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Evaluation of appropriate follow-up after curative surgery for patients with colorectal cancer using time to recurrence and survival after recurrence: a retrospective multicenter study

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Oncotarget. 2018; 9:25474-25490. https://doi.org/10.18632/oncotarget.25312

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Tomoki Yamano _, Shinichi Yamauchi, Kiyoshi Tsukamoto, Masafumi Noda, Masayoshi Kobayashi, Michiko Hamanaka, Akihito Babaya, Kei Kimura, Chihyon Son, Ayako Imada, Shino Tanaka, Masataka Ikeda, Naohiro Tomita and Kenichi Sugihara and Japanese Study Group for Postoperative Follow-up of Colorectal Cancer

Abstract

Tomoki Yamano1, Shinichi Yamauchi2, Kiyoshi Tsukamoto1, Masafumi Noda1, Masayoshi Kobayashi1, Michiko Hamanaka1, Akihito Babaya1, Kei Kimura1, Chihyon Son1, Ayako Imada1, Shino Tanaka1, Masataka Ikeda1, Naohiro Tomita1, Kenichi Sugihara2 and Japanese Study Group for Postoperative Follow-up of Colorectal Cancer

1Division of Lower GI Surgery, Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

2Division of Colorectal Surgery, Department of Surgery, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence to:

Tomoki Yamano, email: yamanot@hyo-med.ac.jp

Keywords: colorectal cancer; curative surgery; follow-up; recurrence; survival

Received: March 02, 2018    Accepted: April 12, 2018    Published: May 22, 2018

ABSTRACT

Background: The follow-up schedule for colorectal cancer patients after curative surgery is inconsistent among the guidelines. Evaluation of time to recurrence (TTR) and survival after recurrence (SAR) may provide evidence for appropriate follow-up.

Methods: We assessed 3039 colon cancer (CC) and 1953 rectal cancer (RC) patients who underwent curative surgery between 2007 and 2008. We evaluated the pre- and post-recurrent clinicopathological factors associated with TTR and SAR in each stage of CC and RC.

Results: The recurrence rates of stages I, II, and III were 1.2%, 13.1%, and 26.3%, respectively, for CC, and 8.4%, 20.0%, and 30.4%, respectively, for RC. In CC patients, high carcinoembryonic antigen (CEA) level and lymphovascular invasion were independent predictors of short TTR. In RC patients, metastatic factors (liver metastasis in stage III) and venous invasion (stage III) were independent predictors of short TTR. The prognostic factors of SAR were age (stage II CC and stage III RC), female gender (stage III RC), high CEA level (stage II RC), histological type (stage III CRC), nodal status (stage III CC), recurrence within 1 year (stage III RC), M1b recurrence (stage II CRC), local recurrence (stage II CC), and no surgical resection after recurrence (stage II and III CRC).

Conclusions: The follow-up schedule for stage I should be different from that for the other stages. We recommend that intensive follow-up is appropriate in stage III CC patients with undifferentiated adenocarcinoma or N2 nodal status, stage II RC patients with high preoperative CEA level, and stage III RC patients.


INTRODUCTION

Colorectal cancer (CRC) is one of the most common malignancies worldwide [1]. CRC has been increasing annually in Japan, and was estimated to be the most common malignancy in 2016 and the second most common cause of cancer-related deaths in 2014 [2].

Recurrence rates vary among patients who receive curative surgery, with recurrence reported in about 30% of stage III patients, 15% of stage II patients, and <5% of stage I patients in Japan [3]. Adequate surveillance is therefore required to both reduce costs and improve survival. However, surveillance is generally provided for patients without any recurrence.

The usefulness of intensive surveillance with routine carcinoembryonic antigen (CEA) monitoring and computed tomography (CT) scans remains controversial. Although early detection of recurrence has been shown to improve survival, early detection using intensive surveillance did not always result in improved overall survival [49]. The guidelines of the Japanese Society for Cancer of the Colon and Rectum propose intensive surveillance, including CEA checks every 3 months and CT every 6 months for 3 years, regardless of clinical stage and risk of recurrence [10]. This reflects the intensive surveillance schedules recommended by the European Society for Medical Oncology, American Society of Clinical Oncology, and National Comprehensive Cancer Network (NCCN) guidelines, which recommended CEA checks every 3–6 months and CT every 6–12 months for 2–3 years, depending on the risk of the patient [1115].

However, these surveillances are not strictly categorized by risk factors other than clinical stage. Information on time to recurrence (TTR) and survival after recurrence (SAR) may help to determine the appropriate follow-up schedule, and has previously been used to evaluate the usefulness of intensive follow-up in clinical trials and meta-analysis [3, 5, 7, 8].

