1. Post-operative Radiotherapy for Esophageal Cancer Parag Sanghvi, M.D., M.S.P.H. Department of Radiation Medicine Esophageal Care Conference 3/26/2007

2. Background 5 year OS for locally advanced esophageal cancers (T3 or above, N+) is dismal

3. Preoperative ChemoRT vs. Post- operative ChemoRT This has not been studied in a randomized trial head to head Prefer pre-operative chemoRT  Allows for tumor downstaging  R0 resection  Complete pathologic response improves survival  Feasibility and Patient compliance  ? Earlier control of micro-metastatic disease Only 1 of 6 randomized trials have shown OS benefit to neoadjuvant chemoRT (Walsh)

4. Preoperative ChemoRT trials

5. Post-operative RT+/- Chemotherapy Data is primarily from Asia and Europe Most randomized trials have looked at Surgery + RT vs. Surgery alone No randomized trial has compared post- operative concurrent chemoRT to either chemotherapy or RT alone

6. Indications for Post-operative RT Standard Indications  Positive Margins  Gross Residual Disease Less Clear  + LN  + ECE on adenopathy

7. Current NCCN Guidelines for Post-operative Therapy

8. Randomized Trials Teniere et al Surg Gynecol Obstet. Aug 1991; 173(2): 123-30 (France)  S+ RT vs. S Fok et al Surgery. Feb 1993; 113(2) 138-47 (Hong Kong)  S + RT vs. S Xiao et al The Annals of Thoracic Surgery Feb 2003; 75(2): 331-336 (China)  LN +  S+ RT vs. S Macdonald et al NEJM. Sept 2001; 345:725-730 (USA)  GE junction  S + CRT vs. S

9. French trial – Post-operative Radiation for Esophageal SCCA 221 patients treated with “curative” resection Squamous cell histology; mid/distal location Post-op RT 45-55 Gy vs. Observation Post-op RT did not improve OS 5 y OS 19% (38% if node -; 7% if node + Locoregional failure decreased after RT: 30 %  15% Benefit significant in node negative patients: 35% LR failure vs. 10%

10. Hong Kong Trial – Postoperative RT for Esophageal cancer Single institution randomized trial, 130 patients  Curative Resection 60 patients  30 S+ RT vs. 30 S  Palliative Resection 70 patients  35 S + RT vs. 35 S RT dose/technique unknown

11. Hong Kong Trial - Results Overall Median Survival, All patients  S + RT 8.7 months vs. S 15.2 months (p=0.02) Local Recurrence, Palliative Surgery patients  S+ RT 20% vs. S 46 % (p=0.04) Local Recurrence, Curative Surgery  S+RT 10% vs. S 13% Complications  S+RT 37% vs. S 6% (p<0.0001) Intra-thoracic recurrence, All patients  S+RT 4 patients vs. S 13 patients (p=0.01)

12. Chinese trial – Post-operative radiation for Esophageal SCCA Randomized to post-operative RT vs. observation; 495 patients  275 S, 220 S+ RT Most of mid thoracic esophagus (67%), T3 (69%) and 48% had + LN Margin status unknown

13. Chinese Trial – RT parameters RT  Extended Field RT Included bilateral SCV, mediastinal and peri- gastric LN  60 Gy

14. Chinese Trial - Results 5 y OS  S+ RT 41.3 % vs. S 37.1 % (p=0.45) LN –  S+RT 52.8 % vs. S 51% (p=0.95) LN+  S+RT 29.2 % vs. S 14.7% (p=0.07) Stage II  S+ RT 50.3 % vs. S 51.3 % (p=0.63) Stage III OS  S+ RT 35.1% vs. S 13.1 % (p=0.003)

15. Chinese trial - Results Stage III

16. Chinese trial - Results LN + patients

17. Chinese Trial - Sites of Failure

18. Conclusions Post-operative RT improves OS in Stage III and potentially LN + patients Post-operative RT decreases risk of intra- thoracic LN recurrence and anastomotic recurrence

19. Macdonald trial – Post-operative chemoRT for GE junction/stomach adenoCA Randomized to post-operative chemoradiation vs. observation 556 patients; 20% GE junction tumors Stage IB – IV M0, negative margins Adenocarcinoma histology D2 dissection recommended  10% D2; 36% D1; 54% D0

20. Macdonald Trial - Treatment Schema Chemotherapy  d 28 ChemoRT  2 cycles additional chemotherapy Chemotherapy  5FU + Leucovorin RT – 45 Gy/25 fx  Tumor bed + Regional LN + 2 cm margin 64% completed chemoRT as planned

21. Macdonald Trial – Tumor Characteristics

22. Macdonald Trial Results 5 year Median Survival  S+ CRT 36 months vs. S 27 months 3 y OS  S+ CRT 50% vs. S 41% (p= 0.005) 3 y RFS  S + CRT 48% vs. S 31% (p <0.001)

23. Macdonald Trial – Overall Survival

24. Macdonald Trial – Relapse Free Survival

25. Macdonald Trial – Sites of Relapse

26. Macdonald Trial - Conclusions Add chemoRT for GE junction adenoCA  T3 or higher  + LN  + margins, + residual disease  ? Selected T2 cases

27. Non Randomized Trials Liu HC et al. World J. Gastroenterology. 2005; 11(34): 5367-5372  S+ CRT vs. S + RT Bedard EL et al. Cancer Jun 2001; 91(12): 2423-2430  N1 patients  S + CRT vs. S

