Clinicopathologic Characteristics
The NCDB participant user file for rectal cancer included 314,844 patients. After application of inclusion/exclusion criteria, 19,867 patients with clinical stage II/III rectal adenocarcinoma who completed long-course neoadjuvant CRT and underwent resection remained (Fig. 1). Mean age for the entire cohort was 58.6 ± 12.0 years, and 12,396 (62.4%) were males. There were 17,249 (86.8%) patients with clinical stage T3, and 10,662 (53.7%) were node-positive (clinical stage III). Of 19,867 patients, 11,991 (60.4%) underwent resection within 5–8 weeks from conclusion of neoadjuvant CRT, and the most commonly performed procedure was LAR (N = 13,801, 69.5%). The median number of retrieved nodes was 16, and pCR was documented in 3,801 cases (19.1%). 8.167 patients (41.1%) received AC and median follow up time was 55.1 months. Table 1 summarizes the demographic, clinical, and pathologic characteristics of the selected population.
Table 1
Summary of the demographic and clinical characteristics of the selected patient population
N
|
|
19,867
|
Age (years)
|
Mean ± SD
Median
|
58.6 ± 12.0
59
|
Sex
|
Male
Female
|
12,396 (62.4%)
7,471 (37.6%)
|
Race
|
White
Black
Other
|
16,267 (81.9%)
1,439 (7.2%)
2,161 (10.9%)
|
Charlson Score
|
0
1
2
3+
|
15,854 (79.8%)
3,099 (15.6%)
625 (3.1%)
289 (1.5%)
|
Grade
|
Well differentiated
Moderately differentiated
Poorly differentiated
Not reported
|
1,412 (7.1%)
13,657 (68.7%)
1,857 (9.3%)
2,941 (14.8%)
|
Clinical T stage
|
T1
T2
T3
T4
|
116 (0.6%)
958 (4.8%)
17,249 (86.8%)
1,544 (7.8%)
|
Clinical N stage
|
Negative
Positive
|
9,205 (46.3%)
10,662 (53.7%)
|
Clinical stage
|
Stage II
Stage III
|
9,205 (46.3%)
10,662 (53.7%)
|
Radiation-surgery interval
|
5–8 weeks
9–12 weeks
|
11,991 (60.4%)
7,876 (39.6%)
|
Surgery
|
LAR
APR
Proctocolectomy
Exenteration
|
13,801 (69.5%)
4,938 (24.9%)
541 (2.7%)
587 (3.0%)
|
Approach
|
Open
Minimally-invasive
|
12,964 (65.3%)
6,903 (34.7%)
|
Retrieved lymph nodes
|
Mean ± SD
Median
|
18.7 ± 7.6
16
|
Pathologic T stage
|
T0
T1
T2
T3
T4
|
4,525 (22.8%)
1,221 (6.1%)
5,045 (25.4%)
8,528 (42.9%)
548 (2.8%)
|
Pathologic N stage
|
N0
N1
N2
|
13,992 (70.4%)
4,088 (20.6%)
1,787 (9.0%)
|
Response
|
Complete response
Partial response
No response
|
3,801 (19.1%)
10,122 (50.9%)
5,944 (29.9%)
|
Adjuvant systemic therapy
|
No
Yes
|
11,700 (58.9%)
8,167 (41.1%)
|
Follow up (months)
|
Mean ± SD
Median
|
62.4 ± 35.6
55.1
|
Propensity Score Matching
As described above, the included cohort was stratified into pCR (N = 3,801) and pIR (N = 16,066) groups, with the pIR group further subcategorized into ypN0 (N = 10,191) and ypN+ (N = 5,875) subgroups. Within the pCR group, 2,505 patients did not receive AC whereas 1,296 did. Baseline characteristics among these two subgroups was conducted and, notably, patients who received AC were significantly younger (57.1 ± 11.2 vs. 60.8 ± 12.5 years; p < 0.001), more likely to have a Charlson score of 0 (82.8% vs. 78.9%; p = 0.039), more commonly had clinical stage III tumors (56.4% vs. 46.1%; p < 0.001), and were more likely to undergo minimally-invasive surgical resection (39.3% vs. 34.1%; p = 0.001). Propensity score was carried out as described among 1,292 patients from each subgroup, which resulted in well-balanced cohorts. Standardized mean differences were calculated for each variable and ranged between 0.01 and 0.05, indicating good balance (Table 2).
