Improved local control of rectal cancer reduces ... - Wiley Online Library

doi:10.1111/j.1463-1318.2012.03089.x

Original article

Improved local control of rectal cancer reduces distant metastases T. E. Bernstein*, B. H. Endreseth*†, P. Romundstad‡ and A. Wibe*† on behalf of the Norwegian Colorectal Cancer Registry *Department of Surgery, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, †Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway and ‡Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway Received 13 January 2012; accepted 27 March 2012; Accepted Article online 31 May 2012

Abstract Aim The purpose of the present national study was to determine whether improved local control has been accompanied by a change in the incidence of metastases.

decreased from 25% to 19% (P < 0.001) from the first to the last period. The risk of metastases decreased by 29% (hazard ratio 0.71, 95% CI 0.60–0.84).

Method The data were from a national population-based rectal cancer registry and included all 6501 rectal cancer patients treated for cure. The study periods were 1993– 1997, 1998–2000, 2001–2003 and 2004–2006.

Conclusion Improved diagnostics and treatment of rectal cancer aiming at better local control and survival have resulted in a significant reduction in the incidence of distant metastases.

Results Major changes in the handling of rectal cancer from the first to the last study period included an increased use of MRI from zero to 81% and the use of preoperative radiotherapy from 5% to 20%. The proportion of patients with circumferential resection margin (CRM) £ 2 mm decreased from 23% to 13%. The 4-year rate of local recurrence decreased from 13% to 8% (P < 0.001), the overall survival increased from 65% to 73% (P < 0.001) and the incidence of distant metastases

Keywords Rectal cancer, national study, metastases, prognostic factors

Introduction Twenty years ago the prognosis of rectal cancer was poor due to high rates of local recurrence [1]. The introduction of total mesorectal exision (TME), improved preoperative assessment with MRI, multidisciplinary teams and tailored radiochemotherapy have resulted in a significant reduction in the rate of local recurrence [2–5]. Even today 20–40% of radically treated rectal cancer patients develop distant metastases [6], and only 25–40% of patients radically treated for metastases survive 5 years [7–11]. Among patients with metastatic disease not amenable for cure, although treated by modern chemotherapy and ⁄ or antibodies, the mean overall survival is

Correspondence to: Tor Eivind Bernstein MD, Department of Surgery, St Olavs Hospital, Trondheim N-7006, Norway. E-mail: [email protected]

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What is new in this paper? The present national cohort study, including 6501 rectal cancer patients treated for cure, is the first to report a reduced risk for metachronic distant metastases following the effort of improving the diagnostics and treatment of rectal cancer.

20–26 months [12,13]. Following the considerable reduction in local recurrence, metastatic disease is the present predominant cause of death for patients with rectal cancer. As more patients survive their local disease, more patients will be at risk of metastases. Thus, it may be anticipated that the incidence of distant metastases will increase when the rate of local recurrence is being reduced. The purpose of the present study was to examine whether the rate of distant metastases has increased during the significant reduction in local recurrence in Norway since 1993.

Method Since 1993, the Norwegian Rectal Cancer Register has prospectively collected clinical and histopathological data on standard forms for all patients treated for rectal cancer

2012 The Authors Colorectal Disease 2012 The Association of Coloproctology of Great Britain and Ireland. 14, e668–e678

Distant metastases in rectal cancer

T. E. Bernstein et al.

R0 – R2 N = 11594 Palliative patients N = 3389 Unknown R status N = 518 R0 – R1 N = 7687 Not TME, N = 934 Not AR/APR/Hartmann, N = 47 Unkn. differentiation, N = 159 Unkn. T status, N = 25 Unkn. N status,

N = 21

Study group N = 6501 Figure 1 The selection process of the study.

