1. ANDREW NG PRINCE OF WALES HOSPITAL Role of primary chemoradiation in esophageal carcinoma

2. Cancer of the esophagus Often presenting as advanced disease – 40-50% stage III disease among pre-operative cases Poor 5-year survival after primary resection  10-15% for stage III tumors Esophagectomy remains a major undertaking  Mortality 4-10%  Morbidity 26-41%

3. Neo-adjuvant chemoradiation Advent of neo-adjuvant chemoradiation – Chemotherapy to treat micro-metastasis – Radiotherapy for improved local control Many RCTs compare neoadjuvant chemoRT to surgery alone  Limited by small sample size  Nearly all suggest no benefit

4. Neo-adjuvant chemoradiation Neo- adjuvant chemoRT: 623 Surgery alone: 586 Val Gebski et. al: Lancet Oncol 2007;8:226-34

5. Neo-adjuvant chemoradiation Improvement in median overall survival after neo- adjuvant chemoRT – 24 months to 49.4 months (Hazard ratio of 0.657; p=0.003) Improvement in rate of clear resection margins – 92% to 69% (p<0.001) n = 366 Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer - Van Hagen et. al.: NEJM 2012; 355:2074-84

6. Primary chemoradiation Advent of primary chemoradiation in advanced tumors High rates of complete response to neo-adjuvant treatment – ~25% with complete patho-histologic remission High operative mortality after neo-adjuvant chemoRT  10 -16% Good survival after primary chemoRT – 27% 5 year survival – In comparison with primary radiotherapy

7. Primary chemoradiation Chemoradiation with curative intent  Higher doses of radiotherapy  Total dose of over 50Gy  Prolonged course of chemotherapy  usually Cisplatin and 5-Fluorouracil Mostly studies involve advanced disease  Stage III disease

8. Primary chemoRT vs Surgery alone

9. 2 year Overall survival: Esophagectomy: 54.5% Chemoradiation 58.3% Chiu P. W. Y. et. al: J Gastrointest Surg 2005;9:794-802 n = 81

10. Primary chemoRT vs Surgery alone Median disease free survival Esophagectomy: 24 months ChemoRT: 20 months Chiu P. W. Y. et. al: J Gastrointest Surg 2005;9:794-802 n = 81

11. Primary chemoRT versus Neoadjuvant chemoRT

12. Overall survival at 2 years similar between groups NeoAdjv: 39.9%; ChemoRT: 35.4% Median survival similar NeoAdjv: 16.4; ChemoRT: 14.9 n = 172 Neoadjuvant chemoRT Primary chemoRT Stahl M. et. al: J Clin Oncol 2005; 23:2310- 2317

13. Primary chemoRT versus Neoadjuvant chemoRT 2 year freedom from progression significantly better in surgery arm Neoadjv: 64%; ChemoRT: 40.7%; Hazard ratio for ChemoRT vs Neoadjv: 2.1, p=0.003 Neoadjuvant chemoRT Primary chemoRT Stahl M. et. al: J Clin Oncol 2005; 23:2310- 2317 n = 172

14. Tumor response found to be an independent prognostic factor in cases of SCC of the esophagus  Patients with tumor response had 3 year survival of >50% regardless of treatment group  Non-responders  After surgery: 3 year survival of 17.9%  After chemoRT group: 3 year survival of 9.4% Stahl M. et. al: J Clin Oncol 2005; 23:2310- 2317 Primary chemoRT versus Neoadjuvant chemoRT

16. 30Gy 46Gy 66Gy 45Gy 259 patients randomized: 129 arm A 130 to arm B Bedenne L et. al.: J Clin Oncol 2007; 25:1160-1168 57% responders to induction Primary chemoRT versus Neoadjuvant chemoRT

17. Similar two year survival Surgery: 34% ChemoRT: 40% Hazard ratio of ChemoRT vs Surgery: 0.9, p=0.44 Similar median survival Surgery: 17.7m ChemoRT: 19.3m Bedenne L et. al.: J Clin Oncol 2007; 25:1160-1168 Primary chemoRT versus Neoadjuvant chemoRT

18. More locoregional relapse after primary chemoradiation (p=0.0014)  Surgery: 33.6%  ChemoRT: 43.0% Primary chemoRT versus Neoadjuvant chemoRT

19. Morbidity and mortality

20. Treatment related mortality significantly higher in surgery group  12.8% vs 3.5% (p=0.03)  Stahl M. et. al: J Clin Oncol 2005; 23:2310-2317  9% vs 1% (p=0.002) in 3 months from randomization  Bedenne L et. al.: J Clin Oncol 2007; 25:1160-1168 Mortality from chemoRT due to neutropenic infections Mortality from surgery due to complications including leaking anastomosis, pneumonia

21. Mortality and morbidity Bedenne L et. al.: J Clin Oncol 2007; 25:1160-1168 SurgeryPrimary ChemoRT P Patients requiring palliation for dysphagia 31 (24%)60 (46.2%)0.0002 Dilatation24 (18.6%)18 (13.8%) Stenting7 (5.4%)42 (32.3%)

22. Quality of Life

23. Quality of life Bonnetain et. al.: Ann Onc 2006; 17: 827–834 Mean Spitzer index in Surgery arm Mean Spitzer index in Primary ChemoRT arm P Baseline8.358.940.14 First FU7.959.210.01 Second FU8.688.97 2-year follow-up subgroup

24. Conclusion Primary chemoRT for locally advanced Ca esophagus is at least as good as surgery alone  Overall survival  Locoregional control When compared to neo-adjuvant chemoRT followed by surgery, primary chemoRT provides  Possibly similar overall survival  Inferior locoregional control

25. Remaining questions Optimal timing and dosage of primary chemoRT  Variance between trials Role in Adenocarcinomas Role in early esophageal tumors Monitoring response - when to abandon?  Role of induction chemoRT

26. The End