Table 2
Comparison of the unmatched and matched datasets of the patient subgroup who achieved pathologic complete response (N = 3,801) by the receipt of adjuvant systemic therapy. APR: Abdominoperineal Resection; AC: Adjuvant Systemic Therapy; Diff.: Differentiated; LAR: Low Abdominal Resection; MIS: Minimally Invasive Surgery. * Statistically significant.
|
Unmatched dataset
|
Matched dataset 1:1
|
|
No AC
|
AC
|
p
|
No AC
|
AC
|
p
|
N
|
2,505
|
1,296
|
|
1,292
|
1,292
|
|
Age (years)
|
60.8 ± 12.5
|
57.1 ± 11.2
|
< 0.001*
|
57.3 ± 12.0
|
57.1 ± 11.1
|
0.713
|
Sex
Male
Female
|
1,567 (62.6%)
938 (37.4%)
|
779 (60.1%)
517 (39.9%)
|
0.141
|
777 (60.1%)
515 (39.9%)
|
779 (60.3%)
513 (39.7%)
|
0.936
|
Race
White
Black
Other
|
2,077 (82.9%)
184 (7.3%)
244 (9.7%)
|
1,071 (82.6%)
78 (6.0%)
147 (11.3%)
|
0.115
|
1,073 (83.0%)
78 (6.0%)
141 (10.9%)
|
1,068 (82.7%)
78 (6.0%)
146 (11.3%)
|
0.952
|
Charlson Score
0
1
2
3+
|
1,976 (78.9%)
413 (16.5%)
84 (3.4%)
32 (1.3%)
|
1,073 (82.8%)
176 (13.6%)
35 (2.7%)
12 (0.9%)
|
0.039*
|
1,079 (83.5%)
165 (12.8%)
33 (2.6%)
15 (1.2%)
|
1,069 (82.7%)
176 (13.6%)
35 (2.7%)
12 (0.9%)
|
0.851
|
Grade
Well diff.
Moderately diff.
Poorly diff.
Not reported
|
162 (6.5%)
1,572 (62.8%)
184 (7.3%)
587 (23.4%)
|
91 (7.0%)
827 (63.8%)
88 (6.8%)
290 (22.4%)
|
0.723
|
84 (6.5%)
831 (64.3%)
82 (6.3%)
295 (22.8%)
|
90 (7.0%)
825 (63.9%)
87 (6.7%)
290 (22.4%)
|
0.936
|
Clinical stage
Stage II
Stage III
|
1,349 (53.9%)
1,156 (46.1%)
|
565 (43.6%)
731 (56.4%)
|
< 0.001*
|
559 (43.3%)
733 (56.7%)
|
564 (43.7%)
728 (56.3%)
|
0.843
|
Rad-surg interval
5–8 weeks
9–12 weeks
|
1,449 (57.8%)
1,056 (42.2%)
|
758 (58.5%)
538 (41.5%)
|
0.703
|
739 (57.2%)
553 (42.8%)
|
755 (58.4%)
537 (41.6%)
|
0.524
|
Surgery
LAR
APR
Proctocolectomy
Exenteration
|
1,775 (70.9%)
608 (24.3%)
68 (2.7%)
54 (2.2%)
|
915 (70.6%)
313 (24.2%)
41 (3.2%)
27 (2.1%)
|
0.888
|
920 (71.2%)
303 (23.5%)
40 (3.1%)
29 (2.2%)
|
914 (70.7%)
312 (24.1%)
39 (3.0%)
27 (2.1%)
|
0.972
|
Approach
Open
MIS
|
1,652 (65.9%)
853 (34.1%)
|
787 (60.7%)
509 (39.3%)
|
0.001*
|
784 (60.7%)
508 (39.3%)
|
785 (60.8%)
507 (39.2%)
|
0.968
|
Retrieved nodes
|
18.2 ± 7.1
|
18.6 ± 7.7
|
0.113
|
18.3 ± 7.1
|
18.5 ± 7.6
|
0.471
|
Median follow up
|
56.2
|
56.8
|
0.828
|
56.3
|
56.5
|
0.906
|
Association of Adjuvant Chemotherapy with Survival in Matched Subgroups
Survival was then estimated for matched subgroups, and patients who received AC had increased mean OS compared to no AC in the pCR subgroups (139.1 ± 1.9 vs. 134.0 ± 2.2 months, median not reached in both groups; p < 0.001). The absolute 5-year OS benefit of AC was 4% (92% vs. 88%; p < 0.001).