In this study, we evaluated the clinicopathological factors predicting TTR and SAR in patients with colon cancer (CC) or rectal cancer (RC) during intensive follow-up after curative resection, to determine the factors influencing the appropriate follow-up schedule.

RESULTS

Differences in clinicopathological factors between CC and RC

We compared the clinicopathological factors between CC and RC (Table 1). Age group, gender, preoperative CEA level, tumor depth, nodal status, venous invasion, application of adjuvant therapy, and clinical stage all differed significantly between the two locations.

Table 1: Clinicopathological factors of patients by tumor location

Location

CC

RC

P value

CC

RC

P value

Factors

(N=3039)
Number (%)

(N=1953)
Number (%)

CC vs RC

Recurrence
rate

P value

Recurrence
rate

P value

CC vs RC

Age

  ≤64

1041 (34)

998 (51)

<0.0001

15.4%

NS

19.3%

NS

0.018

  65–74

1090 (36)

629 (32)

13.1%

21.6%

<0.0001

  75≤

908 (30)

326 (17)

13.4%

18.4%

0.03

Gender

  Male

1678 (55)

1192 (61)

<0.0001

14.8%

NS

21.4%

0.041

<0.0001

  Female

1361 (45)

761 (39)

13.0%

17.6%

0.0044

Preoperative CEA

  High

831 (27)

561 (29)

0.043

23.9%

<0.0001

30.5%

<0.0001

0.0068

  Normal

2115 (70)

1310 (67)

10.3%

15.3%

<0.0001

  Unknown

93 ( 3)

82 (4)

9.7%

20.7%

0.04

Histological Type

  Well/Moderately

2867 (94)

1881 (96)

0.0069

13.6%

NS

19.2%

0.0002

<0.0001

  Poorly

74 (2)

31 (2)

21.6%

41.9%

0.034

  Mucinous

98 (3)

41 (2)

18.4%

36.6%

0.021

Tumor depth

  T1

592 (19)

355 (18)

<0.0001

1.0%

<0.0001

4.8%

<0.0001

0.0003

  T2

447 (15)

438 (22)

3.6%

11.9%

<0.0001

  T3

1411 (46)

971 (50)

14.0%

25.4%

<0.0001

  T4

589 (19)

189 (10)

35.0%

38.6%

NS

Nodal status

  N0

2039 (67)

1256 (64)

<0.0001

7.9%

<0.0001

14.1%

<0.0001

<0.0001

  N1

786 (26)

483 (25)

22.3%

26.3%

NS

  N2

214 (7)

214 (119)

41.1%

39.7%

NS

Lymphatic invasion

  ly0

1323 (44)

793 (41)

NS

8.9%

<0.0001

13.1%

<0.0001

0.0023

  ly1

1261 (41)

853 (44)

14.9%

21.3%

0.0001

  ly2

378 (12)

262 (13)

23.5%

32.4%

0.013

  ly3

58 (2)

37 (2)

48.3%

45.9%

NS

  Unknown

19 (1)

8 (0)

10.5%

12.5%

NS

Venous invasion

  v0

1193 (39)

610 (31)

<0.0001

6.4%

<0.0001

10.5%

<0.0001

0.0025

  v1

1188 (39)

765 (39)

15.3%

19.3%

0.021

  v2

493 (16)

436 (22)

23.5%

30.0%

0.025

  v3

140 (5)

125 (6)

32.1%

35.2%

NS

  Unknown

25 (1)

17 (1)

20%

11.8%

NS

Stage

  I

890 (29)

641 (33)

<0.0001

1.2%

<0.0001

8.4%

<0.0001

<0.0001

  II

1149 (38)

614 (31)

13.1%

20.0%

0.0002

  III

1000 (33)

697 (36)

26.3%

30.4%

NS

Adjuvant therapy

 Stage I

  Yes

18 (2)

26 (4)

0.019

5.6%

NS

7.7%

NS

NS

  No

872(98)

615 (96)

1.1%

8.5%

<0.0001

 Stage II

  Yes

184 (16)

126 (20)

0.019

17.9%

0.036

25.4%

NS

NS

  No

965 (84)

489 (80)

12.2%

18.6%

0.001

 Stage III

  Yes

643 (64)

509 (73)

0.0002

25.8%

NS

31.0%

NS

NS

  No

357 (36)

188 (27)

27.2%

28.7%

NS

CEA: Carcinoembryonic antigen, CC: colon cancer, NS: Not significant, Poorly: poorly differentiated adenocarcinoma, Mucinous: mucinous adenocarcinoma.

RC: rectal cancer, Well/Moderately: well differentiated/moderately differentiated adenocarcinoma.

