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Post-operative Radiotherapy for Esophageal Cancer

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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 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

    16. Chinese trial - Results

    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

    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 & ?-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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