In the pIR ypN0 group, 6,202 patients did not receive AC whereas 3,989 did. Comparison of baseline characteristics similarly revealed that AC patients were younger (56.8 ± 10.9 vs. 60.6 ± 12.1 years; p < 0.001), had higher rates of Charlson score 0 (81.5% vs. 76.7%; p < 0.001), underwent surgery within 5–8 weeks (61.0% vs. 58.3%; p = 0.005), had minimally-invasive procedures (38.5% vs. 34.9%; p < 0.001), and sustained T downstaging (77.4% vs. 73.0%; p < 0.001). Propensity-score matching was carried out similarly to yield 2,970 well balanced cohorts (Table 3). Again, AC patients had a longer mean OS compared to those who did not receive AC (141.6 ± 1.5 vs. 129.9 ± 1.2 months, medians not reached in both groups; p < 0.001). The absolute incremental 5-year OS advantage associated with AC was 6% (89% vs. 83%; p < 0.001, Fig. 3).
Table 3
Comparison of the unmatched and matched datasets of the patient subgroup who achieved pathologic incomplete response with ypN0 (N = 10,191) by the receipt of adjuvant systemic therapy. APR: Abdominoperineal Resection; AC: Adjuvant Systemic Therapy; Diff.: Differentiated; LAR: Low Abdominal Resection; MIS: Minimally Invasive Surgery. * Statistically significant.
|
Unmatched dataset
|
Matched dataset 1:1
|
|
No AC
|
AC
|
p
|
No AC
|
AC
|
p
|
N
|
6,202
|
3,989
|
|
3,970
|
3,970
|
|
Age (years)
|
60.6 ± 12.1
|
56.8 ± 10.9
|
< 0.001*
|
57.1 ± 11.5
|
57.0 ± 10.8
|
0.697
|
Sex
Male
Female
|
3,920 (63.2%)
2,282 (36.8%)
|
2,520 (63.2%)
1,469 (36.8%)
|
0.974
|
2,508 (63.2%)
1,462 (36.8%)
|
2,507 (63.1%)
1,463 (36.9%)
|
0.981
|
Race
White
Black
Other
|
5,072 (81.8%)
473 (7.6%)
657 (10.6%)
|
3,287 (82.4%)
271 (6.8%)
431 (10.8%)
|
0.283
|
3,255 (82.0%)
286 (7.2%)
429 (10.8%)
|
3,269 (82.3%)
271 (6.8%)
430 (10.8%)
|
0.804
|
Charlson Score
0
1
2
3+
|
4,756 (76.7%)
1,086 (17.5%)
241 (3.9%)
119 (1.9%)
|
3,250 (81.5%)
579 (14.5%)
102 (2.6%)
58 (1.5%)
|
< 0.001*
|
3,217 (81.0%)
599 (15.1%)
93 (2.3%)
61 (1.5%)
|
3,232 (81.4%)
578 (14.6%)
102 (2.6%)
58 (1.5%)
|
0.825
|
Grade
Well diff.
Moderately diff.
Poorly diff.
