1. Effect of Neoadjuvant Concurrent Chemoradiotherapy on Locally Advanced Middle and Low Rectal Cancer— A Propensity Score Matching Study
官泰全,林春吉,楊純豪,姜正愷,林宏鑫,藍苑慈,
張世慶,王煥昇,陳維熊,林資琛,林楨國
Division of Colorectal surgery, Department of Surgery
Taipei Veterans General Hospital

2. Introduction

3. Neoadjuvant Concurrent Chemoradiotherapy (nCCRT)
Locally Advanced Rectal Cancer (LARC), (T3-4, or N+ )
Neoadjuvant Concurrent Chemoradiotherapy (nCCRT)
 Total Mesorectal Excision (TME) Surgery
Medicine (Baltimore) 2014 Dec;93(28):e231
J Clin Oncol 2012 Jun 1;30(16):
National Comprehensive Cancer Network- Rectal Cancer; 2017
Standard Treatment
Pros
Cons
Downstage
↓tumor size
↑pathological complete response (pCR)
↑local control rate
preserving anal sphincter function
minimal acute toxicity of radiation
Overtreatment of T1, T2
Cause other malignancy
↑adherence
↑ anastomosis leakage/ stricture
↑ sexual/ bowel dysfunction
no improvement of overall survival
Onco Lette. 2015 Jan;9(1):

4. nCCRT effects on middle/ low rectal cancer
Trials almost before 2000
Include upper, middle, low rectal cancer
N Eng J Med 1997;336(14):980-7
N Eng J Med 2001 Aug 30;345(9):638-46
Jama. 2000;284(8):
Upper rectal cancer: good quality TME OP is enough
Dis Colon Rectum. 2015 Jun;58(6):556-65
Medicine (Baltimore). 2016 May;95(22):e2990.
nCCRT effect was mainly on middle, low rectal cancer ?
Little direct proof
Aim:
nCCRT effects on middle/ low rectal cancer

5. Material & Methods

6. Definition
Rectum Level: Low: 0-5 cm from anal verge Middle: 6-10 cm from anal verge Upper: cm from anal verge Circumferential Resection Margin (CRM) Positive: < 1mm, Negative: > 1 mm AJCC Tumor Regression Grade (TRG)

7. Patients Inclusion Exclusion
Database of Taipei Veterans General Hospital 2000/1/1–2012/5/31
Inclusion
Exclusion
MRI defined stage II/III
Middle/ low rectal cancer
Curative surgery
Stage I/ IV
Follow up < 3 months
Interval from nCCRT to surgery < 4 weeks
Short course radiotherapy

8. Propensity score Matching

9. Treatment TME-based operation: nCCRT Chemotherapy:
FOLFOX (fluorouracil, 5-FU/ leucovorin/ oxaliplatin)
oral Tegafur
oral Capecitabine
Long course radiotherapy: Gy/25 fractions in 5-6 weeks
TME-based operation:
Low anterior resection (LAR); Abdominoperineal resection (APR)

10. Abdominal CT/ Chest CT per 6-12 months Alive/ Lost follow-up/ Expired
nCCRT
nCCRT OP
> 4weeks
TME Surgery
TME Surgery
CEA per 3 months
Abdominal CT/ Chest CT per 6-12 months
5 years
Alive/ Lost follow-up/ Expired

11. Statistics Matched Independent Variables:
Propensity Score Matching (PSM)
1:1 match
Nearest neighbor matching, Non-replacement principle
Logistic regression model
Matched Independent Variables:
Age / Gender / Tumor location / Preoperative CEA / cT, cN stage
Category variables: Chi-squared test, Fisher test
Continuous variables: T-test
Survival Analysis: Kaplan-Meier/ Log-rank test
Multivariate Analysis: COX regression
Significance: p value < 0.05

12. Results

13. Unmtached Matched OP group (n=117) nCCRT group (n=159) p value
Age (mean + SD)
0.004
0.132
Gender (%)
0.142
0.746
Male
71(60.7)
110(69.2)
54(64.3)
56(66.7)
Female
46(39.3)
49(30.8)
30(35.7)
28(33.3)
Tumor Site (%)
0.1
0.641
Middle
56(47.9)
92(57.9)
46(54.8)
49(58.3)
Lower
61(52.1)
67(42.1)
38(45.2)
35(41.7)
Preoperative CEA
0.186
0.885
<5
80(68.4)
93(58.5)
57(67.9)
>5
36(30.7)
62(39.0)
26(31.0)
29(34.5) NA
1(0.9)
4(2.5)
1(1.1)
1(1.2)
Preoperative stage(%)
<0.001
0.822 II
35(29.9)
14(8.8)
11(13.1)
12(14.3)
III
82(70.1)
145(91.2)
73(86.9)
72(85.7)
Preoperative T stage(%)
0.125
0.97
cT1
2(1.7)
0(0)
cT2
15(12.8)
11(6.9)
10(11.9)
9(10.7)
cT3
84(71.8)
122(76.7)
61(72.6)
62(73.8)
cT4
16(13.7)
26(16.4)
13(15.5)
Preoperative N stage(%)
0.972
cN0
cN1
43(36.8)
62(40.0)
37(44.0)
36(42.9)
cN2
39(33.3)
83(52.2)

14. Accuracy of MRI Unmatched OP group (n=126) pT1 pT2 pT3 pT4 cT1 1 cT2 2
cT2 2 5 8
cT3 20 66
cT4 11 7
pN0
pN1
pN2
cN0 29 4
cN1 25 13 6
cN2 16 22
MRI
Stage
T stage: 62.7 %; N stage: 50.8%
Underestimate
Overestimate

