Esophageal cancer: Current Trends and controversies

1. Andy Freeman, MD Dept of Radiation Oncology March 17, 2011 Esophageal cancer: Current Trends and controversies

2. Outline • Overview • Anatomy • Epidemiology • Treatment modalities • Literature Review • Surgical Approaches • Trimodality Therapy • Chemotherapy and RT • Future Directions • Conclusions

3. Anatomy • Thin walled structure 25 cm in length • Squamous epithelium • Replacement by glandular epithelium is metaplasia (Barrett’s Esophagus) • Thoracic Esophagus – thoracic inlet to GE junction • Lymphatics – longitudinal and interconnecting

4. Anatomy

5. Epidemiology • 1% all malignancies • 15,500 new cases in US; 13,940 deaths • Male:Female, 3.5:1 • Histologic Subtypes • SCC • Adenocarcinoma • SCC still more prevalent in African American population

6. Epidemiology • 50-60% present with locally advanced, unresectable disease • Survival correlated with disease stage • 5y OS T1-2 – 34-62% • 5y OS IIB-III – 17-25% • 5y OS 15%, up from 5% in 1970s • Median Survival 9 mo • Survival similar for Adeno v SCC histology

7. Risk Factors • SCC – tobacco and alcohol • Plummer-Vinson Syndrome • Nitrosamines – smoked/pickled foods • Adenocarcinoma – GERD • GERD – 44x increase in risk • Smoking 2-3x

8. Natural History/Patterns of Spread • Local growth and spread to LN • Upper lesion – TE fistula, recurrent laryngeal nerve invasion • T1 lesion – 15-20% LN rate • T2 lesion – 40-60% • T3/T4 – close to 100% LN involvement • Metastatic Disease – LN, Lungs, Liver, Adrenals

9. LN Spread

10. Staging • T1a – Lamina propria or muscularis mucosa • T1b - Submucosa • T2 – Invasion of muscularis propria • T3 – Invasion of adventitia • T4a – Resectable; pleura, pericardium, diaphragm • T4b – Unresectable; aorta, VB, trachea

11. Nodal • N1 – 1-2 nodes • N2 – 3-6 nodes • N3 - >7 nodes • Regional nodes include periesophageal, perigastric, celiac, supraclavicular

12. Clinical Presentation • Obstruction with progressive dysphagia • Weight loss • Retrosternal pain • Regurgitation of undigested food • Chronic Hoarseness • Iron deficiency anemia • Acute bleed rare but occurs with aorta involvement • TE fistula – late complication; MS 4 mo

13. Diagnostic Workup • Barium studies suggestive • EGD w/ biopsy diagnostic

15. Staging Evaluation/Workup • CT Chest/Abdomen – limited value for locoregional staging • 42% accurate • Low sensitivity for small mets • PET – detects metastatic disease in 20% • Better correlation with local disease extent • EUS – detailed images of 5 layer esophagus • T staging accurate in 90% • N staging accuracy 80%

16. Staging Workup EUS - normal EUS - Pathologic

17. Invasive Staging Workup • Laparoscopy – assessment of abdominal cavity in low esophageal lesion • Thoracoscopy – LN assessment • Improves staging workup • Benefit? • Bronchoscopy • Tumors above carina to rule malignant T-E fistula

18. General Management • Surgery with curative intent • Curative Combination Therapy • Bimodality • Trimodality • Palliation • Esophageal Stenting • Brachytherapy

19. QOL is Key Palliative Technique

20. Palliation • Palliative esophagectomy • No longer valid as R1/R2 resection limits ability for long term control with chemo/XRT with significant morbidity • Long term dysphagia control with non-surgical options • EBRT – poor results for long term control

21. Dysphagia Palliation • EBRT – 90% palliation for 3 months • TE fistula – mostly associated with progression • Esophageal strictures • Brachytherapy – durable therapy, logistically difficult • Esophageal Stenting – immediate relief

22. Surgical Technique

23. Factors Determining Technique • Tumor location and length • Lymphadenectomy desired • Conduit for replacement • +/- neoadjuvant therapy • Concern for post op bile reflux • Surgeon preference