Not reported
|
497 (8.0%)
4,374 (70.5%)
481 (7.8%)
850 (13.7%)
|
291 (7.3%)
2,839 (71.2%)
325 (8.1%)
534 (13.4%)
|
0.491
|
288 (7.3%)
2,847 (71.7%)
316 (8.0%)
519 (13.1%)
|
291 (7.3%)
2,828 (71.2%)
321 (8.1%)
530 (13.4%)
|
0.972
|
Rad-surg interval
5–8 weeks
9–12 weeks
|
3,614 (58.3%)
2,588 (41.7%)
|
2,435 (61.0%)
1,554 (39.0%)
|
0.005*
|
2,393 (60.3%)
1,577 (39.7%)
|
2,419 (60.9%)
1,551 (39.1%)
|
0.550
|
Surgery
LAR
APR
Proctocolectomy
Exenteration
|
4,311 (69.5%)
1,531 (24.7%)
159 (2.6%)
201 (3.2%)
|
2,745 (68.8%)
1,019 (25.5%)
108 (2.7%)
117 (2.9%)
|
0.612
|
2,742 (69.1%)
1,008 (25.4%)
103 (2.6%)
117 (2.9%)
|
2,732 (68.8%)
1,014 (25.5%)
107 (2.7%)
117 (2.9%)
|
0.990
|
Approach
Open
MIS
|
4,035 (65.1%)
2,167 (34.9%)
|
2,454 (61.5%)
1,535 (38.5%)
|
< 0.001*
|
2,455 (61.8%)
1,515 (38.2%)
|
2,446 (61.6%)
1,524 (38.4%)
|
0.835
|
Retrieved nodes
|
18.4 ± 7.5
|
18.7 ± 7.3
|
0.028*
|
18.6 ± 7.8
|
18.7 ± 7.2
|
0.513
|
T downstaging
Achieved
Not achieved
|
4,562 (73.0%)
1,640 (26.4%)
|
3,086 (77.4%)
903 (22.6%)
|
< 0.001*
|
3,059 (77.1%)
911 (22.9%)
|
3,067 (77.3%)
903 (22.7%)
|
0.831
|
Path T stage
T0
T1
T2
T3
T4
|
0 (0.0%)
618 (10.0%)
2,306 (37.2%)
3,086 (49.8%)
192 (3.1%)
|
0 (0.0%)
386 (9.7%)
1,529 (38.3%)
1,943 (48.7%)
131 (3.3%)
|
0.600
|
0 (0.0%)
371 (9.3%)
1,513 (38.1%)
1,965 (49.5%)
121 (3.0%)
|
0 (0.0%)
383 (9.6%)
1,523 (38.4%)
1,933 (48.7%)
131 (3.3%)
|
0.829
|
Median follow up
|
56.1
|
54.9
|
0.011*
|
55.0
|
55.0
|
0.875
|
Finally, in patients with pIR and ypN+, 2,993 did not receive AC whereas 2,882 did. Baseline comparison of clinicopathologic factors revealed that AC patients were younger (55.9 ± 11.5 vs. 58.3 ± 12.7 years; p < 0.001) and more commonly underwent minimally-invasive resections more commonly (33.2% vs. 29.5%; p = 0.002) but were less likely to be downstaged to ypT0 (10.7% vs. 13.9%; p = 0.003). 2,629 patients were matched by AC receipt status, and matched subgroups were well balanced (Table 4). Survival was improved with AC in matched pIR and ypN + patients (median OS in the AC subgroup (155.9 ± 5.4 vs. 126.5 ± 7.6 months; p < 0.001). The absolute 5-year OS advantage associated with AC was 7% (76% vs. 69%; p < 0.001, Fig. 4).
Table 4
Comparison of the unmatched and matched datasets of the patient subgroup who achieved pathologic incomplete response with ypN+ (N = 5,875) by the receipt of adjuvant systemic therapy. APR: Abdominoperineal Resection; AC: Adjuvant Systemic Therapy; Diff.: Differentiated; LAR: Low Abdominal Resection; MIS: Minimally Invasive Surgery. * Statistically significant.