in Norway [2]. Survival data are given by the Norwegian Cause of Death Register. Between November 1993 and December 2006, some 11 594 patients had rectal cancer in Norway. Patients in a palliative setting, those not operated with TME or not by anterior resection, abdominoperineal excision (APR) or Hartmann’s procedure and patients with unknown tumour characteristics were excluded from detailed analysis (Fig. 1). The study cohort consisted of 6501 patients with rectal cancer located within 15 cm from the anal verge who were treated for cure by major surgery between November 1993 and December 2006. All patients underwent TME, with or without preoperative or postoperative radiochemotherapy. Short-course radiotherapy and adjuvant chemotherapy have not been used for rectal cancer in Norway. The treatment cohort was divided into four periods, 1993–1997, 1998–2000, 2001–2003 and 2004–2006, containing comparable numbers of patients. The national guidelines for neoadjuvant and adjuvant treatment have changed during the project. In 1993, TME was introduced and was soon implemented as the standard rectal resection method at a national level [2,14]. At that time long-course preoperative radiochemotherapy was recommended for fixed, primarily non-resectable tumours [3]. Postoperative radiochemotherapy was recommended

from 1999 if the circumferential resection margin (CRM) was measured to be 1 mm or less in the pathological specimen or following intra-operative perforation. Preoperative radiochemotherapy has been recommended since 2005 for T4 tumours or if the predicted CRM was 3 mm or less on MRI, given as 50 Gy in 2-Gy fractions concomitant with a radiosensitizing agent (mainly 5-fluorouracil), followed by surgery after 6–8 weeks. Stage was given in accordance with the TNM classification of malignant tumours, fifth edition (1997) [15]. The internationally accepted definition of an involved margin is a CRM £ 1 mm. As no difference exists in 5year local recurrence for patients with a CRM of 1 mm and patients with a CRM of 2 mm, analyses with CRM £ 2 mm were also included [16]. Local recurrence was defined as any clinically or histopathologically verified tumour growth within the pelvis following primary surgery. Local recurrence rates were calculated as the sum of isolated local recurrence and local recurrence with concomitant distant metastases. Distant metastasis was defined as recurrent disease outside the pelvis. In order to prevent influence from potential ‘missed’ or unconfirmed metastases during the preoperative evaluation, metastases discovered within 4 months after surgery were considered synchronous. The rates of distant metastases were calculated as the sum of metastases with or without local recurrence. Survival rates denote overall survival. As the cut-off point for follow-up was set for 31 December 2008, the Kaplan– Meier outcomes are given as 4-year rates. As information on CRM is missing for 32% of the total cohort, the multivariable analysis was run both with and without CRM. No substantial differences were observed for the impact of the periods with or without CRM. Statistical analysis

Differences between study periods were evaluated using the v2 test (Tables 1, 2 and Table 4). The Kaplan–Meier method was used to estimate 4-year rates of local recurrence, distant metastases and overall survival

Table 1 Total cohort of 10 338 patients stratified by known R-stage status. 1993–1997

1998–2000

2001–2003

2004–2006

R status

n

%

n

%

n

%

n

%

P*

R0 R1 R2

2146 224 679

70.4 7.3 22.3

1624 168 525

70.1 7.3 22.6

1704 204 556

69.2 8.3 22.5

1821 146 541

72.6 5.8 21.6

0.032

There are 1256 patients missing who were not operated on and had no known R status. *v2 test. 2012 The Authors Colorectal Disease 2012 The Association of Coloproctology of Great Britain and Ireland. 14, e668–e678

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Table 2 Characteristics of the total cohort of 6501 rectal cancer patients treated radically with TME, RT + TME and TME + RT divided in four periods. 1993–1997

Sex F M Age < 50 50–59 60–69 70–79 > 80 Tumour level 12–15 cm 6–11 cm 0–5 cm Type of resection AR APR Hartmann Tumour status (T) 1 2 3 4 Nodal status (N) 0 1 2 Differentiation High Moderate Low TNM I II III Perforation Yes No Missing Neo ⁄ adjuvant TME RT + TME TME + RT CRM £ 2 mm ‡ 3 mm Missing R stage R1 R0

