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

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CROSS study
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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CROSS study
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

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CROSS study
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%
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CROSS study
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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CROSS study
Accrual

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CROSS study
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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CROSS study
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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CROSS study
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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CROSS study
Baseline uTN-stage

Number of patients

TN-Stage

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CROSS study
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%)

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CROSS study
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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CROSS study
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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CROSS study
Pathology after CRT

Pathologic complete response rate 32% in primary tumors

(in 145 revised resection specimens of 158 in total)

TGR1: No vital cells (pCR)

Number of patients

TGR2: <10% vital cells

TGR3: 10-50% vital cells

TGR4: >50% vital cells

Tumor Regression Grade

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CROSS study
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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CROSS study
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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CROSS study
 Overall survival

CRTx

Surgery

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

HR 0.67 95% CI (0.49 - 0.91)

Nos at risk
188 131 71 44 22 1
Surgery alone

175 144 85 55 30 2
CRT + surgery
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CROSS study
HRs (95% CI) for death according to baseline variables

Overall 0.67 (0.49 0.91)

N0 0.49 (0.27 0.90)

N1 0.72 (0.50 1.04)

Male 0.62 (0.44 0.87)

Female 0.92 (0.45 1.89)

AC 0.82 (0.58 1.16)

SCC 0.34 (0.17 0.68)

WHO 0 0.67 (0.49 0.94)

WHO 1 0.67 (0.32 1.41)

0.0 0.5 1.0 1.5 2.0

Favors preoperative CRT Favors surgery alone

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CROSS study
 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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