Postoperative Radiotherapy for Esophageal Cancer

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 345725-730
  (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 (p0.02)
• Local Recurrence, Palliative Surgery patients
• S RT 20 vs. S 46 (p0.04)
• Local Recurrence, Curative Surgery
• SRT 10 vs. S 13
• Complications
• SRT 37 vs. S 6 (plt0.0001)
• Intra-thoracic recurrence, All patients
• SRT 4 patients vs. S 13 patients (p0.01)

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 (p0.45)
• LN
• SRT 52.8 vs. S 51 (p0.95)
• LN
• SRT 29.2 vs. S 14.7 (p0.07)
• Stage II
• S RT 50.3 vs. S 51.3 (p0.63)
• Stage III OS
• S RT 35.1 vs. S 13.1 (p0.003)

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 lt0.001)

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 lt4 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 114204-205
• 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
• SC vs. S alone
• Chemo 2 cycles of Cisplatin (80 mg/m2) 5 FU
  (800mg/m2/5 day infusion)
• 5 y OS 61 vs. 52 (p0.13)5 y DFS 55 vs. 45
  (p0.04) 5 y DFS in N patients 52 vs. 38
  (p0.04)
• 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