2. What is the optimal pre-op therapy for esophagus and GE junction cancers?
Michael G. Haddock M.D.
Mayo Clinic
Rochester, MN

3. Esophageal and GEJ Cancer
CT  S or
CT/RT  S

4. Proposition
Chemoradiation is preferred over chemotherapy alone as preop therapy for esophageal and GE junction cancers

5. Assumptions Stage: T2-4, N0 or N+, M0 Performance status 0-1
Good candidate for surgery medically
Surgery is indicated
Locoregional control is important
Can’t cure patient unless locoregional disease is eliminated

9. What is the evidence for preop chemoradiation as a strategy?

10. Esophageal Cancer: Preop RT + CT Dublin Trial
113 pts, all ACA
surgical resection alone
40 Gy / 15 fractions
5FU, 15 mg/kg/day x 5 d, weeks 1, surgery
CDDP, 75 mg/m2 weeks 1,6 R
Walsh, NEJM 335: , 1996.

11. Esophageal Cancer: Preop RT + CT Dublin Trial Results
hospital median 3 yr 5 yr
treatment mortality survival S S*
surgery alone (55) 4% 12 mo. 6% 5%
preop RT/CT (58) 9% 17 mo. 32% 29%
p = 0.01
*crude survival, all patients followed > 5 yrs
Walsh, NEJM 335: , 1996 and Dis Esophagus 15: , 2002

12. Esophageal Cancer: Preop RT + CT Dublin Trial Results
Survival (%)
Multimodal therapy (n=58)
Surgery alone (n=55)
Months
Walsh et al: NEJM 335:465, 1996

13. Esophageal Cancer: Preop RT + CT CALGB C-9781
500 pts/ 5 yrs
SQC or ACA
T1-3 NxM0
Resectable
Not more than
2 cm into cardia
surgery alone
5-FU + CDDP Gy R
followed by surgery
Closed Early (56 pts) due to poor accrual
Tepper, JCO 2008;26:

14. CALGB 9781 Overall survival (%) Years from study entry P<0.008
Trimodality (30)
Surgery (26)
Years from study entry
Adapted from Krasna et al: ASCO GI Symposium, 2006 Original:

15. TROG Phase III trial Preop CT/RT vs S alone
Med S LRR
Surgery mo %
35 Gy/15
CDDP  S mo 21%
5-FU
257 pts
T1-3N0-1
37% SQC R
Burmeister, Lancet Oncology 2005; 6:659-68

16. Adapted from Burmeister, Lancet Oncology 2005; 6:659-68

17. Adapted from Burmeister, Lancet Oncology 2005; 6:659-68

18. FFCD 9901 Preop CT/RT vs S alone
195 pts
30 centers
9 years
SQC 137
ACA 57
3-yr S yr S Hosp. mort.
Surgery % % 3.4%
45 Gy
CDDP S 48% 41% 11.1%
5-FU R
P = 0.94
P = .05
Mariette, JCO 32: , 2014

19. FFCD 9901 Preop CT/RT vs S alone
195 pts
30 centers
9 years
SQC 137
ACA 57
LRR DM
Surgery % %
45 Gy
CDDP S 15% 23%
5-FU R
P = .02
P = .31
Mariette, JCO 32: , 2014

20. Kaplan-Meier estimates of overall survival by treatment arm measured from study entry to death resulting from any cause.
Mariette C et al. JCO 2014;32:
©2014 by American Society of Clinical Oncology

21. CROSS Phase III trial Preop CT/RT vs S alone
Med S 5-yr S
Surgery 24 mos 34%
41.4 Gy
CBDCA S 49 mos 47%
paclitaxel
366 pts
T2-3N0-1
84 SQC
275 ACA R
P = 0.003
pCR 23% ACA
49% SQC
Hospital mortality 4% in both arms
Van Hagen, N Eng J Med 2012;366:

22. CROSS Phase III trial Preop CT/RT vs S alone
Adapted from Van Hagen, N Eng J Med 2012;366:

23. CROSS Phase III trial Preop CT/RT vs S alone
Adapted from Van Hagen, N Eng J Med 2012;366:

24. CROSS Phase III trial Preop CT/RT vs S alone
LRR peritoneal heme mets
Surgery % % 35%
41.4 Gy
Carbo S 14%* 4% 29%
paclitaxel
374 pts
T2-3N0-1
90 SQC
282 ACA R
P < .001
P < .001
P = .025
*Relapse in RT fields: 5%
V. Oppedijk, JCO 2014;32:

25. Preoperative Chemoradiation Summary
Study
LR Control Benefit
Survival Benefit
Walsh
Not reported
Yes
CALGB 9781
TROG
Yes, in SQC
FFCD 9901
Not significant
CROSS