Factors associated with recurrence

The recurrence rates of stages I, II, and III CC were 1.2% (11/890), 13.1% (151/1149), and 26.3% (263/1000), and of RC were 8.4% (54/641), 20.0% (123/614), and 30.4% (212/697), respectively (Table 1). High preoperative CEA level, tumor depth, nodal status, lymphatic invasion, venous invasion, and clinical stage were significantly associated with recurrence, regardless of tumor location (Table 1). Gender and histological type were significantly associated with recurrence in RC, but not in CC.

We also assessed the influence of tumor location on recurrence in relation to each clinicopathological factor (Table 1). There were significant differences in recurrence rates between CC and RC for patients in each age group, with each CEA level, each histological type, and with tumor depth of T1-3, N0 nodal status, lymphatic invasion of ly0-2, venous invasion of v0-2, stage I-II and stage I-II without adjuvant therapy. However, there were no significant differences in recurrence rates by tumor location in relation to clinically-advanced factors including: depth of T4, N1 and N2 nodal status, lymphatic invasion of ly3, venous invasion of v3, and stage III.

Factors associated with RFS and OS

RFS was significantly influenced by preoperative CEA level, histological type, tumor depth, nodal status, stage, lymphatic invasion, and venous invasion, regardless of tumor location (Figures 1, 2). RFS was also significantly influenced by gender in patients with RC (Figure 2). OS was significantly influenced by age, gender, preoperative CEA level, tumor depth, nodal status, stage, lymphatic invasion, and venous invasion, regardless of tumor location (Figures 3, 4). OS was also significantly influenced by histological type in RC alone (Figure 4).

Figure 1:

Figure 1: Relapse-free survival (RFS) in colon cancer according to (A) age, (B) gender, (C) CEA level, (D) histological type, (E) tumor depth, (F) nodal status, (G) clinical stage, (H) lymphatic invasion, and (I) venous invasion. Subgroups were compared with log-rank test. P values were provided when differences were significant (P<0.05) and as NS when differences were not significant.

Figure 2:

Figure 2: Relapse-free survival (RFS) in rectal cancer according to (A) age, (B) gender, (C) CEA level, (D) histological type, (E) tumor depth, (F) nodal status, (G) clinical stage, (H) lymphatic invasion, and (I) venous invasion. Subgroups were compared with log-rank test. P values were provided when differences were significant (P<0.05) and as NS when differences were not significant.

Figure 3:

Figure 3: Overall survival (OS) in colon cancer according to (A) age, (B) gender, (C) CEA level, (D) histological type, (E) tumor depth, (F) nodal status, (G) clinical stage, (H) lymphatic invasion, and (I) venous invasion. Subgroups were compared with log-rank test. P values were provided when differences were significant (P<0.05) and as NS when differences were not significant.

Figure 4:

Figure 4: Overall survival (OS) in rectal cancer according to (A) age, (B) gender, (C) CEA level, (D) histological type, (E) tumor depth, (F) nodal status, (G) clinical stage, (H) lymphatic invasion, and (I) venous invasion. Subgroups were compared with log-rank test. P values were provided when differences were significant (P<0.05).

Clinicopathological factors in patients with recurrence

Age group, gender, tumor depth, nodal status, stage, TTR, type of recurrence, and sites of recurrence differed significantly between CC and RC in patients with recurrence (Table 2). The liver was the most common metastatic site in CC patients, followed by the lungs, peritoneum, and distant lymph nodes. In contrast, the lungs were the most common metastatic site in RC patients, followed by the liver, local recurrence, and distant lymph nodes. There was no significant difference in preoperative CEA, histological type, or treatment after recurrence according to tumor location.

Table 2: Clinicopathological factors of patients with recurrence by tumor location

Factors / Location

CC (N=425)
Number (%)

RC (N=389)
Number (%)

P value CC vs RC

Age

 ≤64 / 65–74/ 75≤

160/143/122
(38/33/29)

193/136/60
(50/35/15)

<0.0001

Gender

 Male / Female

248/177
(58/42)

255/134
(66/34)

0.035

Preoperative CEA

 High / Normal / Unknown

199/217/9
(47/51/2)

171/201/17
(44/52/4)

NS

Histological Type

 Well/Moderately / Poorly /Mucinous

391/16/18
(92/2/2)

361/13/15
(93/3/4)

NS

Tumor depth

 T1 / T2 / T3 / T4

6/16/197/206
(1/4/46/48)

17/52/247/73
(4/13/63/19)

<0.0001

Nodal status

 N0 / N1 / N2

162/175/88
(38/41/21)

177/127/85
(46/33/22)

0.034

Lymphatic invasion

 ly0 / ly1 / ly2 / ly3/Unknown

118/188/89/28/2
(28/44/21/7/1)

104/182/85/17/1
(27/47/22/4/0)

