Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or

esophagogastric junction cancer: Results from a multicenter randomized phase III study.

A. van der Gaast, P. van Hagen, M. Hulshof, M.I. van Berge Henegouwen, G.A. Nieuwenhuijzen, J.T. Plukker, J.J.

Bonenkamp, E.W. Steyerberg, H.W. Tilanus. CROSS study group

Erasmus Medisch Centrum, Rotterdam

Academisch Medisch Centrum, Amsterdam

Catharina Ziekenhuis, Eindhoven

UMC St. Radboudt, Nijmegen

Universitair Medisch Centrum Groningen

VU Medisch Centrum, Amsterdam

Rijnstate Ziekenhuis, Arnhem

CROSS study2

Background

The incidence of esophageal (adenocarcinomas) cancer

increases

Despite careful preoperative staging in 20% - 30% an

irradical resection is performed

A radical resection is a strong prognostic factor

Preoperative chemoradiotherapy may increase the number

of radical resection and therefore the prognosis of these

patients

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Objectives

Primary endpoints

To compare median survival rates between patients treated

for resectable esophageal adenocarcinoma or squamous cell

carcinoma

To compare quality of life before, during and after treatment

Secondary endpoints

To compare pathological responses

To compare progression free survival

To compare the number of R0 resections

To compare treatment toxicity

To compare costs

CROSS study4

Eligibility criteria

Major Inclusion criteria:

Esophageal SCC or AC (cT1N1, T2-3Nx, M0)

Adequate hematologic, renal, hepatic and pulmonary

functions

WHO 0, 1 or 2

Written informed consent

Major exclusion criteria:

T1N0 or M+

Tumor length > 8 cm

Weight loss > 10%CROSS study

5

Statification and statistical considerations

Stratification parameters

WHO performance

N- stage

Tumor type

Hospital

Sample size calculation

16 versus 22 months median survival

175 patients per treatment-arm

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Accrual

0

10

20

30

40

50

60

2004

1st q

uarter

2005

2nd q

uarte

r 200

5

3rd q

uarte

r 200

5

4th q

uarter

2005

1st q

uarter

2006

2nd q

uarte

r 200

6

3rd q

uarte

r 200

6

4th q

uarter

2006

1st q

uarter

2007

2nd q

uarte

r 200

7

3rd q

uarte

r 200

7

4th q

uarter

2007

1st q

uarter

2008

2nd q

uarte

r 200

8

3rd q

uarte

r 200

8

4th q

uarter

2008

0

50

100

150

200

250

300

350

400

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Chemoradiotherapy treatment regimen

Chemoradiotherapy regimen:

Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29

Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy

Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)

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Baseline characteristics (1)

Surgery alone CRT + Surgery

Performance (WHO)

Median 0 (0-1) 0 (0-1)

cN-stage

cN1 66% 67%

Sex

Male 81% 75%

Histology

AC 139 (74%) 129 (74%)

SCC 44 (23%) 40 (23%)

Other 5 (3%) 6 (3%)

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Baseline characteristics (2)

Surgery alone CRT + Surgery

Age (y)

Median 60 (36-73) 60 (37-79)

Dysphagia score

Median 1 (0-4) 1 (0-4)

Tumor length (cm)

Median 4 (1-10) 4 (1-13)

Tumor location

proximal 4 3

mid 18 27

distal 145 122

GEJ 21 23

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0

20

40

60

80

100

120

Surgery alone

CRT

Baseline uTN-stage

Nu

mb

er

of p

atie

nts

TN-Stage

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Delivery of treatment

Number of courses:

1 course = 175 pts

2 courses = 172 pts

3 courses = 172 pts

4 courses = 167 pts

5 courses = 163 pts

Number of operated patients:

CRT arm: 166/175 (95%)

Surgery arm: 184/188 (98%)

50

60

70

80

90

100

% of patientscompleted

%

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Toxicity of treatment (chemoradiotherapy)

Major toxicities (grade 3-5 CTC 3.0)

Hematologic: n=12 (6.8%)

Grade 3: n=12

Grade 4: n=0

Grade 5: n=0

Non-hematologic: n=28 (16%)

Grade 3: n=26

Grade 4: n=1

Grade 5: n=1

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Resection rate and resection margins

Resection rate of all randomised patients

Surgery alone CRT + surgery

162/188 (86%) 157/175 (90%)

Resection margins

Surgery alone CRT + surgery

R0 110 (67%) 145 (92.3%) p<0.002

R1 52 (33%) 12 (7.6%)

R0 = no tumor within 1 mm of the resection margins

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Pathology after CRT

Pathologic complete response rate 32% in primary tumors

(in 145 revised resection specimens of 158 in total)

0

10

20

30

40

50

60

TGR1 TGR2 TGR3 TGR4

Nu

mb

er

of p

atie

nts

Tumor Regression Grade

TGR1: No vital cells (pCR)

TGR2: <10% vital cells

TGR3: 10-50% vital cells

TGR4: >50% vital cells

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Morbidity and Mortality (postoperative)

Surgery alone CRT + Surgery

Pulmonary complications 66% 69%

Cardiac complications 24% 23%

Chylothorax 8% 11%

Mediastinitis 6% 4%

Anastomotic leakage 25% 22%

In-hospital mortality 7 (3.8%) 6 (3.4%)

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Follow-up and survival

Median follow-up 32 months

Surgery alone CRT + Surgery

1 year survival rate 70% 82%

2 year survival rate 52% 67%

3 year survival rate 48% 59%

Median survival 26 months 49 months

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188 131 71 44 22 1

175 144 85 55 30 2

No’s at risk

Surgery alone

CRT + surgery

HR 0.67 95% CI (.49 - .91) P=0.012

Overall survival

HR 0.67 95% CI (0.49 - 0.91)

CRTx

Surgery

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HR’s (95% CI) for death according to baseline variables

0.0 0.5 1.0 1.5 2.0

WHO 1

WHO 0

SCC

AC

Female

Male

N1

N0

Overall

Favors preoperative CRT Favors surgery alone

CROSS study

0.67 (0.49 – 0.91)

0.49 (0.27 – 0.90)

0.72 (0.50 – 1.04)

0.62 (0.44 – 0.87)

0.92 (0.45 – 1.89)

0.82 (0.58 – 1.16)

0.34 (0.17 – 0.68)

0.67 (0.49 – 0.94)

0.67 (0.32 – 1.41)

19

CONCLUSION

Neoadjuvant chemoradiotherapy with weekly

administrations of carboplatin and paclitaxel and

concurrent radiotherapy followed by surgery

improves survival compared to surgery alone

In this study we observed no increase in

postoperative complications or postoperative

mortality with preoperative chemoradiotherapy

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ACKNOWLEDGEMENTS

We want to thank all our patients and families

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