Post-operative Radiotherapy for Esophageal Cancer

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Post-operative Radiotherapy for Esophageal Cancer

  1. 1. Post-operative Radiotherapy for Esophageal Cancer Parag Sanghvi, M.D., M.S.P.H. Department of Radiation Medicine Esophageal Care Conference
  2. 2. Background <ul><li>5 year OS for locally advanced esophageal cancers (T3 or above, N+) is dismal </li></ul>
  3. 3. Preoperative ChemoRT vs. Post-operative ChemoRT <ul><li>This has not been studied in a randomized trial head to head </li></ul><ul><li>Prefer pre-operative chemoRT </li></ul><ul><ul><li>Allows for tumor downstaging  R0 resection </li></ul></ul><ul><ul><li>Complete pathologic response improves survival </li></ul></ul><ul><ul><li>Feasibility and Patient compliance </li></ul></ul><ul><ul><li>? Earlier control of micro-metastatic disease </li></ul></ul><ul><li>Only 1 of 6 randomized trials have shown OS benefit to neoadjuvant chemoRT (Walsh) </li></ul>
  4. 4. Preoperative ChemoRT trials
  5. 5. Post-operative RT+/- Chemotherapy <ul><li>Data is primarily from Asia and Europe </li></ul><ul><li>Most randomized trials have looked at Surgery + RT vs. Surgery alone </li></ul><ul><li>No randomized trial has compared post-operative concurrent chemoRT to either chemotherapy or RT alone </li></ul>
  6. 6. Indications for Post-operative RT <ul><li>Standard Indications </li></ul><ul><ul><li>Positive Margins </li></ul></ul><ul><ul><li>Gross Residual Disease </li></ul></ul><ul><li>Less Clear </li></ul><ul><ul><li>+ LN </li></ul></ul><ul><ul><li>+ ECE on adenopathy </li></ul></ul>
  7. 7. Current NCCN Guidelines for Post-operative Therapy
  8. 8. Randomized Trials <ul><li>Teniere et al Surg Gynecol Obstet . Aug 1991; 173(2): 123-30 ( France ) </li></ul><ul><ul><li>S+ RT vs. S </li></ul></ul><ul><li>Fok et al Surgery . Feb 1993; 113(2) 138-47 ( Hong Kong ) </li></ul><ul><ul><li>S + RT vs. S </li></ul></ul><ul><li>Xiao et al The Annals of Thoracic Surgery Feb 2003; 75(2): 331-336 ( China ) </li></ul><ul><ul><li>LN +  S+ RT vs. S </li></ul></ul><ul><li>Macdonald et al NEJM . Sept 2001; 345:725-730 ( USA ) </li></ul><ul><ul><li>GE junction  S + CRT vs. S </li></ul></ul>
  9. 9. French trial – Post-operative Radiation for Esophageal SCCA <ul><li>221 patients treated with “curative” resection </li></ul><ul><li>Squamous cell histology; mid/distal location </li></ul><ul><li>Post-op RT 45-55 Gy vs. Observation </li></ul><ul><li>Post-op RT did not improve OS </li></ul><ul><li>5 y OS 19% (38% if node -; 7% if node + </li></ul><ul><li>Locoregional failure decreased after RT: 30 %  15% </li></ul><ul><li>Benefit significant in node negative patients: 35% LR failure vs. 10% </li></ul>
  10. 10. Hong Kong Trial – Postoperative RT for Esophageal cancer <ul><li>Single institution randomized trial, 130 patients </li></ul><ul><ul><li>Curative Resection 60 patients  30 S+ RT vs. 30 S </li></ul></ul><ul><ul><li>Palliative Resection 70 patients  35 S + RT vs. 35 S </li></ul></ul><ul><li>RT dose/technique unknown </li></ul>
  11. 11. Hong Kong Trial - Results <ul><li>Overall Median Survival, All patients </li></ul><ul><ul><li>S + RT 8.7 months vs. S 15.2 months (p=0.02) </li></ul></ul><ul><li>Local Recurrence, Palliative Surgery patients </li></ul><ul><ul><li>S+ RT 20% vs. S 46 % (p=0.04) </li></ul></ul><ul><li>Local Recurrence, Curative Surgery </li></ul><ul><ul><li>S+RT 10% vs. S 13% </li></ul></ul><ul><li>Complications </li></ul><ul><ul><li>S+RT 37% vs. S 6% (p<0.0001) </li></ul></ul><ul><li>Intra-thoracic recurrence, All patients </li></ul><ul><ul><li>S+RT 4 patients vs. S 13 patients (p=0.01) </li></ul></ul>