NS

Venous invasion

 v0 / v1 / v2 / v3 / Unknown

77/182/116/45/5
(18/43/27/11/1)

64/148/131/44/2
(16/38/34/11/1)

NS

Stage

 I / II / III

11/151/263
(3/36/62)

54/123/212
(14/32/54)

<0.0001

Time to recurrence (year)

 < 1 / 1–2/ 2–3 / 3≤

190/136/64/35
(45/32/15/8)

142/122/57/68
(37/31/15/17)

0.0007

Type of recurrence

 Local alone /M1a / M1b

29/251/145
(7/59/34)

77/243/69
(20/62/18)

<0.0001

Liver metastasis

 (+) / (-)

203/222
(48/52)

128/261
(33/67)

<0.0001

Lung metastasis

 (+) / (-)

130/295
(31/69)

148/241
(38/62)

0.025

Peritoneal metastasis

 (+) / (-)

83/342
(20/80)

28/361
(7/93)

<0.0001

Local metastasis

 (+) / (-)

41/384
(10/90)

112/277
(29/71)

<0.0001

Distant lymph node metastasis

 (+) / (-)

63/362
(15/85)

45/344
(12/88)

NS

Adjuvant therapy

 (+) / (-)

200/225
(47/53)

192/197
(49/51)

NS

Treatment after recurrence

 Best supportive care / Surgery (-) / Surgery (+)

38/188/199
(9/44/47)

30/167/192
(8/43/49)

NS

CEA: Carcinoembryonic antigen, CC: colon cancer, Mucinous: mucinous adenocarcinoma, NS: Not significant, Poorly: poorly differentiated adenocarcinoma, RC: rectal cancer, Well/Moderately: well differentiated/moderately differentiated adenocarcinoma

Time to recurrence (TTR)

TTR was significantly longer in stage III patients with RC compared with CC patients, but not in stage I and II patients (Figure 5A-5C). The 1-, 2-, 3-, and 5-year accumulative recurrence rates in CC patients were 18%, 46%, 73%, and 91% for stage I; 46%, 78%, 90% and 99% for stage II; 53%, 80%, 94% and 97% for stage III, respectively (Figure 5D). The equivalent recurrence rates in RC patients were 17%, 41%, 65%, and 87% for stage I; 49%, 81%, 94%, and 98% for stage II; 44%, 71%, 83%, and 98% for stage III respectively (Figure 5E).

Figure 5:

Figure 5: Time to recurrence (TTR) and accumulative recurrence rate (A-E), and survival after recurrence (SAR) and survival rate (F-J), by clinicopathological factors. TTR and accumulative recurrence rate in: (A) stage I patients by colon cancer (CC) and rectal cancer (RC), (B) stage II patients by CC and RC, (C) stage III patients by CC and RC, (D) CC by stage, (E) RC by stage. SAR and survival rate in: (F) stage I patients by CC and RC, (G) stage II patients by CC and RC, (H) stage III patients by CC and RC, (I) CC by stage, (J) RC by stage. Subgroups were compared with log-rank test. P values were provided when differences were significant (P<0.05) and NS was used when differences were not significant.

We further assessed TTR for CC and RC patients depending on stage, except for stage I, because there were fewer patients and longer TTR than for the other stages.

TTR in stage II CC was significantly associated with gender, preoperative CEA level, lymphatic invasion, and distant lymph node metastasis (Table 3). TTR in stage III CC was significantly associated with preoperative CEA level, lymphatic invasion, and venous invasion (Table 3). Multivariate analysis showed that high preoperative CEA level and lymphatic invasion were independent predictors for short TTR in both stage II and stage III CC (Table 4).

Table 3: Summary of associations between clinicopathological factors and TTR

Location

Colon cancer

Rectal cancer

Stage

Stage II (N=151)

Stage III (N=263)

Stage II (N=123)

Stage III (N=212)

Factors

Mean
(months)

P

Mean (months)

P

Mean
(months)

P

Mean
(months)

