than ECF: 11.2 versus 9.9 months [10]
    3. Capecitabine oral (Xeloda®) is not inferior to infused 5-FU when either is combined with either EC or EO
    4. Oxaliplatin main side effects diarrhea and neuropathy; reduced neutropenia, alopecia, renal toxicity, thromboembolism versus cisplatin
    5. Combined radiation and chemotherapy is superior to radiation alone [14]
    6. Preoperative chemotherapy (two cycles cisplatin+5FU) improves median survival in patients with operable esophageal cancer from 405 to 512 days [15]
    7. Preoperative chemotherapy or chemoradiotherapy improve mortality in both squamous cell carcinoma and adenocarcinoma of the esophagus [19]
    8. Combination chemotherapy in Stage IV disease induces responses in ~50%
    9. Most responses are not durable and last only several months
    10. Median survival in Stage IV disease is typically <1 year
  6. Porfimer (Photofrin®)
    1. Palliative treatment in patients with totally obstructing tumors
    2. This is a photosensitizing method with endoscopic photodynamic therapy
    3. Objective tumor response in 32% of treated patients
    4. May be better than thermal laser ablation
  7. Combination (Multimodal) Therapy
    1. Conflicting results have been obtained
    2. Preoperative chemoradiotherapy superior to surgery alone in only one (small) study [16]
    3. Median survivals: 16 months for mutlimodality therapy versus 11 months for surgery [16]
    4. Other studies have demonstrated no benefit to preoperative chemo± radiotherapy [1]
    5. Cisplatin+5-FU added to radiation therapy was better than radiation alone for patients with T1-3 N0-1 M0 (26% versus 0% 5 year survival) without surgery [14]
    6. Stage I/II disease 3 year survival: 40% for both multimodal and surgery alone [17]
    7. Disease-free survival was slightly better in multimodal group versus surgery [17]
    8. In adenocarcinoma or epidermiod carcinoma, surgery alone was as good as pre- operative chemotherapy (cisplatin + 5-FU) with surgery [18]
    9. Survivals were equal: 60% at one year and ~35% at two years [18]
    10. It remains controversial whether peroperative adjuvant therapy provides survival advantage
    11. Trials to evaluate survival advantage with adjuvant therapy are underway
  8. Early local dissemination of tumors is main reason for poor survival rates

References navigator

  1. Enzinger PC and Mayer RJ. 2003. NEJM. 349(23):2241 abstract
  2. Krakauer EL, Zhu AX, Bounds BC, et al. 2005. NEJM. 352(8):817 (Case Record) abstract
  3. Lagergren J, Bergstrom R, Lindgren A, Nyren O. 1999. NEJM. 340(11):825 abstract
  4. Eckardt VF, Kanzler G, Bernhard G. 2001. Am J Med. 111(1):33 abstract
  5. Gerson LB and Triadafilopoulos G. 2002. Am J Med. 113(6):499 abstract
  6. Lagergren J, Bergstrom R, Adami HO, Nyren O. 2000. NEJM. 133(3):165 abstract
  7. Ahsan H and Neugut AI. 1998. Ann Intern Med. 128(2):114 abstract
  8. Lagergren J, Bergstrom R, Nyren O. 1999. Ann Intern Med. 130(11):883 abstract
  9. Lagergren J, Wang Z, Bergstrom R, et al. 1999. JAMA. 281(18):1718
  10. Cunningham D, Starling N, Rao S, et al. 2008. NEJM. 358(1):36 abstract
  11. Hulscher JBF, van Sandick JW, de Boer AGEM, et al. 2002. NEJM. 347(21):1662 abstract
  12. Van Dam J and Brugge WR. 1999. NEJM. 341(23):1738 abstract
  13. Baron TD. 2001. NEJM. 344(22):1680
  14. Cooper JS, Guo MD, Herskovic A, et al. 1999. JAMA. 281(17):1623 abstract
  15. 1Medical Research Council Esophageal Cancer Working Party. 2002. Lancet. 359(9319):1727 abstract
  16. Walsh TN, Noonan N, Hollywood D, et al. 1996. NEJM. 335(7):462 abstract
  17. Bosset JF, Gignoux M, Triboutlet JP, et al. 1997. NEJM. 337(3):161 abstract
  18. Kelsen DP, Ginsberg R, Pajak T, et al. 1998. NEJM. 339(27):1979 abstract
  19. Gebski V, Burmeister B, Smithers BM, et al. 2007. Lancet Oncol. 8(3):226 abstract