Neoadjuvant Therapy for Esophageal Cancer

Daniel Morgensztern, M.D.

Overview

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

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

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

AJCC StagingT Stage

AJCC StagingN stage

AJCC Staging and Prognosis After Complete Surgical Removal of the Tumor

Ezinger PC, N Engl J Med 2003; 349:2241-2252

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

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

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

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

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

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

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

Neoadjuvant chemotherapyMAGIC Trial

Cunningham ASCO 2005

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

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

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.

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

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

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

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)

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

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

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

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

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

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

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

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