Introduction
Materials and methods
Patients
Neoadjuvant therapy
Pathologic examination and tumor budding
Follow-up and oncologic outcomes
Statistical analysis
Results
Patients
All (n = 128) | Tumor budding | |||||||
---|---|---|---|---|---|---|---|---|
Characteristics | BD-0 (n = 47) | BD-1 (n = 81) | P-value | Test | ||||
Age
| 0.44 | |||||||
Mean, years (SD) | 64 | (10) | 63 | (10) | 64 | (10) | T | |
Gender, n (%)
| 0.45 | |||||||
Female | 41 | (32) | 17 | (41) | 24 | (59) | C | |
Male | 87 | (68) | 30 | (34) | 57 | (66) | ||
ASA classification, n (%)
| 0.44 | |||||||
1 | 24 | (19) | 11 | (46) | 13 | (54) | C | |
2 | 77 | (60) | 25 | (32) | 52 | (68) | ||
3 | 27 | (21) | 11 | (41) | 16 | (59) | ||
BMI
| 0.54 | |||||||
Mean, kg/m2 (SD) | 25.2 | (3.9) | 25.5 | (4.1) | 25.0 | (3.8) | T | |
Clinical UICC stage, n (%)
| 0.60 | |||||||
I | 1 | (1) | 1 | (100) | 0 | (0) | E | |
II | 57 | (45) | 21 | (37) | 36 | (63) | ||
III | 66 | (52) | 23 | (35) | 43 | (65) | ||
No. missing | 4 | (3) | 2 | – | 2 | – | ||
Clinical T stage, n (%)
| 0.008 | |||||||
T1 | – | – | – | – | – | – | E | |
T2 | 3 | (2) | 2 | (67) | 1 | (33) | ||
T3 | 107 | (84) | 43 | (40) | 64 | (60) | ||
T4 | 16 | (13) | 1 | (6) | 15 | (94) | ||
No. missing | 2 | (2) | 1 | – | 1 | – | ||
Clinical N stage, n (%)
| 0.90 | |||||||
N0 | 58 | (45) | 22 | (38) | 36 | (62) | E | |
N1 | 56 | (44) | 20 | (36) | 36 | (64) | ||
N2 | 10 | (8) | 3 | (30) | 7 | (70) | ||
No. missing | 4 | (3) | 2 | – | 2 | – | ||
Procedure, n (%)
| 0.75 | |||||||
APE | 36 | (28) | 14 | (39) | 22 | (61) | C | |
LAR | 92 | (72) | 33 | (36) | 59 | (64) | ||
Other malignancies, n (%)
| 0.07 | |||||||
No | 110 | (86) | 44 | (40) | 66 | (60) | E | |
Yes | 18 | (14) | 3 | (17) | 15 | (83) | ||
Time: end CRT to surgery
| 0.68 | |||||||
Median, weeks | 5.1 | 5.1 | 5.1 | M | ||||
(Range) | (2.7–9.3) | (2.9–8.9) | (2.7–9.3) |
All (n = 128) | Tumor Budding | |||||||
---|---|---|---|---|---|---|---|---|
Characteristics | BD-0 (n = 47) | BD-1 (n = 81) | P-value | Test | ||||
AJCC/CAP TRG, n (%)
| <0.001 | |||||||
0 | 16 | (13) | 16 | (100) | 0 | (0) | E | |
1 | 39 | (30) | 26 | (67) | 13 | (33) | ||
2 | 54 | (42) | 3 | (6) | 51 | (94) | ||
3 | 19 | (15) | 2 | (11) | 17 | (89) | ||
Histologic grade, n (%)
| 0.15 | |||||||
Well/moderate | 106 | (83) | 42 | (40) | 64 | (60) | E | |
Poor | 22 | (17) | 5 | (23) | 17 | (77) | ||
ypUICC, n (%)
| <0.001 | |||||||
0 | 15 | (12) | 15 | (100) | 0 | (0) | E | |
I | 38 | (30) | 22 | (58) | 16 | (42) | ||