28. Taiwan Study – Postoperative ChemoRT vs. RT for esophageal SCCA 60 patients; 30 patients in each arm T3/T4 N0/N1 M0 thoracic esophageal SCCA Surgery included  En-bloc esophagectomy – sub-total resection of esophagus with bilateral 10 cm adjacent soft-tissue margin  followed by proximal gastrectomy/porta hepatis LN dissection  Cervical LN sampling Prospectively enrolled into post-operative chemoRT vs. RT alone

29. Taiwan study – RT parameters Treatment started within 3 weeks of surgery RT  40 Gy AP/PA followed by 15-20 Gy 3 D boost  standard 1.8 Gy/fx  Margins Sup / Inf 5 cm Elsewhere 3 cm  Mean dose 58.32 Gy (50.4 – 59.4 Gy)

30. Taiwan study - Chemotherapy Chemotherapy  6 weekly cycles CDDP 30 mg/m2 during RT  4 weeks after chemoRT, additional adjuvant chemotherapy 4 cycles of CDDP 20mg/m2 + 5 FU 1000mg/m2 X 5 days bolus infusion

31. Taiwan study - Patient Characteristics

33. Taiwan Study - Results ChemoRT  30/30 received planned dose RT  15/30 received planned dose concurrent chemo; 10 received 4/6 weekly cycles; 5 received <4 cycles  15/30 received adjuvant chemotherapy RT  24/30 received planned dose RT Median follow-up 18 months

34. Taiwan Study - Results ChemoRT  Mean survival 31.9 months  3 y/o OS 70%  3 y/o LRF 40%  3 y/o DF 27% RT  Mean survival 20.7 months  3 y/o OS 33.7%  3 y/o LRF 60%  3 y/o DF 57% Treatment modality and tumor grade were significant on multi-variate analysis

35. Taiwan Study - Results

37. Taiwan Study - ChemoRT complications Complications  Anastomotic Stricture 36%  Chronic Aspiration 33%  Pneumonia 20%

38. Taiwan Study - Conclusions ChemoRT showed improved OS compared to RT alone in T3 or higher patients Improved overall survival compared to historical data for surgery alone

39. Canadian Study – Postoperative chemoRT in patients with N+ esophageal cancer Retrospective review of N1 patients – chemo RT vs. surgery alone; 70 patients 39 pts to chemoRT arm vs. 31 patients to surgery alone; in final analysis 38 pts. ChemoRT & 28 pts. Surgery alone Thoracic & GE junction tumors AdenoCA & Squamous histology T1-T4, all N1 Transhiatal esophagectomy

40. Canadian Study - Treatment Schema 2 cycles of chemotherapy  RT with 3 rd & 4 th cycle of chemotherapy Chemotherapy  CDDP 60 mg/m2  Continuous infusion 5-FU  Epirubicin 50 mg/m2 in last 6 patients RT  50 Gy (36 Gy AP/PA followed by 14 Gy 3D planning)

41. Canadian Study - Patient Characteristics Patient characteristics and tumor characteristics well balanced between two groups No data on # LN + or ECE status provided

42. Canadian Study –Tumor Characteristics

43. Canadian Study - Results Median follow-up 19 months Surgery + ChemoRT  Median DFS – 10.2 months  Local Recurrence 13%  Median Time to LR 22.2 months  Median OS 47.5 months  5 y OS 48% Surgery  Median DFS – 10.6 months  Local Recurrence 35%  Median Time to LR 9.5 months  Median OS 14.1 months  5 y OS 0%

44. Canadian Study – Overall Survival

45. Canadian Trial - Conclusion Benefit of ChemoRT in node + patients

46. Additional abstracts Kurtzman SM et al. (ASTRO 1995)  192 patients  Esophageal adenoCA  Post-op RT with 5FU/Leucovorin & γ- Interferon  39% 3 y OS

47. Additional abstracts Kang HJ et al (ASCO 1992) Phase 2 trial ChemoRT  40-50 Gy  CDDP + 5 FU 47% 20 month survival rate 93% LCR

48. What about post-op chemotherapy alone? 2 randomized Japanese trials  Ando N et al. J of Thoracic and Cardiovascular Surgery. 1997; 114;204-205 Randomized study; 205 patients S + C vs. S alone Chemo – 2 cycles of Cisplatin (70 mg./m2) + Vindesine 5 y OS S + C 48.1 % vs. S 44.9% (p = NS)  Ando N et al. JCO. Dec 2003; 21(24): 4592-4596 Randomized study; 242 patients Thoracic SCCA S+C vs. S alone Chemo – 2 cycles of Cisplatin (80 mg/m2) + 5 FU (800mg/m2/5 day infusion) 5 y OS 61 vs. 52 % (p=0.13);5 y DFS 55% vs. 45% (p=0.04); 5 y DFS in N + patients 52% vs. 38% (p=0.04) Significant nodal failure in S + C patients; role of RT??

49. Overall Conclusions Treatment decisions need to be individualized Pre-operative chemoRT preferable when needed  Recognize the morbidity of neoadjuvant chemoRT; consider surgery first in resectable patients with marginal performance status Post-operative chemoRT for  + margins, residual gross disease  + LN  locally advanced disease (T3 or higher) with – margins, - LN?

50. Acknowledgements Dr. John Holland Dr. Charles Thomas Dr. Tasha Mcdonald