P

Age

 ≤74

17.5

NS

16.6

NS

16.2

NS

20.0

NS

 75≤

18.0

13.9

17.4

19

Gender

 Male

19.6

0.04

16.5

NS

16.9

NS

20.5

NS

 Female

15.3

14.8

15.3

18.7

Preoperative CEA

 High

14.7

0.02

14.1

0.04

16

NS

18.8

NS

 Normal/Unknown

20.3

17.5

16.7

20.9

Histological Type

 Well/Moderately

17.5

NS

16.0

NS

16.3

NS

20.2

NS

 Poorly/Mucinous

20.5

14.1

18

16.7

Tumor depth

 T1

-

NS

15.3

NS

NS

28.5

NS

 T2

-

14.9

30.7

 T3

19.3

13.9

15.7

19.2

 T4

15.6

15.8

19.2

18.7

Nodal status

 N0

17.7

-

NS

16.4

-

0.03

 N1

16.3

21.8

 N2

14.9

16.9

Lymphatic invasion

 ly0/1

18.5

0.008

16.7

NS

15.8

NS

16.7

NS

 ly2/3

11.4

15.1

20.4

22.0

 ly0-2

17.8

NS

16.4

0.008

16.4

-

20.6

0.009

 ly3

13

10.3

-

11.9

Venous invasion

 v0/1

18.7

NS

17.2

NS

15.3

NS

22.4

0.02

 v2/3

15.7

14.0

17.5

17.1

 v0-2

17.9

NS

16.6

0.001

16.3

NS

20.0

NS

 v3

15.2

9.7

16.9

18.9

Adjuvant therapy

 Yes

16.3

NS

16.9

NS

13.9

NS

19.7

NS

 No

18.1

14.0

17.3

20.3

Type of recurrence

 M1a

18.8

NS

15.5

NS

17.4

NS

21.0

0.02

 M1b

15.0

15.2

13

14.8

 Local alone

20.5

23.4

15.7

22.9

Liver metastasis

 (-)

18.6

NS

16.9

NS

18.6

0.01

23.0

<0.0001

 (+)

16.8

14.5

13

12.8

Lung metastasis

 (-)

17.2

NS

15.6

NS

15.8

NS

19.4

NS

 (+)

18.5

16.2

17.6

20.4

Peritoneal metastasis

 (-)

17.8

NS

16.2

NS

16.4

NS

20.2

NS

 (+)

16.9

14.3

16

17.3

Local recurrence

 (-)

17.6

NS

15.5

NS

16.8

NS

19.4

NS

 (+)

18.1

18.9

15.4

21.1

Distant LN metastasis

 (-)

18.3

0.04

15.2

NS

27.7

0.02

19.8

NS

 (+)

11.9

18.4

15.5

20.4

CEA: Carcinoembryonic antigen, LN: lymph node, Mucinous: mucinous adenocarcinoma, NS: Not significant, Poorly: poorly differentiated adenocarcinoma, TTR: time to recurrence, Well/Moderately: well differentiated/moderately differentiated adenocarcinoma.

Table 4: Multivariate analysis of predictors for short TTR

Location

Colon cancer

Rectal cancer

Stage

Stage II

Stage III

Stage II

Stage III

Factors

HR
CI

P

HR
CI

P

HR
CI

P

HR
CI

P

Gender: Male

0.73
0.53-1.02

NS

CEA: High

1.47
1.06-2.03

0.02

1.34
1.04-1.73

0.02

Nodal status: N2

1.23
0.92-1.64

NS

Lymphatic invasion

 ly2/3

1.83
1.03-3.05

0.04

 ly3

1.73
1.09-2.64

0.02

1.5
0.86-2.45

NS

Venous invasion

 v2/3

1.42
1.07-1.88

0.01

 v3

1.63
1.09-2.36

0.02

Type of recurrence:

 M1b

1.25
0.88-1.74

NS

Recurrence sites

 Liver (+)

1.44
0.99-2.09

NS

1.92
1.41-2.61

<0.0001

 Distant LN: (+)

1.53
0.84-2.61

NS

0.52
0.23-1.03

NS

CEA: Carcinoembryonic antigen, CI: confidence interval, HR: hazard ratio, LN: lymph node, NS: Not significant, TTR: time to recurrence.

TTR in stage II RC was significantly associated with metastatic factors (liver metastasis and distant lymph node metastasis), but not pathological factors. TTR in stage III RC was significantly associated with both pathological factors (lymphatic invasion and vascular invasion) and metastatic factors (M1b recurrence and liver metastasis) (Table 3). Multivariate analysis showed that venous invasion and liver metastasis were independent predictors for short TTR in stage III RC (Table 4).

Survival after recurrence (SAR)

The 5-year survival rates after recurrence for CC and RC were 81% and 77% in stage I; 55% and 58% in stage II; 40% and 39% in stage III, respectively (Figure 5F–5H). There were significant differences in the 5-year SAR rates among stages, but not between CC and RC (Figure 5F–5J).

SAR was significantly associated with age (all groups), gender (stage III RC), CEA level (stage I/II RC), histological type (stage III CRC), tumor depth (CC), nodal status (stage III CC), lymphatic invasion (stage III CRC), adjuvant therapy (stage III RC), recurrence within 1 year (stage III RC), M1b recurrence (stage II/III CRC), liver metastasis (stage II RC), peritoneal metastasis (CC and stage III RC), local recurrence (stage II CC), and treatment after recurrence (all groups) (Table 5).