II | 38 | (30) | 3 | (8) | 35 | (92) | ||
III | 37 | (29) | 7 | (19) | 30 | (81) | ||
Pathologic T stage, n (%)
| <0.001 | |||||||
T0 | 16 | (13) | 16 | (100) | 0 | (0) | E | |
T1 | 7 | (5) | 5 | (71) | 2 | (29) | ||
T2 | 36 | (28) | 19 | (53) | 17 | (47) | ||
T3 | 64 | (50) | 7 | (11) | 57 | (89) | ||
T4 | 5 | (4) | 0 | (0) | 5 | (100) | ||
Pathologic N stage, n (%)
| 0.01 | |||||||
N− | 92 | (72) | 40 | (43) | 52 | (57) | C | |
N+ | 36 | (28) | 7 | (19) | 29 | (81) | ||
Nodes examined
| 0.54 | |||||||
Median (range) | 14 | (0–33) | 14 | (0–27) | 14 | (3–33) | M | |
Mean (SD) | 13.6 | (5.9) | 13.1 | (5.7) | 14 | (6.0) | ||
Nodes involved
| 0.02 | |||||||
Median (range) | 0 | (0–14) | 0 | (0–12) | 0 | (0–14) | M | |
Mean (SD) | 1 | (2.4) | 0.6 | (2) | 1.2 | (2.5) | ||
Lymphatic invasion, n (%)
| 0.003 | |||||||
No | 90 | (83) | 40 | (44) | 50 | (56) | E | |
Yes | 19 | (17) | 2 | (11) | 17 | (89) | ||
No. missing | 19 | 5 | 14 | |||||
Venous invasion, n (%)
| 0.13 | |||||||
No | 105 | (95) | 42 | (40) | 63 | (60) | E | |
Yes | 6 | (5) | 0 | (0) | 6 | (100) | ||
No. missing | 17 | 5 | 12 | |||||
Adjuvant Chemotherapy, n (%)
| 0.70 | |||||||
No | 57 | (45) | 22 | (39) | 35 | (61) | C | |
Yes | 71 | (55) | 25 | (35) | 46 | (65) | ||
CRM, n (%)
| 0.09 | |||||||
>1 mm | 121 | (95) | 46 | (38) | 75 | (62) | E | |
≤1 mm | 6 | (5) | 0 | (0) | 6 | (100) | ||
No. missing | 1 | 1 | 0 |
Tumor budding and response
Follow-up and events
Time to event analyses
5-year estimates (95% CI) | |||||||||
---|---|---|---|---|---|---|---|---|---|
Parameter | Events |
n
| All gradesa | BD-0 (n = 47) | BD-1 (n = 81) | P-valueb | |||
Overall survival | 20 | 126 | 84 | (76–89) | 90 | (76–96) | 80 | (69–87) | 0.09 |
Relapse-free survival | 27 | 126 | 78 | (70–84) | 90 | (76–96) | 71 | (60–80) | 0.02 |
Overall recurrence | 15 | 126 | 11 | (7–18) | 2 | (0–16) | 16 | (9–26) | 0.04 |
Local recurrence | 6 | 126 | 5 | (2–11) | 0 | – | 7 | (3–17) | 0.27 |
Distant recurrence | 12 | 126 | 9 | (5–16) | 2 | (0–16) | 12 | (7–23) | 0.03 |
Parameter | 5-year RFS (%) | P-valuea |
---|---|---|
BD
|
0.015
| |
None/minimal (BD-0) | 90 | |
Moderate/severe (BD-1) | 71 | |
Age, years
|
0.03
| |
≤64 | 86 | |
>64 | 68 | |
Gender
| 0.23 | |
Female | 85 | |
Male | 74 | |
ASA classification
|
0.002
| |
ASA 1 and 2 | 84 | |
ASA 3 | 54 | |
BMI (kg/m
2
)
| – | 0.64 |
Surgical procedure
|
0.05
| |
APE | 67 | |
LAR | 82 | |
Laparoscopic
|
0.08
| |
No | 73 | |
Yes | 88 | |
Adjuvant chemotherapy
| 0.22 | |
No | 73 | |
