effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable...
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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
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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
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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
CROSS study3
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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
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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
CROSS study6
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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)
CROSS study8
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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
CROSS study13
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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
CROSS study14
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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
CROSS study15
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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%)
CROSS study16
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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
CROSS study17
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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
CROSS study18
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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)
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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
CROSS study20
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ACKNOWLEDGEMENTS
We want to thank all our patients and families
CROSS study21