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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