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1998–2000 n

2001–2003

n

%

763 1041

42.3 57.7

660 891

42.6 57.4

708 959

42.5 57.5

640 839

43.3 56.7

0.950

97 255 493 682 277

5.4 14.1 27.3 37.8 15.4

83 219 397 547 305

5.4 14.1 25.6 35.3 19.6

95 253 434 541 344

5.7 15.2 26.0 32.5 20.6

103 207 379 461 329

7.0 14.0 25.6 31.2 22.2

< 0.001

474 795 535

26.3 44.1 29.6

467 620 464

30.1 40.0 29.9

493 675 499

29.6 40.5 29.9

449 622 408

30.4 42.1 27.5

0.051

1183 536 85

65.6 29.7 4.7

966 450 135

62.3 29.0 8.7

1027 491 149

61.6 29.5 8.9

965 398 116

65.2 26.9 7.9

< 0.001

130 492 1041 141

7.2 27.3 57.7 7.8

129 403 904 115

8.3 26.0 58.3 7.4

115 477 992 83

6.9 28.6 59.5 5.0

121 467 818 73

8.2 31.6 55.3 4.9

< 0.001

1215 427 162

67.4 23.6 9.0

1004 357 190

64.7 23.0 12.3

1059 404 204

63.5 24.2 12.3

996 333 150

67.3 22.5 10.2

0.013

154 1477 173

8.5 81.9 9.6

121 1254 176

7.8 80.9 11.3

78 1394 195

4.7 83.6 11.7

70 1237 172

4.7 83.6 11.6

< 0.001

529 686 589

29.3 38.0 32.7

436 567 548

28.1 36.6 35.3

469 590 608

28.1 35.4 36.5

465 527 487

31.5 35.6 32.9

0.093

152 1621 31

8.6 91.4

145 1375 31

9.5 90.5

162 1465 40

10.0 90.0

96 1327 56

6.7 93.3

0.010

1653 81 65

91.9 4.5 3.6

1348 103 100

86.9 6.6 6.5

1338 187 132

80.7 11.3 8.0

1075 282 63

75.7 19.9 4.4

< 0.001

213 733 858

22.5 77.5

204 861 486

19.2 80.8

229 928 510

19.8 80.2

158 1087 234

12.7 87.3

< 0.001

147 799

15.5 84.5

133 932

12.5 87.5

166 991

14.3 85.7

102 1143

8.2 91.8

< 0.001

%

n

2004–2006 %

n

%

P*




Table 2 (Continued) 1993–1997

Preop MRI Yes No Missing

1998–2000

2001–2003

2004–2006

n

%

n

%

n

%

n

%

P*

0 73 1731

10 330 1211

2.9 97.1

360 887 420

28.9 71.1

1160 270 49

81.1 18.9

< 0.001

100

TME, total mesorectal excision; RT, radiotherapy; AR, anterior resection; APR, abdominoperineal excision; CRM, circumferential resection margin. *v2 test. Seventy-four patients missing.

Table 3 Four-year rates of local recurrence, distant metastases* and overall survival among 6501 patients with rectal cancer treated for cure according to period of treatment. Local recurrence %

Metastases 95% CI

(a) All 6501 patients treated 1993–1997 12.9 11.1–14.7 1998–2000 12.9 11.1–14.7 2001–2003 9.5 7.9–11.1 2004–2006 8.1 6.3– 9.9 P < 0.001 (b) Treated with surgery only 1993–1997 12.2 10.4–14.0 1998–2000 11.6 9.8–13.4 2001–2003 8.4 6.8–10.0 2004–2006 8.1 6.1–10.1 P < 0.001 (c) Treated with preoperative radiotherapy 1993–2000 19.6 13.2–26.0 2001–2006 9.6 6.4–12.8 P 0.001

%

Survival 95% CI

%

95% CI

25.2 21.1 23.5 18.5 < 0.001

23.0–27.4 18.9–23.3 21.3–25.7 16.1–20.9

65.4 66.9 70.4 73.4 < 0.001

63.2–67.6 64.7–69.1 68.2–70.6 70.8–76.0

23.3 20.0 20.7 16.5 < 0.001

21.1–25.5 17.6–22.4 18.3–23.1 13.7–19.3

66.5 67.7 71.1 75.5 < 0.001

64.1–68.9 64.1–69.3 68.7–73.5 72.5–78.5

33.8 26.8 0.135

26.2–41.4 22.2–31.4

53.3 68.5 < 0.001

46.1–60.5 63.5–73.1

*Follow-up from 4 months after operation (44 months follow-up). Kaplan–Meier, log-rank test.