Yes | 83 | |
Time CRT to surgery (weeks)
| – | 0.97 |
Other malignancies
b
|
0.01
| |
No | 81 | |
Yes | 61 | |
ypUICC
|
0.01
| |
0/I | 86 | |
II | 67 | |
III | 78 | |
ypT
|
0.02
| |
0/1/2 | 87 | |
3/4 | 70 | |
ypN−/+
| 0.84 | |
Negative | 78 | |
Positive | 78 | |
Angiolymphatic invasion
| 0.97 | |
No | 77 | |
Yes | 76 | |
Grading
| 0.80 | |
1 | 100 | |
2 | 78 | |
3 | 77 | |
CRM
|
<0.001
| |
>1 mm | 80 | |
≤1 mm | 33 |
95% CI for HR | ||||
---|---|---|---|---|
HR | Lower | Upper | P-value | |
Tumor budding
| 0.02 | |||
BD-0 (none/mild) | 1 | – | – | – |
BD-1 (moderate/severe) | 3.44 | 1.23 | 9.63 | – |
ASA classification
| 0.003 | |||
ASA 1 and 2 | 1 | – | – | – |
ASA 3 | 3.23 | 1.48 | 7.08 | – |
CRM
| 0.02 | |||
>1 mm | 1 | – | – | – |
≤1 mm | 3.09 | 1.21 | 7.89 | – |
Discussion
Huebner et al. [37] | Du et al. [39] | Bhangu et al. [24] | Sannier et al. [38] | Present study | |
---|---|---|---|---|---|
Design | RS | RS | RS | RS | RS |
Publication year | 2012 | 2012 | 2013 | 2014 | 2018 |
Institute | Mayo Clinic, Rochester, USA | Beijing Cancer Hospital China | Imperial College, London, UK | Beaujon Hospital, Clichy, France | PMU, Salzburg, Austria |
Period | 1996–2006 | 2001–2005 | 2009–2011 | 2005–2010 | 2003–2012 |
Intent | Curative | Curative | Curative | Curative | Curative |
Patients (n) | 237 | 96 | 69 | 113 | 128 |
Age (years) | Mean 60 | Median 57 | 14 of 54 > 65 | Median 59 | Mean 64 |
Type of tumor | Primary | Primary | Recurrent: n = 15 Primary: n = 54 | Primary | Primary |
Tumor location (from anal verge) | ≤12 cm | ≤1 cm | – | ≤12 cm | ≤12 cm |
Tumor stage | I, II, III | II, III | Locally advanced | I–IV | II, III |
Neoadjuvant therapy | CRT | RT | CRT | CRT | CRT |
Radiation scheme | Not mentioned | 3000 cGy in 10 fractions in 2 weeks (36 Gy) | Fractionated, maximum dose of 54 Gy | 45–50 Gy over 5–6 weeks | 45–50 Gy over 5–6 weeks |
Concurrent chemotherapy | 5-FU | – | 5-FU or capecitabine | 5-FU | 5-FU, capecitabine, Oxaliplatin |
Interval to surgery (weeks) | 6–8 | 2–3 | ≤6 | 6–9 | 3–9 |
Postoperative chemotherapy | 233 (98.3%) | All patients | Not found | If ypN+ staged or distant metastases | 47.9% (58 of 121) |
Tumor budding present | 24 (10.1%) | 36 (37.5%) | 25 of 45 (55.5%) | 25 (22.1%) | 81 (63.2%) |
Median follow-up (years) | 3.5 | 5.9 | – | 2.9 | 7 |
Associated with | CSS, RFS | DFS | OS, CSS | LR | DR, OR, RFS |
Local recurrence | 6 (2.5%) | – | – | 5 (4.6%) | 6 (4.7%) |
Distant recurrence | 43 (18.1%) | – | – | 30 (27.8%) | 12 (9.4%) |