Table 5: Summary of associations between clinicopathological factors and SAR

Location

Colon cancer

Rectal cancer

Stage

Stage II (N=151)

Stage III (N=263)

Stage II (N=123)

Stage III (N=212)

Factors

Mean
(months)

P

Mean (months)

P

Mean
(months)

P

Mean
(months)

P

Age

 ≤74

59.1

0.0001

46.9

0.005

64.2

0.01

51.1

<0.0001

 75≤

33.3

34.1

35.0

24.2

Gender

 Male

51.9

NS

44.9

NS

59.5

NS

51.6

0.004

 Female

51.9

41.5

64.7

39.6

Preoperative CEA

 High

48.8

NS

44.9

NS

46.8

0.049

45.6

NS

 Normal/Unknown

55.4

41.6

67.9

50.0

Histological Type

 Well/Moderately

52.6

NS

45.8

0.003

61.8

NS

50.3

<0.0001

 Poorly/Mucinous

44.5

18.4

17.4

23.8

Tumor depth

 T1

0.009

16

0.002

NS

55

NS

 T2

34.7

42.8

 T3

49.3

53.4

62.8

49.7

 T4

48.4

35.8

55.9

48.0

Nodal status

 N1

47.1

0.02

50.3

NS

 N2

36.4

41.5

Lymphatic invasion

 ly0/1

51.4

NS

46.5

NS

63.2

NS

50.7

NS

 ly2/3

49.6

38.7

37.2

40.7

 ly0-2

53.4

NS

45.5

0.004

61.6

-

49.2

0.005

 ly3

14.7

16.3

-

29.6

Venous invasion

 v0/1

51.5

NS

44.0

NS

65.8

NS

48.9

NS

 v2/3

51.3

43.3

54.3

45.6

 v0-2

50.6

NS

44.3

NS

60.7

NS

48.3

NS

 v3

58.1

38.8

53.7

44.2

Adjuvant therapy

 Yes

57.0

NS

45.0

NS

65.5

NS

50.9

0.02

 No

50.9

41.1

58.8

37.7

Time to recurrence

 less than 1 year

48.9

NS

37.8

NS

58.1

NS

41.2

0.004

 more than 1 year

53.0

48.1

62.9

50.4

Type of recurrence

 M1a

59.0

0.0002

49.8

0.0001

61.2

0.001

53.6

0.0002

 M1b

43.8

33.6

35.2

29.6

 Local alone

42.7

46.8

64.9

43.2

Liver metastasis

 (-)

46.7

0.01

41.3

NS

60.4

NS

47.4

NS

 (+)

57.8

46.3

48.9

48.4

Lung metastasis

 (-)

56.0

NS

42.8

NS

65.9

0.02

46.0

NS

 (+)

42.7

45.0

46.3

49.0

Peritoneal metastasis

 (-)

54.2

0.03

47.8

<0.0001

62.5

NS

50.0

0.001

 (+)

45.2

29.3

15.4

21.8

Local recurrence

 (-)

54.1

0.04

44.1

NS

59.6

NS

48.3

NS

 (+)

42.6

41.2

57.0

46.0

Distant LN metastasis

 (-)

53.7

NS

44.5

NS

61.2

NS

49.4

NS

 (+)

43.1

37.4

66.8

28.9

Therapy after recurrence

 Surgical resection (-)

34.2

<0.0001

32.9

<0.0001

44.0

<0.0001

35.1

<0.0001

 Surgical resection (+)

65.8

57.5

74.4

62.2

CEA: Carcinoembryonic antigen, LN: lymph node, NS: Not significant, Mucinous: mucinous adenocarcinoma, Poorly: poorly differentiated adenocarcinoma, SAR: survival after recurrence, Well/Moderately: well differentiated/moderately differentiated adenocarcinoma.

Multivariate analysis identified the following independent prognostic factors: age (stage II CC and stage III RC), female gender (stage III RC), high CEA level (stage II RC), histological type (stage III CRC), nodal status (stage III CC), recurrence within 1 year (stage III RC), M1b recurrence (stage II CRC), local recurrence (stage II CC), and no surgical resection after recurrence (stage II and III CRC) (Table 6).