  12. 12. Chinese trial – Post-operative radiation for Esophageal SCCA <ul><li>Randomized to post-operative RT vs. observation; 495 patients  275 S, 220 S+ RT </li></ul><ul><li>Most of mid thoracic esophagus (67%), T3 (69%) and 48% had + LN </li></ul><ul><li>Margin status unknown </li></ul>
  13. 13. Chinese Trial – RT parameters <ul><li>RT </li></ul><ul><ul><li>Extended Field RT </li></ul></ul><ul><ul><ul><li>Included bilateral SCV, mediastinal and peri-gastric LN </li></ul></ul></ul><ul><ul><li>60 Gy </li></ul></ul>
  14. 14. Chinese Trial - Results <ul><li>5 y OS </li></ul><ul><ul><li>S+ RT 41.3 % vs. S 37.1 % (p=0.45) </li></ul></ul><ul><li>LN – </li></ul><ul><ul><li>S+RT 52.8 % vs. S 51% (p=0.95) </li></ul></ul><ul><li>LN+ </li></ul><ul><ul><li>S+RT 29.2 % vs. S 14.7% (p=0.07) </li></ul></ul><ul><li>Stage II </li></ul><ul><ul><li>S+ RT 50.3 % vs. S 51.3 % (p=0.63) </li></ul></ul><ul><li>Stage III OS </li></ul><ul><ul><li>S+ RT 35.1% vs. S 13.1 % (p=0.003) </li></ul></ul>
  15. 15. Chinese trial - Results Stage III
  16. 16. Chinese trial - Results LN + patients
  17. 17. Chinese Trial - Sites of Failure
  18. 18. Conclusions <ul><li>Post-operative RT improves OS in Stage III and potentially LN + patients </li></ul><ul><li>Post-operative RT decreases risk of intra-thoracic LN recurrence and anastomotic recurrence </li></ul>
  19. 19. Macdonald trial – Post-operative chemoRT for GE junction/stomach adenoCA <ul><li>Randomized to post-operative chemoradiation vs. observation </li></ul><ul><li>556 patients; 20% GE junction tumors </li></ul><ul><li>Stage IB – IV M0, negative margins </li></ul><ul><li>Adenocarcinoma histology </li></ul><ul><li>D2 dissection recommended </li></ul><ul><ul><li>10% D2; 36% D1; 54% D0 </li></ul></ul>
  20. 20. Macdonald Trial - Treatment Schema <ul><li>Chemotherapy  d 28 ChemoRT  2 cycles additional chemotherapy </li></ul><ul><li>Chemotherapy </li></ul><ul><ul><li>5FU + Leucovorin </li></ul></ul><ul><li>RT – 45 Gy/25 fx </li></ul><ul><ul><li>Tumor bed + Regional LN + 2 cm margin </li></ul></ul><ul><li>64% completed chemoRT as planned </li></ul>
  21. 21. Macdonald Trial – Tumor Characteristics
  22. 22. Macdonald Trial Results <ul><li>5 year Median Survival </li></ul><ul><ul><li>S+ CRT 36 months vs. S 27 months </li></ul></ul><ul><li>3 y OS </li></ul><ul><ul><li>S+ CRT 50% vs. S 41% (p= 0.005) </li></ul></ul><ul><li>3 y RFS </li></ul><ul><ul><li>S + CRT 48% vs. S 31% (p <0.001) </li></ul></ul>
  23. 23. Macdonald Trial – Overall Survival
  24. 24. Macdonald Trial – Relapse Free Survival
  25. 25. Macdonald Trial – Sites of Relapse
  26. 26. Macdonald Trial - Conclusions <ul><li>Add chemoRT for GE junction adenoCA </li></ul><ul><ul><li>T3 or higher </li></ul></ul><ul><ul><li>+ LN </li></ul></ul><ul><ul><li>+ margins, + residual disease </li></ul></ul><ul><ul><li>? Selected T2 cases </li></ul></ul>
  27. 27. Non Randomized Trials <ul><li>Liu HC et al. World J. Gastroenterology . 2005; 11(34): 5367-5372 </li></ul><ul><ul><li>S+ CRT vs. S + RT </li></ul></ul><ul><li>Bedard EL et al. Cancer Jun 2001; 91(12): 2423-2430 </li></ul><ul><ul><li>N1 patients  S + CRT vs. S </li></ul></ul>