15. Down stage OP group (n=84) nCCRT group (n=84) P value Operation Type
0.292
LAR
59(70.2)
65(77.4)
APR
25(29.8)
19(22.6)
Pathological stage
<0.001
stage 0
0(0)
17(20.2) I
13(15.5)
20(23.8) II
27(32.1)
24(28.6)
III
44(52.4)
23(27.4)
pathological T stage
pT0/ypT0
18(21.4)
pT1/ypT1
2(2.4)
4(4.8)
pT2/ypT2
pT3/ypT3
60(71.4)
42(50)
pT4/ypT4
9(10.7)
1(1.2))
pathological N stage
0.001
pN0/ypN0
40(47.6)
61(72.6)
pN1/ypN1
17(20.3)
14(16.7)
pN2/ypN2
Down stage

16. Better pathological pattern
OP group (n=84)
nCCRT group (n=84)
P value
Postoperative CEA
0.683
<5
58(69.1)
62(73.8)
>5
9(10.7)
6(7.1) NA
17(20.2)
16(19.1)
Grade of Differentiation
0.027
well + moderately
73(86.9)
82(97.6)
poor
1(1.2)
2(2.4)
Mucinous component
0.059
<50%
77(91.7)
67(79.8))
>50%
4(4.8)
3(3.5)
11(13.1)
Perineural invasion
0.514
negative
78(92.9)
80(95.2)
positive
isolated cancer nodule at mesentery
0.192
81(96.4)
7(8.3)
3(3.6)
Inflammatory change around cancer
0.001
66(78.6)
18(21.4)
Lymphovascular invasion
69(82.1)
15(17.9)
Better pathological pattern

17. Less metastatic LNs, better CRM
OP group (n=84)
nCCRT group (n=84)
P value
Tumor regression grade, TRG
<0.001 NA
84(100)
22(26.2)
complete response
20(23.8)
moderate response
33(39.3)
minimal response
9(10.7)
Circumferential resection margin
0.009 25 10
negative 58 70
positive 1 4
Harvest LN (Mean + SD)
14 + 7
Metastatic LNs
4 + 9
1 + 3
0.006
Adjuvant chemotherapy
0.089
No adjuvant chemotherapy
42(50)
54(64.3)
Oral UFUR
15(17.9)
10(11.9) FL
8(9.5)
FOLFOX
12(14.3)
FOLFIRI
3(3.5))
0(0)
Less metastatic LNs, better CRM

18. Similar permanent rate
OP group (n=84)
nCCRT group (n=84)
P value
Stoma
Initial Stoma rate (%)
58(69)
78(92.9)
<0.001
Initial LAR + temperal stoma (%)
33(39.3)
59(70.2)
APR + permanent stoma (%)
25(29.8)
19(22.6)
0.292
Initial LAR + permanent stoma (%)
2(2.4)
3(3.6)
0.715
Reason:
Local recurrence, s/p APR (%)
1(1.2)
Anastomosis Complication (%)
Complication
Total Complication (%)
20(23.8)
0.384
Anastomosis Leakage (%)
7(8.3)
5(6.0)
0.549
Anastomosis Stricture (%)
0(0)
0.155
Wound infection/ disruption (%)
8(9.5) 1
Stoma complication (%)
0.081
Others (%)
0.787
High initial rate
Similar permanent rate

19. OP group (n=84) nCCRT (n=84)
p value
5 year overall survival rate (%)
88.1
89.3
0.582
5 year overall recurrence rate (%)
32.1 25
0.139
5 year Cancer specific survival rate (%) 94
0.193
5 year Local recurrence rate (%)
11.9
4.8
0.042
Local recurrence pattern (%)
0.132
Central
8.3
Lateral
3.6
5 year Distant recurrence rate (%)
22.6
21.4
0.525
Distant recurrence pattern
Lung Mets (%)
15.5
0.501
Liver Mets (%)
10.7 6
0.264
Peritoneal Seeding (%)
2.4
0.497
Other Mets (%)
0.72

20. Overall Survival Analysis

21. Disease-Free Survival Analysis

22. Cancer-Specific Survival Analysis

23. Distant Recurrence Analysis

24. Local Recurrence Analysis

25. Discussion

26. Oncologic Outcomes TME-based surgery is enough for T2N+, T3N0
Benefit
No Benefit
Local Recurrence Control
Overall Survival
Disease Free Survival
Cancer-specific Survival
Distant Recurrence Control
N Eng J Med. 2001;345(9):638-46
Jama. 2000;284(8):
TME-based surgery is enough for T2N+, T3N0
Prior studies before 2000, include: short/ long, pre/ postoperative radiotherapy
Radiotherapy↑ pathological complete response in selective cases . Initial pattern dominates.
International journal of colorectal disease. 2010;25(9):
Cancer. 2011;117(14):
Jama. 2000;284(8):

27. Stoma/ Complication Stoma Complication Similar permanent stoma rate
(p value: 0.292)
Similar stoma reversal rate (OP:93.9%, nCCRT: 94.9%, p value: 0.715)
Like other studies
No sphincter functional data !!!
Similar complication rate
Wound problems are most
Surgical oncology. 2012;21(3):e103-9
Yonsei medical journal. 2015;56(2):447-53
Annals of coloproctology. 2015;31(3):98-102

28. Limitations
Retrospective, single-centre study
Small size, other 80% patients had CT alone
Poor accuracy of MRI (T:62.7%, N:50.8%)
No T3a/ T3b/ T3c/ T3d Data (recommended by ESMO)
Much missing data: CRM (21%), TRG (26%)
We provided the real world data which was compatible to clinical trials.

29. Conclusion
Neoadjuvant concurrent chemoradiotherapy may only improves Local Control, but not overall survival or distant control in locally advanced middle and low rectal cancer.

30. Thank you for listening !
官泰全 MD.