26. What is the evidence for preop chemotherapy without radiation as a strategy?

27. Esophageal Cancer: Neoadjuvant Chemo MRC-OE02
802 pts, resectable
SQC (247)
ACA (533)
Med S 2 yr S
5-FU Surgery 17 mo 43%
CDDP
Surgery 13.5 mo 34% R
P = 0.004
Preoperative radiotherapy allowed (9%), same on both arms
MRC Lancet 359: , 2002

28. MRC-OE02 Survival (%) Years CS P=0.004 S Pt at risk (events)
Adapted from MRC Lancet 359: , 2002

29. Esophageal Cancer Neoadjuvant Chemo: INT 0113, RTOG 8911
Med S 2 yr S LF
16.1 mo 38% 27%
16.8 mo 40% 29%*
Preop*
CDDP
5-FU x3
Surgery R
443 pts
207 SQC
236 ACA
*1.5% neutropenic sepsis deaths
*29% LF in R0, 41% in R1
Kelsen, NEJM339:1979, 1998

30. Esophageal Cancer Neoadjuvant Chemo: INT 0113, RTOG 8911
Overall survival (%)
Surgery (n=234)
Chemotherapy plus surgery (n=233)
Years
No. of patients at risk
Chemotherapy surgery
Surgery

31. Chemotherapy compared to Chemoradiotherapy?

32. Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) T3-4 GE junction ACA
Arm A
PLF I
PLF II
PLF III (3 weeks)
Surgery
Week 1 6 7 13 14 17
20-21
PLF I
PLF II
15 x 2 Gy in 3 weeks
Surgery
PE (1 week)
Arm B
PLF: Cisplatin 50mg/m2, 1h, d 1, 15, 29. Leukovorin/5-FU 500 mg/m2 d 1, 8, 15, 22, 29, 36
PE: Cisplatin 50 mg/m2, 1h, d Etoposide 80 mg/m2, 1h, d 3-5
Stahl, JCO 27:851, 2009

33. Phase III Study of Preoperative ChemoRT or Chemo in GE Junction ACA (POET) T3-4 GE junction ACA
Endpoint CT alone CT + RT
pCR 2% 16%
ypN0 38% 64%
3-yr Survival 28% 47%
Stahl, JCO 27:851, 2009

34. Adapted from Stahl, JCO 27:851, 2009

35. Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Overall Survival
Strata
5FU/CDDP  S (2% pCR)
CTCDDP/etop/ Gy/15S (16% pCR)
Survival
Arm B (60)
P=0.07
Arm A (59)
Years
Adapted from Stahl, JCO 27:851, 2009

36. Survival distribution function
Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Freedom from Local Tumor Progression
Strata
Randomized Arm A
Censored randomized Arm A
Randomized Arm B
Censored randomized Arm B
Survival distribution function
Arm B
Arm A
P=0.06
Years
Adapted from Stahl, JCO 27:851, 2009

37. Esophageal Cancer Locoregional Relapse Phase III trial results
Surgery alone
CT  Surgery
CT/RT  Surgery
FNCLCC/FFCD
26%
24%
INT 0113
29%
27%
OE02
23%
TROG
40%
21%
FFCD 9901
15%
CROSS
36%
14%
POET
41%

38. Australian Meta-Analysis Chemotherapy and RT vs Surgery Alone
Study
Nygaard
Apinop
LePrise
Bosset
Urba
Walsh
Burmeister
Lee
All (published)
Tepper
All
0.2
0.5 1 2 5
Favors
chemoradiotherapy
surgery alone
Val Gebski et al: Lancet Oncol 8:226, 2007 CP

39. Australian Meta-Analysis Chemotherapy vs Surgery Alone
Study
Roth
Nygaard
Maipang
Schlag
Law
Kelsen
Ancona
MRC
All
0.2
0.5 1 2 5
Favors
chemotherapy
Favors
surgery alone
Val Gebski et al: Lancet Oncol 8:226, 2007 CP

40. Australian Meta-Analysis
Hazard ratio for all cause mortality for preoperative chemoRT was 0.81 (P = )
Hazard ratio for all cause mortality for preoperative chemotherapy was 0.90 (P = 0.05)
Val Gebski, et al. Lancet Oncol 8:226-34, 2007

41. Australian Meta-Analysis Update
Compared 12 CT/RT trials and 7 CT trials
All cause mortality HR for CT/RT vs. CT alone: (p= 0.07)
Sjoquist, Lancet Oncol 12:681-92, 2011

42. Preop CT/RT for Esophageal Ca Conclusions
5 Phase III trials show benefit in S or LC or both compared to S alone
CT alone trials mixed results
CT/RT better than CT in direct comparison (POET)
Meta-analysis suggests CT/RT better than CT alone