24. Transhiatal Esophagectomy • Blunt dissection of thoracic esophagus • Cervical anastomosis • Inability for full thoracic lymphadenectomy • Perioperative mortality 4% Orringer et al.. Transhiatal esophagectomy. 1999. Ann Surg. 230:392

25. Ivor-Lewis Transthoracic • Laparotomy and Thoracotomy • Allows for complete lymphadectomy • Limited superior margin • Intrathoracic anastomosis give higher likelihood of bile reflux • Modification includes thoracoabdominal incision with gastric pull up • High risk of post op reflux

26. TriincisionalEsophagectomy. En bloc resection • Incorporates advantages of previous two techniques • 3 incisions, en bloc resection and complete nodal dissection • Cervical anastomosis • Perioperative mortality 4% in experienced centers

27. Do improved techniques alleviate the need of chemo/XRT Surgery Alone

28. Historical Controls

29. Newer Surgical Approaches • Tri-Incisional Approach • N= 324; non-randomized, single institution • 5y OS 35% Collard et al. Ann Surg. 2001. Skeletonizing en bloc esophagectomy for cancer. 234:25

30. Transhiatal vs. Transthoracic • N=220 • Transhiatal had few complications • 5y followup • No difference in DFS, local recurrence, MS or OS Hulscher et al. Extended transthoracic resection.. NEJM. 2002. 347:1662.

31. Conclusions • In experienced hands, newer surgical technique may improve outcomes • Randomized data to date does not support one approach superior to another

32. Radiation Alone

33. XRT Alone • RCT comparing RT alone v Surgery • N=269, SCC only • XRT delivered 69 Gy • 45 Gy daily and then 24 Gy in 1.5 Gy/fx bid • 3D-CRT Yu et al. J Clin Oncol. 2006. 24:181s

34. Preliminary Results

36. Problems • Can’t be extrapolated to adenocarcinoma • Single modality therapy has been supplanted by combined therapy

37. RTOG 85-01 • RT alone arm • 64 Gy/2 Gy • 3y OS 0% Herskovic et al. NEJM. 1992. 326:1593

38. Definitive Chemoradiotherapy

39. RTOG 85-01 • Landmark trial for chemoradiation • XRT alone (64 Gy) vs Concurrent chemoradiation (50 Gy) • 5-FU 1000mg/m2 Days 1-4, Wk 1 and 5 • Cisplatin 75mg/m2 Day 1 Wk 1 and 5 • 2 additional courses q3wk after XRT • N-121, 90% SCC • Closed early because of superiority of chemoradiation arm • Chemoradiation is standard treatment for unresectable carcinoma Herskovic et al. NEJM. 1992. 326:1593

40. OS benefit to chemoradiation

41. Local Recurrence

42. Intergroup 0123 • Radiation Dose Escalation • Chemotherapy as in 85-01 • Randomization between 50.4 Gy vs 64.8 Gy • N =236, 85% SCC Minsky et al. 2002. J Clin Oncol. 20(5):1167

45. Summary • CMT – ChemoRT is superior to RT alone in non-operable patients • Dose escalation does not appear to increase LC or OS • 3y OS 30-35%

46. Role of pCR after Preoperative Therapy

47. Fox Chase • Retrospective analysis • N=177, 80% Adeno • pCR rate 32% • 5y OS 48 v 18% • MS 50 v 28 mo Berger et al. JCO. 2005. 23(19)

48. Preoperative Chemoradiotherapy

49. Rationale • Poor long-term prognosis with surgery alone • Improve loco-regional and micrometastatic disease • 7 trials comparing surg +/- preop chemo/XRT • 5 published • 2 showing improvement, both using concurrent therapy

50. Irish Trial • N = 113; adenocarcinoma only • Surgery +/- chemoradiation • 5-FU 15mg/kg days 1-5 • Cisplatin 75 mg/m2 Day 7 • 40 Gy in 15 fx • pCR in 25% • Improved Median Survival 16 v 11 mo • Improved 3 y OS 32 v 6% Walsh et al. NEJM. 1996. 335:462