Neoadjuvant therapy, including chemotherapy and chemoradiotherapy, is being investigated for the treatment of esophageal cancer. While some studies have shown improved survival rates with neoadjuvant therapy compared to surgery alone, the evidence from clinical trials remains conflicting. Achieving a complete pathological response after neoadjuvant therapy is associated with significantly improved long-term survival. Further research is still needed to determine the optimal neoadjuvant approaches and to improve outcomes by reducing distant metastases.

1. Neoadjuvant Therapy for
Esophageal Cancer
Daniel Morgensztern, M.D.

2. Overview
• Background
• Neoadjuvant radiotherapy
• Neoadjuvant chemotherapy
• Neoadjuvant chemoradiotherapy
• Neoadjuvant or definitive chemoradiotherapy
• The significance of pathologic CR
• Strategies to improve outcome
• Conclusions

3. Epidemiology
Worldwide
Worldwide estimates for 2000
• Eight most common cancer
with 412,000 new cases
• Sixth most common cause of
cancer death with 338,000
deaths
• 2002 update
462,000 new cases
386,000 deaths
Parkin DM, Lancet Oncol 2001; 2: 533-543
Parkin DM, CA Cancer J Clin. 2005;55:74-108

4. Epidemiology
US
US estimates for 2005
• 14,520 new cases
- 11,220 male
- 3,300 female
• 13,570 deaths
Jemal A CA Cancer J Clin. 2005;55:10-30

5. AJCC Staging
T Stage

6. AJCC Staging
N stage

7. AJCC Staging and Prognosis After Complete
Surgical Removal of the Tumor
Ezinger PC, N Engl J Med 2003; 349:2241-2252

8. Neoadjuvant Radiotherapy
Rationale
• Decrease tumor size with potential increase in resectability
• Improve local control
• Decrease the number of viable cells with possible minimization of
intraoperative spilling
Disadvantages
• No effect in micrometastatic disease
• Delay in definitive therapy

9. Neoadjuvant Radiotherapy
Randomized Trials
Study Patients Dose of RT Median survival (months) 5-year survival (%) p Value
Launois (1981) RT + S 62
S 47
40 Gy 10
12
10
12
NS
Gignoux (1988) RT + S 115
S 114
33 Gy 48
45
10
9
NS
Wang (1989) RT + S 104
S 102
40 Gy NA
NA
35
30
NS
Arnott (1992) RT + S 90
S 86
20 Gy 8
8
9
17
NS
Fok (1994) RT + S 58
S 50
35-53 Gy 11
22
10
16
NS

10. Neoadjuvant Radiotherapy
Meta-analysis
Oesophageal Cancer Collaborative Group
- 5 trials including 1147 patients
- Increased 2-year survival from 30% to 34% (95% CI 0-9%)
- Increased 5-year survival from 15% to 18% (95% CI 0-8%)
Arnott SJ, Int J Radiat Oncol Biol Phys 1998; 41: 579-583
Arnott SJ, Cochrane Database Syst Rev 2000; 4: CD001799

11. Neoadjuvant chemotherapy
Rationale
• Downstage of the disease with potential increase in resectability
• Improvement in local control
• Eradication of micrometastatic disease
• Pathologic evaluation of treatment response with possible selection of adjuvant
therapy
Disadvantages
• Delay in definitive therapy with risk of disease spreading
• Limited efficacy of the available chemotherapeutic agents

12. Neoadjuvant chemotherapy
Randomized Trials
Study (year) Patients Chemotherapy pCR (%) Median
Survival (mo)
5-year
Survival (%)
P value
Roth (1988) C + S 19
S 20
Neo: C,Vin, Bleo
Adjuvant: C,
Vin
NA 9
9
NA
NA
NS
Nygaard (1992) C + S 50
S 41
C, Bleo NA 8
8
3-y 3
9
NS
Ancona (2001) C + S 47
S 47
CF X 2 or 3 13% 25
24
34
22
NS
Schlag (1992) C + S 22
S 24
CF X 3 NA 10
10
NA NS
INT 0113 (1998) C + S 213
S 227
Neo CF X 3
Adj CF X 2
2.5% 14.9
16.1
2 y 35
37
NS
MRC (2002) C + S 400
S 402
CF X 2 4% 16.8
13.3
2 y 43
34
P = 0.004

13. Neoadjuvant chemotherapy
INT 0113 and MRC Trials
INT (S) INT (CS) MRC (S) MRC (CS)
Patients
S (%)/A (%)
227
47/53
213
46/54
401
31/67
400
31/66
Chemotherapy ----------- C 100 D1, F 1000 D1-5
q4wX3
Adjuvant C 75 F 1000 X 2
------------ C 80 D1, F 1000 D1-4 q3wX2
Percentage receiving all
neoadjuvant therapy
----------- 71 ------------ 90
Surgery (%)
R0 (%)
92
59
80
62
97
54
92
60
pCR ----------- 2.5% ------------ 4%
Median time to surgery
(days)
9 93 16 63
Median survival (months) 16.2 14.9 13.3 16.8
2-year survival (%) 37 35 34 43