|
Unmatched dataset
|
Matched dataset 1:1
|
|
No AC
|
AC
|
p
|
No AC
|
AC
|
p
|
N
|
2,993
|
2,882
|
|
2,629
|
2,629
|
|
Age (years)
|
58.3 ± 12.7
|
55.9 ± 11.5
|
< 0.001*
|
56.9 ± 12.3
|
56.5 ± 11.5
|
0.180
|
Sex
Male
Female
|
1,862 (62.2%)
1,131 (37.8%)
|
1,748 (60.7%)
1,134 (39.3%)
|
0.220
|
1,633 (62.1%)
996 (37.9%)
|
1,596 (60.7%)
1,033 (39.3%)
|
0.295
|
Race
White
Black
Other
|
2,411 (80.6%)
236 (7.9%)
346 (11.6%)
|
2,349 (81.5%)
197 (6.8%)
336 (11.7%)
|
0.306
|
2,131 (81.1%)
198 (7.5%)
300 (1.4%)
|
2,142 (81.5%)
187 (7.1%)
300 (11.4%)
|
0.843
|
Charlson Score
0
1
2
3+
|
2,407 (80.4%)
459 (15.3%)
90 (3.0%)
37 (1.2%)
|
2,392 (83.0%)
386 (13.4%)
73 (2.5%)
31 (1.1%)
|
0.087
|
2,140 (81.4%)
388 (14.8%)
71 (2.7%)
30 (1.1%)
|
2,166 (82.4%)
365 (13.9%)
69 (2.6%)
29 (1.1%)
|
0.824
|
Grade
Well diff.
Moderately diff.
Poorly diff.
Not reported
|
197 (6.6%)
2,024 (67.6%)
409 (13.7%)
363 (12.1%)
|
174 (6.0%)
2,021 (70.1%)
370 (12.8%)
317 (11.0%)
|
0.222
|
166 (6.3%)
1,805 (68.7%)
349 (13.3%)
309 (11.8%)
|
166 (6.3%)
1,832 (69.7%)
340 (12.9%)
291 (11.1%)
|
0.836
|
Rad-surg interval
5–8 weeks
9–12 weeks
|
1,876 (62.7%)
1,117 (37.3%)
|
1,859 (64.5%)
1,023 (35.5%)
|
0.146
|
1,662 (63.2%)
967 (36.8%)
|
1,678 (63.8%)
951 (36.2%)
|
0.647
|
Surgery
LAR
APR
Proctocolectomy
Exenteration
|
2,027 (67.7%)
784 (26.2%)
81 (2.7%)
101 (3.4%)
|
2,028 (70.4%)
683 (23.7%)
84 (2.9%)
87 (3.0%)
|
0.114
|
1,822 (69.3%)
640 (24.3%)
75 (2.9%)
92 (3.5%)
|
1,829 (69.6%)
642 (24.4%)
76 (2.9%)
82 (3.1%)
|
0.897
|
Approach
Open
MIS
|
2,110 (70.5%)
883 (29.5%)
|
1,926 (66.8%)
956 (33.2%)
|
0.002*
|
1,806 (68.7%)
823 (31.3%)
|
1,778 (67.6%)
851 (32.4%)
|
0.407
|
Retrieved nodes
|
19.1 ± 8.1
|
19.4 ± 7.8
|
0.832
|
19.2 ± 8.3
|
19.3 ± 7.7
|
0.587
|
Positive nodes
|
3.4 ± 3.5
|
3.4 ± 3.5
|
0.146
|
3.4 ± 3.5
|
3.4 ± 3.5
|
0.887
|
T downstaging
Achieved
Not achieved
|
1,277 (42.7%)
1,716 (57.3%)
|
1,197 (41.5%)
1,685 (58.5%)
|
0.379
|
1,074 (40.9%)
1,555 (59.1%)
|
1,103 (42.0%)
1,526 (58.0%)
|
0.417
|
Path T stage
T0
T1
T2
T3
T4
|
417 (13.9%)
115 (3.8%)
591 (19.7%)
1,755 (58.6%)
115 (3.8%)
|
307 (10.7%)
102 (3.5%)
619 (21.5%)
1,744 (60.5%)
110 (3.8%)
|
0.003*
|
304 (11.6%)
92 (3.5%)
543 (20.7%)
1,582 (60.2%)
108 (4.1%)
|
302 (11.5%)
94 (3.6%)
554 (21.1%)
1,573 (59.8%)
106 (4.0%)
|
0.996
|
Median follow up
|
52.8
|
53.3
|
0.411
|
53.0
|
53.1
|
0.908
|