  28. 28. Taiwan Study – Postoperative ChemoRT vs. RT for esophageal SCCA <ul><li>60 patients; 30 patients in each arm </li></ul><ul><li>T3/T4 N0/N1 M0 thoracic esophageal SCCA </li></ul><ul><li>Surgery included </li></ul><ul><ul><li>En-bloc esophagectomy – sub-total resection of esophagus with bilateral 10 cm adjacent soft-tissue margin </li></ul></ul><ul><ul><li>followed by proximal gastrectomy/porta hepatis LN dissection </li></ul></ul><ul><ul><li>Cervical LN sampling </li></ul></ul><ul><li>Prospectively enrolled into post-operative chemoRT vs. RT alone </li></ul>
  29. 29. Taiwan study – RT parameters <ul><li>Treatment started within 3 weeks of surgery </li></ul><ul><li>RT </li></ul><ul><ul><li>40 Gy AP/PA followed by 15-20 Gy 3 D boost </li></ul></ul><ul><ul><li>standard 1.8 Gy/fx </li></ul></ul><ul><ul><li>Margins </li></ul></ul><ul><ul><ul><li>Sup / Inf 5 cm </li></ul></ul></ul><ul><ul><ul><li>Elsewhere 3 cm </li></ul></ul></ul><ul><ul><li>Mean dose 58.32 Gy (50.4 – 59.4 Gy) </li></ul></ul>
  30. 30. Taiwan study - Chemotherapy <ul><li>Chemotherapy </li></ul><ul><ul><li>6 weekly cycles CDDP 30 mg/m2 during RT </li></ul></ul><ul><ul><li>4 weeks after chemoRT, additional adjuvant chemotherapy 4 cycles of CDDP 20mg/m2 + 5 FU 1000mg/m2 X 5 days bolus infusion </li></ul></ul>
  31. 31. Taiwan study - Patient Characteristics
  32. 32. Taiwan study - Patient Characteristics
  33. 33. Taiwan Study - Results <ul><li>ChemoRT </li></ul><ul><ul><li>30/30 received planned dose RT </li></ul></ul><ul><ul><li>15/30 received planned dose concurrent chemo; 10 received 4/6 weekly cycles; 5 received <4 cycles </li></ul></ul><ul><ul><li>15/30 received adjuvant chemotherapy </li></ul></ul><ul><li>RT </li></ul><ul><ul><li>24/30 received planned dose RT </li></ul></ul><ul><li>Median follow-up 18 months </li></ul>
  34. 34. Taiwan Study - Results <ul><li>ChemoRT </li></ul><ul><ul><li>Mean survival 31.9 months </li></ul></ul><ul><ul><li>3 y/o OS 70% </li></ul></ul><ul><ul><li>3 y/o LRF 40% </li></ul></ul><ul><ul><li>3 y/o DF 27% </li></ul></ul><ul><li>RT </li></ul><ul><ul><li>Mean survival 20.7 months </li></ul></ul><ul><ul><li>3 y/o OS 33.7% </li></ul></ul><ul><ul><li>3 y/o LRF 60% </li></ul></ul><ul><ul><li>3 y/o DF 57% </li></ul></ul><ul><li>Treatment modality and tumor grade were significant on multi-variate analysis </li></ul>
  35. 35. Taiwan Study - Results
  36. 36. Taiwan Study - Results
  37. 37. Taiwan Study - ChemoRT complications <ul><li>Complications </li></ul><ul><ul><li>Anastomotic Stricture 36% </li></ul></ul><ul><ul><li>Chronic Aspiration 33% </li></ul></ul><ul><ul><li>Pneumonia 20% </li></ul></ul>
  38. 38. Taiwan Study - Conclusions <ul><li>ChemoRT showed improved OS compared to RT alone in T3 or higher patients </li></ul><ul><li>Improved overall survival compared to historical data for surgery alone </li></ul>
  39. 39. Canadian Study – Postoperative chemoRT in patients with N+ esophageal cancer <ul><li>Retrospective review of N1 patients – chemo RT vs. surgery alone; 70 patients </li></ul><ul><li>39 pts to chemoRT arm vs. 31 patients to surgery alone; in final analysis 38 pts. ChemoRT & 28 pts. Surgery alone </li></ul><ul><li>Thoracic & GE junction tumors </li></ul><ul><li>AdenoCA & Squamous histology </li></ul><ul><li>T1-T4, all N1 </li></ul><ul><li>Transhiatal esophagectomy </li></ul>
  40. 40. Canadian Study - Treatment Schema <ul><li>2 cycles of chemotherapy  RT with 3 rd & 4 th cycle of chemotherapy </li></ul><ul><li>Chemotherapy </li></ul><ul><ul><li>CDDP 60 mg/m2 </li></ul></ul><ul><ul><li>Continuous infusion 5-FU </li></ul></ul><ul><ul><li>Epirubicin 50 mg/m2 in last 6 patients </li></ul></ul><ul><li>RT </li></ul><ul><ul><li>50 Gy (36 Gy AP/PA followed by 14 Gy 3D planning) </li></ul></ul>
