Erasmus Medisch Centrum, Rotterdam Academisch Medisch Centrum, Amsterdam
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Transcript of Erasmus Medisch Centrum, Rotterdam Academisch Medisch Centrum, Amsterdam
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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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
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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
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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
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3rd q
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3rd q
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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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Surgery alone
CRT
Baseline uTN-stage
Nu
mb
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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%)
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% 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
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TGR1 TGR2 TGR3 TGR4
Nu
mb
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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
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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)
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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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