14. Neoadjuvant chemotherapy
Meta-analysis
Cochrane Database 2003
• 11 Randomized trials involving 2051 patients
• Clinical relevance based on median survival and 1 to 5
year survival
• When specific survival was not available, it was
calculated from the published survival curves
- Pooled response rate to chemotherapy was about 36%
with 3% pCR
- No difference in survival at 1 and 2 years
- Survival advantage starts at 3 years and reaches
statistical significance at 5 years
Cochrane Database Syst Rev 2003; 4: CD001556

15. Neoadjuvant chemotherapy
MAGIC Trial
Cunningham ASCO 2005

16. Neoadjuvant chemotherapy
MAGIC Trial
• Overall, both median survival (24 m vs 20 m) and
5-year OS (36 vs 23%) favored neoadjuvant
therapy
• On multivariate analysis, treatment effect was
unchanged after adjustment for primary site
• Perioperative chemotherapy significantly
increased both PFS and OS in patients with gastric
or lower esophageal cancer

17. Neoadjuvant Chemoradiotherapy
Rationale
• Combine the benefits from both therapeutic modalities: Downstage of the
tumor facilitating surgical resection and eradication of micrometastatic disease
• Increase the number of pathologic complete remissions which may translate
into improved survival
Disadvantages
• Patients may not undergo surgery due to toxicity or tumor progression
• Increased post-operative mortality

18. Neoadjuvant Chemoradiotherapy
Non-Randomized Trials
• 46 trials from 1981 to 1999
• 2704 patients – 69% SCC, 31% Adenocarcinoma
• RT dose from 30 to 60 Gy
• Majority of studies used 5-FU and cisplatin
• Resection rate 74%
• Pathologic CR: 24% (32% surgical patients)
• Patterns of recurrence after surgical resection
- Locoregional 9%
- Distant 31%
- Both 6%
Geh JI, Br J Surg 2001; 88:338-356.

19. Neoadjuvant Chemoradiotherapy
Randomized Trials
Study Patients Histology Chemotherapy
RT
Surgical
mortality
(%)
pCR (%) Median
Survival (mo)
3-year survival
(%)
P value
Nygaard
(1992)
S 41
CS 47
S Cis + Bleo
35 Gy
13
24
NA 7.5
7.5
9
17
NS
Le Prise (1994) S 45
CS 41
S Cis + 5-FU
20 Gy
7
8.5
10 10
10
14
19
NS
Apinop (1994) S 34
CS 35
S Cis + 5-FU
40 Gy
15
14
7
10
20
26
NS
Walsh (1996) S 55
CS 58
A Cis + FU
40 Gy
4
8
22 11
16
6
32
P = 0.01
Law (1998) S 30
CS 30
S Cis + 5-FU
40 Gy
0
0
25 27
26
NA
NA
NS
Bosset (1997) S 139
CS 143
S Cis
37 Gy
4
12.3
26 19
19
37
39
NS
Urba (2001) S 50
CS 50
S (25%)
A (75%)
Cis + 5-Fu + Vin
45 Gy
2
7
28 18
17
16
30
NS
Burmeister
(2002)
S 128
CS 128
S (36%)
A (61%)
Cis + 5-FU
35 Gy
NA 15% 22
19
NA
NA
NS

20. Neoadjuvant Chemoradiotherapy
Meta-analyses
Urschel J, Am J Surg 2003; 185: 538-543
- Neoadjuvant chemoradiation improves 3-year survival, with more
significant benefit in the concurrent studies (OR 0.45, 95% CI 0.26
to 0.79, p = 0.005)
- Decrease LR but not distant recurrences
Fiorica F, Gut 2004;53: 925-930
- Neoadjuvant chemoradiotherapy significantly reduces the 3-year
mortality rate (OR 0.53, 95% CI 0.26 to 0.72, p = 0.03)
- Risk of postoperative mortality is higher in the neoadjuvant
group ( OR 2.10, 95% CI 1.18-3.73, p = 0.01)
Greer SE, Surgery 2005; 137: 172-177
- Neoadjuvant chemoradiotherapy is associated with a small, non-
statistically significant improvement in overall survival (RR of
death in neoadjuvant group 0.86, 95% CI 0.74 to 1.01, p = 0.07)
Malthaner RA, BMC Med 2004; 2: 35
A significant difference in the risk of mortality at 3-years favors
neoadjuvant chemoradiation (RR 0.87, 95% CI 0.80-0.96, p =0.004)
*None of the meta-analysis included Burmeister’s
study, which has been recently published (Lancet
Oncol 2005) and at that time was available only in
abstract form