  41. 41. Canadian Study - Patient Characteristics <ul><li>Patient characteristics and tumor characteristics well balanced between two groups </li></ul><ul><li>No data on # LN + or ECE status provided </li></ul>
  42. 42. Canadian Study –Tumor Characteristics
  43. 43. Canadian Study - Results <ul><li>Median follow-up 19 months </li></ul><ul><li>Surgery + ChemoRT </li></ul><ul><ul><li>Median DFS – 10.2 months </li></ul></ul><ul><ul><li>Local Recurrence 13% </li></ul></ul><ul><ul><li>Median Time to LR 22.2 months </li></ul></ul><ul><ul><li>Median OS 47.5 months </li></ul></ul><ul><ul><li>5 y OS 48% </li></ul></ul><ul><li>Surgery </li></ul><ul><ul><li>Median DFS – 10.6 months </li></ul></ul><ul><ul><li>Local Recurrence 35% </li></ul></ul><ul><ul><li>Median Time to LR 9.5 months </li></ul></ul><ul><ul><li>Median OS 14.1 months </li></ul></ul><ul><ul><li>5 y OS 0% </li></ul></ul>
  44. 44. Canadian Study – Overall Survival
  45. 45. Canadian Trial - Conclusion <ul><li>Benefit of ChemoRT in node + patients </li></ul>
  46. 46. Additional abstracts <ul><li>Kurtzman SM et al. (ASTRO 1995) </li></ul><ul><ul><li>192 patients </li></ul></ul><ul><ul><li>Esophageal adenoCA </li></ul></ul><ul><ul><li>Post-op RT with 5FU/Leucovorin & γ -Interferon </li></ul></ul><ul><ul><li>39% 3 y OS </li></ul></ul>
  47. 47. Additional abstracts <ul><li>Kang HJ et al (ASCO 1992) </li></ul><ul><li>Phase 2 trial </li></ul><ul><li>ChemoRT </li></ul><ul><ul><li>40-50 Gy </li></ul></ul><ul><ul><li>CDDP + 5 FU </li></ul></ul><ul><li>47% 20 month survival rate </li></ul><ul><li>93% LCR </li></ul>
  48. 48. What about post-op chemotherapy alone? <ul><li>2 randomized Japanese trials </li></ul><ul><ul><li>Ando N et al. J of Thoracic and Cardiovascular Surgery . 1997; 114;204-205 </li></ul></ul><ul><ul><ul><li>Randomized study; 205 patients </li></ul></ul></ul><ul><ul><ul><li>S + C vs. S alone </li></ul></ul></ul><ul><ul><ul><li>Chemo – 2 cycles of Cisplatin (70 mg./m2) + Vindesine </li></ul></ul></ul><ul><ul><ul><li>5 y OS S + C 48.1 % vs. S 44.9% (p = NS) </li></ul></ul></ul><ul><ul><li>Ando N et al. JCO. Dec 2003; 21(24): 4592-4596 </li></ul></ul><ul><ul><ul><li>Randomized study; 242 patients </li></ul></ul></ul><ul><ul><ul><li>Thoracic SCCA </li></ul></ul></ul><ul><ul><ul><li>S+C vs. S alone </li></ul></ul></ul><ul><ul><ul><li>Chemo – 2 cycles of Cisplatin (80 mg/m2) + 5 FU (800mg/m2/5 day infusion) </li></ul></ul></ul><ul><ul><ul><li>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) </li></ul></ul></ul><ul><ul><ul><li>Significant nodal failure in S + C patients; role of RT?? </li></ul></ul></ul>
  49. 49. Overall Conclusions <ul><li>Treatment decisions need to be individualized </li></ul><ul><li>Pre-operative chemoRT preferable when needed </li></ul><ul><ul><li>Recognize the morbidity of neoadjuvant chemoRT; consider surgery first in resectable patients with marginal performance status </li></ul></ul><ul><li>Post-operative chemoRT for </li></ul><ul><ul><li>+ margins, residual gross disease </li></ul></ul><ul><ul><li>+ LN </li></ul></ul><ul><ul><li>locally advanced disease (T3 or higher) with – margins, - LN? </li></ul></ul>
  50. 50. Acknowledgements <ul><li>Dr. John Holland </li></ul><ul><li>Dr. Charles Thomas </li></ul><ul><li>Dr. Tasha Mcdonald </li></ul>

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