Esophageal Cancer

== Esophageal Cancer Trials ==

Epidemiology

Incidence:

  • 12,500 new cases projected for 1999 with 12,200 deaths.
  • Region: The highest incidence occurs in China, the Caspian region of Iran, and the former Soviet Union.
  • The incidence steadily rises with age, reaching a peak in the 6th-7th decades of life.
  • In Western countries, esophageal cancer is much more common in males (6.5:1 for ACA and 2.5:1 for SCCa), however, the ratio of males:females is almost equal in China.
  • The risk of squamous cell declining while adenocarcinoma (ACA) is on the rise.
  • This trend is less apparent in blacks compared to whites.

Risk Factors

  • Alcohol and smoking are the most common risk factors.
  • ABCs….Acalasia (5% risk at 25 years)
  • Barrett’s metaplasia (2-8% risk)
  • Caustic stricture
  • Diverticula
  • Esophageal webs
  • Familial (tylosis-hyperkeratosis of the palms and soles associated with esophageal papilloma)
  • GERD induced stricture.

4. Lymphatics: Peri-esophageal skip metastases are often seen.

Presentation and Evaluation

Anatomy

  • The average length of the esophagus is 25 cm
  • Esophagus beginning at the cricopharyngeous muscles (15 cm from the incisors) and ending at the GE junction (40 cm).
  • Cervical esophagus begins at the cricopharyngeous muscle (C7) and ends at the thoracic inlet (T3).
  • Upper thoracic esophagus extends from the thoracic inlet to the carina (T5).
  • Middle thoracic esophagus extends from the trachea to halfway to the GE junction (T11).
  • The remainder is the lower thoracic esophagus.
  • In sharp contrast to rest of GI track, esophagus is devoid of serosa.
Esophagus-anatomy1.jpg

Presentation:

  • Symptoms are usually present for 3-4 months prior to diagnosis.
  • More than 90% present with dysphagia often resulting in significant weight loss.
  • also associated with pain, anorexia, and vomiting.

Pathology:

  • Adenocarcinoma in the lower esophagus are the most common histologic types.
  • SCCA is common in all other location
  • Other less common histologies include carcinoid, sarcomas, and lymphomas.
location SCC ACA Total
Cervical 8% 0.1% 8.1%
Upper Thoracic 25.2% 1% 26.2%
Lower Thoracic 15% 2.8% 17.8%
Cardia 4.7% 43.2% 47.9%

Staging/Work-up

  • H&P, air contrast barium swallow
  • Endoscopy with bopsy/EUS
  • bronchoscopy for upper/mid thoracic tumors to R/O fistula
  • CT chest and upper abdomen
  • Routine labs.

AJCC 1983 (clinical/CT staging)

T1 5cm or less with no circumferential or obstruction or extraesophageal spread
T2 More than 5 and produces obstruction/circumferential
T3 Extraesophageal spread

AJCC 6th Ed.

T1 Lamina propria
T2 Muscularis propria
T3 Adventitia
T4 Adjacent structures
N1 Regional LNs
M1a cervical LNs for Upper thoracic esophagus
M1a celiac LNs for Lower thoracic esophagus
Stage TNM 5-yr OS
I T1 N0 65%
IIA T2-3 N0 40%
IIB T1-2 N1 20%
III T3 N1; T4 any N 10%
IV M1 <5%

Treatment Recommendations[2]

  • For all localized (non-metastatic) patients
    • Surgery alone is an option
      • Preferred option for non-cervical T1 lesions.
      • Only 20% of esophageal cancers are truly localized to the esophagus.
      • Not preferred for patients with positive node, especially ≥ 4 nodes or node ratio of ≥ 0.1.
    • Definitive Chemoradiotherapy is an option
      • As definitive therapy, strongest support for T3 and T4 squamous-cell carcinomas. (Stahl and Herskovic)
      • For patients with T3/T4 SCCA, non-responders may benefit from "salvage" surgical resection (Stehl)
    • Neoadjuvant Chemoradiotherapy is an option
      • A meta-analysis as well as the Walsh trial has shown 12% 3-OS and 6% 2-OS respectively over surgery alone.
  • In addition, GE junctional tumors
    • Neoadjuvant chemotherapy followed by surgery is appropriate for per MAGIC. (Not part of NCCN guidelines as of 9/2007).
  • No defined role for chemotherapy after definitive treatment. Induction chemotherapy prior to definitive chemoradiation is being studied by RTOG 0113.

