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Post-operative Radiotherapy for Esophageal Cancer

Post-operative Radiotherapy for Esophageal Cancer. Parag Sanghvi, M.D., M.S.P.H. Department of Radiation Medicine Esophageal Care Conference 3/26/2007. Background. 5 year OS for locally advanced esophageal cancers (T3 or above, N+) is dismal. Preoperative ChemoRT vs. Post-operative ChemoRT.

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Post-operative Radiotherapy for Esophageal Cancer

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  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 SurgeryFeb 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. CancerJun 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

  32. 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

  36. 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 3rd & 4th 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

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