Table 6: Multivariate analysis of prognostic factors for SAR

Location

Colon cancer

Rectal cancer

Stage

Stage II

Stage III

Stage II

Stage III

Factors

HR
CI

P

HR
CI

P

HR
CI

P

HR
CI

P

Age:
 75≤

2.71
1.56-4.67

0.0005

1.33
0.93-1.9

NS

1.77
0.81-3.56

NS

1.78
1.03-2.96

0.04

Gender:
 Female

1.69
1.14-2.47

0.009

CEA:
 High

2.33
1.34-4.11

0.003

Histological type:
 Poorly/Mucinous

2.04
1.15-3.41

0.02

2.54
1.34-4.54

0.005

Tumor depth:
 T4

1.42
0.84-2.43

NS

1.32
0.93-1.87

NS

Nodal status:
 N2

1.5
1.05-2.12

0.03

Lymphatic invasion:
 ly3

1.23
0.66-2.15

NS

Recurrence:
 within 1 year

1.64
1.12-2.4

0.01

Type of recurrence:
 M1b

2.50
1.25-4.83

0.01

1.39
0.84-2.18

NS

2.69
1.31-5.25

0.008

1.68
0.97-2.78

NS

Recurrence sites

 Liver (+)

1.04
0.58-1.84

NS

 Lung: (+)

1.25
0.68-2.24

NS

 Peritoneal: (+)

0.74
0.35-1.61

NS

1.37
0.82-2.36

NS

1.11
0.53-2.27

NS

 Local: (+)

3.54
1.5-7.69

0.005

No adjuvant therapy

1.00
0.64-1.53

NS

No surgical resection after recurrence

5.0
2.73-9.45

<0.0001

2.36
1.64-3.43

<0.0001

3.41
1.93-6.18

<0.0001

4.03
2.65-6.25

<0.0001

CEA: Carcinoembryonic antigen, CI: confidence interval, HR: hazard ratio, Mucinous: mucinous adenocarcinoma, NS: Not significant, Poorly: poorly differentiated adenocarcinoma, SAR: survival after recurrence.

DISCUSSION

We evaluated the clinicopathological factors associated with TTR and SAR in patients with CC and RC, as critical factors for guiding appropriate follow-up after curative surgery [35]. Appropriate follow-up after curative surgery has been proposed by TTR or the accumulative recurrence rate, but not SAR.

The recurrence rate in this study (16.3%) was similar to those in previous studies [3, 7]. The recurrence rate in stage I CC patients was only 1.2%, so we excluded these patients from analysis of TTR and SAR. The recurrence rate in stage I RC patients was 8.4%, and the accumulative recurrence rates were 16.7% and 64.8% at 1 and 3 years, respectively. Therefore, stage I RC patients may require different surveillance from stage II and III patients. We also excluded stage I RC patients for further analysis of TTR and SAR.

Among stage II and III patients, the accumulative recurrence rate was about 50% at 1 year, which was higher than in some previous reports, but similar to that in the FACS trial involving intensive surveillance, including CT [3, 7]. The 2- and 3-year recurrence rates in patients with stages II and III were 70%–80% and 80%–90%, respectively. These are similar to the previous data by Kobayashi et al and suggest that intensive surveillance with CEA checks every 3 months are necessary for at least 3 years, in contrast to the NCCN recommendation of 2 years [3, 14, 15].

TTR differed significantly between CC and RC in stage III patients. Predictors for TTR were different between CC and RC. In CC, patients with high preoperative CEA level and lymphovascular invasion could be followed-up as candidates for early recurrence. On the other hand, predictors in RC were venous invasion and liver metastasis. Therefore, follow-up in RC should include CT to evaluate liver metastasis.

Our data showed that predictors for TTR were not prognostic factors for SAR. Short TTR has been previously reported to influence survival in small cases of study [16, 17]. In this study, recurrence within 1 year was an independent prognostic factor for poor SAR in stage III RC patients. Age (≥75), type of recurrence (M1b), and treatment after recurrence (surgical resection) were also identified as independent prognostic factors for SAR in the current study. Surgical resection was considered a strong prognostic factor for advanced CRC [18, 19]. Recent improvement of treatments against metastatic CRC may provide better SAR than that in current study [20, 21].

Therefore, we proposed that patients with prognostic factors for poor SAR should receive intensive treatment and follow-up after curative surgery. These patients include stage III CC patients with undifferentiated adenocarcinoma or N2 nodal status, stage II RC patients with high preoperative CEA level, and stage III RC patients.

Our study had several limitations. First, it was a retrospective study, and we had no genetic information, such as RAS mutation and microsatellite instability statuses, which are critical genetic markers for prognosis and treatment. KRAS mutation analysis has been available for clinical use in Japan since 2010. Moreover, universal screening for Lynch syndrome was performed in <10% of the hospitals specializing in CRC treatment in Japan [22]. Genetic information was therefore not considered for CRC treatment at the time of surgery in this study. Second, this study also lacked information on the usage of molecular-targeted drugs. Vascular endothelial growth factor and epidermal growth factor antibodies have been used clinically in Japan since 2007 and 2008, respectively. Patients with recurrence should thus have received these drugs for treatment after recurrence. Finally, this was a retrospective study with no rules about follow-up or treatment after surgery, or treatment after recurrence.