21. The Role of Surgery after
Chemoradiotherapy
• The 5-year survival for chemoradiotherapy in
patients with unresectable locally advanced
esophageal cancer was 26% in the RTOG 85-01
trial
• The subsequent INT 0123 showed a 2-year survival
of 40% in the control standard-dose RT arm
• These results are similar to those achieved with
surgery alone or neoadjuvant chemoratiotherapy
followed by surgery
Cooper JS, JAMA 1999; 281: 1623-1627
Minsky BD, J Clin Oncol 2002; 20: 1167-1174
INT 0123

22. The Role of Surgery after
Chemoradiotherapy
FFCD 9102 Bedenne ASCO 2002 (abstract # 519)
FC X 2 + RT
Responders randomized to S or additional CRT
S CRT
2-year OS 34% 40% OR 0.91, p = 0.56
Median survival 17.7 m 19.3m
• No significant difference in survival
• Surgery was associated with improved local control
- Decreased use of stent (13% versus 27% ; p = 0.005)
- Decrease use of dilations (22% versus 32% ; p = 0.07)

23. The Role of Surgery after
Chemoradiotherapy
GOCSG Stahl M, J Clin Oncol 2005; 23: 2310-2317
FLEP X 3 → EP + 40 Gy → surgery (89 patients)
FLEP X 3 → EP + > 66Gy (88 patients)
S CRT
3-year OS 31.3% 24.4%
Median survival 16.4 m 14.9 m
- CRT resulted in equivalent survival with preserved
esophagus
- Surgery significantly increased local control
- Survival curves appear to spread after 3 years but without
reaching statistical significance
- Patients responding to induction therapy appear to have
good prognosis regardless of surgical intervention
OS
S
CRT
FLRP
S
CRT

24. Pathologic CR
• Pathologic CR in randomized clinical trials
- Neoadjuvant chemotherapy – 2.5% to 15%
- Neoadjuvant chemoradiotherapy – 10% to 28%
• Several trials have demonstrated improved survival in patients
achieving pCR

25. Pathologic CR
Study Patients who
underwent surgery
Median survival (mo) Survival (%) P value
Urba (2001) pCR 14
No pCR 36
49.7
12
3y 64
19
P = 0.01
Chirieac (2005) pCR 77
No pCR 158
133
10.5 to 38.1
5y 65
29
P = 0.003
Swisher (2005) pCR 86
PR 98
> 50% Residual 53
3y 74
54
24
P < 0.001
Berger (2005) pCR 42
PR 13
No response 76
50
49
25
5y 48
34
15
P = 0.015

26. New Strategies
• Incorporation of new chemotherapy agents
Taxanes, irinotecan, oxaliplatin
• Addition of a targeted agent
- COX-2 inhibitors, EGFR inhibitors, bevacizumab
• Intensification of neoadjuvant therapy
- Triplets with concomitant RT (CF + taxane)
- Triplets without RT (ECF, CF + taxane)
• Induction chemotherapy followed by concomitant chemoratiotherapy

27. Conclusions
• Surgery remains the mainstay for a curative approach in esophageal cancer
• Neoadjuvant RT does not appear to decrease local relapse or improve survival
in patients with resectable esophageal cancer
• The role of neoadjuvant chemotherapy remains undefined with a small 5-year
benefit obtained in a meta-analysis but conflicting results from two large
randomized trials
• The impact of the MAGIC trial is unclear due to the small number of patients
with esophageal cancer
• NCCN v1.2005: Preoperative chemotherapy is not recommended as the
standard of care

28. Conclusions
• Neoadjuvant chemoradiotherapy has been widely accepted in US despite the
lack of conclusive evidence from phase III trials
 The confirmatory trial CALGB 9781 was terminated early due to poor accrual
• Benefit from trimodality therapy may be restricted to patients achieving
significant response or pCR and non-responders may have worse outcome
compared with patients treated with surgery only
• Small benefit observed in the 4 published meta-analysis may change with the
inclusion of Burmeister’s study
 Ongoing Cochrane review
• NCCN v1.2005: Although neoadjuvant chemoradiotherapy represents a
reasonable approach, it remains investigational due to conflicting results from
RCTs

29. Conclusions
• Surgery following neoadjuvant chemoratiotherapy improves
local and regional control but not overall survival
• Post-therapy pathologic status may be a better predictor for
outcome than the baseline clinical AJCC staging system
• The pathologic status achieved with neoadjuvant therapy may
provide an early surrogate benchmark to speed up comparative
trials

30. Conclusions
• Distant relapse continues to be a major challenge in patients
presenting with locally advanced disease
• More intense chemotherapy regimens using third-generation
agents may increase the eradication of micrometastatic disease
• Patients treated with induction chemotherapy may benefit from
early evaluation of response to avoid unnecessary delays in
surgery
• Larger randomized trials of neoadjuvant chemotherapy or
chemoradiotherapy are needed to identify optimal regimens
capable of producing higher pCR rates with acceptable toxicity