Surgery alone

  • Curative surgery involves a total or subtotal esophagectomy. The surgery for cervical esophageal lesions can be complicated involving laryngectomy, partial pharyngectomy, and radical neck dissections in addition to partial esophagectomy.
  • Recent series of stage 0-II patients had OS-5 of 59% with surgery alone. [3]
  • In a recent series no patients with > 4 lymph nodes survived 5 years. [3]
    • Patients with no nodal involvement at the time of surgery will do well with 44% to 59% 5-OS rate.
    • However, of the patients with no nodal involvement by imaging, ~50% will have positive nodes at surgery.
    • They do much worse with 0% to < 15% 5-OS.

Definitive Chemoradiation (and radiation alone)

  • Chemoradiation with 50 Gy improves 2-OS 38% vs 10% compared to RT alone but only for SCCA of thoracic esophagus. Herskovic: RTOG 85-01
  • Dose: 50Gy with chemotherapy and 64 Gy with radiation alone (when chemo is contraindicated).
  • Local failure with radiation alone is 50%-91%

Neoadjuvant Chemoradiation

Randomized Trials

  • Walsh (NEJM 97) is the only one of at least 4 randomized trials to show a survival benefit.
  • However, Walsh (NEJM 97) has been criticized for poor surgical arm (6% OS-3)

Neoadjuvant ChemoRT: Role of Surgery

  • Esophagectomy after radiochemotherapy or preoperative radiochemotherapy has increased the complete surgical resection rate and local regional control without a significant survival benefit.

Meta-analysis

  • Meta-analysis by Urschel (Am J Surg 2003) showed a statisitcally significant OS benefit (per odds ratio) to pre-operative chemoradiation.
  • A significant survival benefit was evident for preoperative chemoradiotherapy[1]
    • Ten randomized comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209)
    • 13% absolute difference in survival at 2 years
    • similar results for SCC and adenocarcinoma.
  • A lesser benefit for chemotherapy in patients with adenocarcinoma of the oesophagus.[1]
    • eight randomized comparisons of neoadjuvant chemotherapy versus surgery alone (n=1724).
    • 2-year absolute survival benefit of 7%.
    • There was no significant effect on all-cause mortality for SCC
    • there was a significant benefit for those with adenocarcinoma

Other Pre-operative Treatment

Pre-op Radiation

  • Randomized trials from 1981 to 1992 has not shown a survival benefit

Pre-op Chemotherapy

  • MAGIC trial as well as Medical Research Council Oesophageal Cancer Working Party has shown survival advantage for neoadjuvant chemotherapy. MAGIC trial showed 36% vs. 23% 5-OS advantage for neoadjuvant chemotherapy in GE junctional tumors. Others trials from Intergroup failed to show improvement.

Post-op Treatments

  • Multiple randomized trial of post-op RT have not shown long-term survival benefit
  • Post-op RT does have local control benefit
  • Chemotherapy in randomized trial by Ando et al. showed 5-DFS 55% vs 45% but OS was not significant (61% vs 52%).
  • Due to conflicting data, recommendation is to receive neoadjuvant chemotherapy.

Radiation Field/ Dose

Margin

  • 5 cm margin superior and inferior to the tumor to 45Gy/25 fxs
  • 2 cm radial margin for 5.4Gy/3 fxs
  • Conedowns off cord often utilize an anterior field with 2 posterior obliques.

Supraclavicular

  • Electively treated inpatients with high thoracic tumors but not those with middle or distal thoracic tumors.
  • ie. tumors that extend 2 cm above the carina. (RTOG 97-16)

Celiac axis

  • little information supports routine treatment of this nodal group without evidence of tumor involvement.
  • Celiac nodes are treated for distal esophageal tumors. (RTOG 97-16)

Results

Outcome

Treatment Local Relapse OS -5
radiation alone 64% 0%
surgery alone 23%
chemoRT 43% 27%

Prognostic Factors

  • Stage, LN involvement, weight loss, and KPS.
  • Patients with upper thoracic lesions do better than lower thoracic esophageal lesions.
  • Larger tumors do worse.

Complications

  • Stricture (high dose EBRT > 60 Gy)
  • Ulceration (brachytherapy)

== Esophageal Cancer Trials ==

Bibliography
1. Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J; Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007 Mar;8(3):226-34. PMID: 17329193
2. Mariette C, Piessen G, Triboulet JP. Therapeutic strategies in oesophageal carcinoma: role of surgery and other modalities. Lancet Oncol. 2007 Jun;8(6):545-53. Review. PMID: 17540306
3. mariette, piessen, balon et al: Surgery alone in the curative treatment of localised oesophageal carcinoma. Eur J Surg Oncol 30: 869-876, 20014.
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