Although it seems advisable to detect recurrence as soon as possible to improve the chances of curative resection, the usefulness of intensive follow-up remains controversial. Furthermore, it is unclear if early detection of recurrence could increase the rate of curative treatment and improve survival. Our data demonstrated that short TTR was an independent prognostic factor for SAR in stage III RC patients, who should have received intensive follow-up. However, further prospective studies are needed to confirm our results. Genetic assessment is indispensable in the era of molecular-targeted therapy.

MATERIALS AND METHODS

Patients and data collection

This retrospective multicenter study was conducted by the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer (JFUP-CRC). Clinical data were collected for CRC patients who underwent curative surgery at 22 hospitals in Japan between 2007 and 2008. The study was approved by the institutional review board or ethics committee at each hospital and was performed according to the Declaration of Helsinki and Ethical Guidelines for Clinical Research. All patients provided written informed consent. The JFUP-CRC office pooled and prepared the data available for clinical study, as described in the 7th edition of the Japanese Classification of Colorectal Carcinoma [23]. Lymphatic (ly) or venous (v) invasion was classified according to the degree of invasion, as follows: no invasion (ly0/v0), minimal invasion (ly1/v1), moderate invasion (ly2/v2), or severe invasion (ly3/v3). A total of 4992 CRC patients who underwent curative resection in 2007 and 2008, without preoperative chemotherapy/radiotherapy, hereditary CRC, lateral lymph node metastasis, or colitic cancer, were considered suitable for assessment. These patients usually received follow-up with CEA tests every 3 months and CT every 6 months for 3 years, and then CEA every 6 months and CT every 12 months for 3–5 years. The median follow-up time was 72 months in all patients and 60 months in patients with recurrence.

Data analysis

Differences in clinicopathological factors according to tumor location (CC or RC) were analyzed for all patients and for patients with recurrence. Factors associated with recurrence were assessed using χ2 tests.

The influences of clinicopathological factors on relapse-free survival (RFS) and overall survival (OS) in all patients, and TTR and SAR in patients with recurrence were assessed using log-rank tests. Prognostic factors associated with TTR and SAR were subjected to multivariate analyses using a Cox proportional hazard model or logistic analysis. A P value of <0.05 was considered significant for all analyses.

CONCLUSIONS

We recommend that intensive follow-up after surgery is appropriate in stage III CC patients with undifferentiated adenocarcinoma or N2 nodal status, stage II RC patients with high preoperative CEA level, and stage III RC patients.

Abbreviations

CC: Colon Cancer; CEA: Carcinoembryonic antigen; CRC: Colorectal cancer; CT: Computed tomography; JFUP-CRC: Japanese study group for postoperative follow-up of colorectal cancer; NCCN: National Comprehensive Cancer Network; OS; Overall survival; RC: Rectal cancer; RFS; Relapse free survival; SAR: Survival after recurrence; TTR: Time to recurrence.

Author contributions

Conception and study design: TY. Data analysis: TY, SY. Acquisition of data: TY, SY, KT, MN, MK, MH, AB, SC, AI, ST, MI, NT, KS. Manuscript writing: TY. All authors read and approved the final version of the manuscript.

ACKNOWLEDGMENTS

We thank the members of JFUP-CRC for collecting the clinical data: I. Takemasa (Sapporo Medical University), K. Hakamada (Hirosaki University), H. Kameyama (Niigata University), Y. Takii (Niigata Cancer Center Hospital), K. Hase (National Defense Medical College), H. Ozawa (Tochigi Cancer Center), H. Nozawa (Tokyo University), K. Takahashi (Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital), Y. Kanemitsu (National Cancer Center Hospital), M. Itabashi (Tokyo Women’s Medical University), H. Yano (National Center for Global Health and Medicine), Y. Kinugasa (Tokyo Medical and Dental University), H. Hasegawa (Keio University), Y. Hashiguchi (Teikyo University), T. Masaki (Kyorin University), M. Watanabe (Kitasato University), T. Hanai (Fujita Health University), K. Komori (Aichi Cancer Center Hospital), Y. Sakai (Kyoto University), M. Ohue (Osaka Medical Center for Cancer and Cardiovascular Diseases), S. Noura (Osaka Rosai Hospital), and Y. Akagi (Kurume University).

We also thank Editage for editing the English text of a draft of this manuscript.

DECLARATIONS

Ethics approval and consent to participate

This study was approved by the Central Institutional Review board (Tokyo Medical and Dental University) and local ethical committee. Written informed consent was obtained from all patients.

Availability of data and material

The datasets used and analyzed during this study are available from the corresponding author on reasonable request under permission of JFUP-CRC.

CONFLICTS OF INTEREST

The authors declare that they have no competing interest.

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