neoadjuvant therapy for esophageal cancer
DESCRIPTION
Pre-operative chemotherapy and radiation has improved treatment outcomes in patients with esophageal cancer.TRANSCRIPT
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Neoadjuvant Therapy for Esophageal Cancer
Daniel Morgensztern, M.D.
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Overview
• Background• Neoadjuvant radiotherapy• Neoadjuvant chemotherapy• Neoadjuvant chemoradiotherapy• Neoadjuvant or definitive chemoradiotherapy• The significance of pathologic CR• Strategies to improve outcome• Conclusions
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EpidemiologyWorldwide
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
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EpidemiologyUS
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
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AJCC StagingT Stage
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AJCC StagingN stage
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AJCC Staging and Prognosis After Complete Surgical Removal of the Tumor
Ezinger PC, N Engl J Med 2003; 349:2241-2252
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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
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Neoadjuvant RadiotherapyRandomized 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
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Neoadjuvant RadiotherapyMeta-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
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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
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Neoadjuvant chemotherapyRandomized 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
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Neoadjuvant chemotherapyINT 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
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Neoadjuvant chemotherapyMeta-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
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Neoadjuvant chemotherapyMAGIC Trial
Cunningham ASCO 2005
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Neoadjuvant chemotherapyMAGIC 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
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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
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Neoadjuvant ChemoradiotherapyNon-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.
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Neoadjuvant ChemoradiotherapyRandomized 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
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Neoadjuvant ChemoradiotherapyMeta-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
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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: 1623-1627Minsky BD, J Clin Oncol 2002; 20: 1167-1174
INT 0123
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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)
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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
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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
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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
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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
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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
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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
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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
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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