according to study periods (Table 3 and Figs 2–4), and to estimate 5-year rates for the same end-points according to tumour characteristics (Table 5). Differences between the groups were evaluated by the log-rank test. Multivariable analyses, adjusting for age, sex, tumour characteristics and periods, were performed using Cox regression (Table 6). Included variables were based on univariable analyses (Table 3 and Table 5). Figures 5–7 were created by Restricted Cubic Splines. The SPSS software for Windows version 18.0 (SPSS, Chicago, Illinois, USA) and STATA version 11.0 (StataCorp, College Station, Texas, USA) were used for all statistical analyses.

Results In the total cohort of 11 594 patients with rectal cancer 4-year overall survival substantially increased from 51.2% in 1993–1997 to 60.5% in 2004–2006 (P < 0.001), although there was only a marginal reduction of R stage during these years (Table 1). In the study cohort of 6501 patients treated by TME for cure, there were 5414 (83%) patients treated with surgery alone, 653 (10%) patients had preoperative radiochemotherapy and 360 (6%) patients had postoperative radiochemotherapy [there were 74 (1%) patients with missing information on radiochemotherapy].


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Proportion of local recurrence (%) 10 20 30 40


1998–2000 2004–2006

0

1993–1997 2001–2003

0

12

Number at risk 1993–1997 1803 1998–2000 1550 2001–2003 1667 2004–2006 1478

24 36 Time since operation (months)

1581 1372 1472 1339

1399 1207 1330 1242

48

1224 1088 1217 755

1115 983 1122 390

40

Figure 2 Local recurrence related to time of follow-up and period of treatment.

1998–2000 2004–2006

0

Proportion metastasis (%) 10 20 30

1993–1997 2001–2003

4 Number at risk 1993–1997 1710 1998–2000 1457 2001–2003 1559 2004–2006 1413

12

24 36 Time since operation (months) 1450 1272 1345 1240

1268 1125 1197 1017

1133 1009 1077 582

48

1040 931 1000 239

Figure 3 Distant metastases related to time of follow-up and period of treatment.

The patient and tumour characteristics of the four periods are shown in Table 2. In the first period 15.5% of the specimens had an involved margin (CRM £ 1 mm) vs 8.2% in the last period (P < 0.001); CRM £ 2 mm was found in 22.5% and 12.7% in the same two periods (P < 0.001). MRI was introduced for rectal cancer in Norway in the late 1990s, and only 2.9% of the patients underwent preoperative MRI between 1998 and 2000, in contrast to 28.9% between 2001 and 2003 and 81.1% of the patients between 2004 and 2006.

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During the study period fewer patients were treated by surgery alone, 91.9% of the patients in the first period and 75.7% in the last period. Similarly, 4.5% had preoperative radiochemotherapy in the first period in contrast to 19.9% between 2004 and 2006. The proportion of patients treated with postoperative radiochemotherapy increased from 3.6% to 8.0% up until 2003. After 2004, fewer patients received postoperative radiochemotherapy. Furthermore, a slight reduction in T4 cancers was observed in the last period. Inadvertent perforation during rectal cancer resection was observed among



Overall survival (%) 40 60 80

100


1998–2000 2004–2006

0

20

1993–1997 2001–2003

12

0 Number at risk 1993–1997 1804 1998–2000 1551 2001–2003 1667 2004–2006 1479

36 24 Time since operation (months)

1635 1411 1506 1365

1471 1283 1399 1291

1298 1148 1278 790

48

1180 1039 1174 414

1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1993

Hazard ratio of distant metastases (95% CI shaded)

Hazard ratio of local recurrence (95% CI-shaded)

Figure 4 Overall survival related to time of follow-up and period of treatment.

1995

1997 1999 2001 Year of operation

2003

2005

1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1993 1995 1997 1999 2001 2003 2005 Year of operation

Figure 5 Risk of local recurrence by year of operation. The grey area represents the 95% confidence intervals.

Figure 6 Risk of distant metastases by year of operation. The grey area represents the 95% confidence intervals.

8.6%, 9.5%, 10% and 6.7% in the four study periods, respectively (P = 0.010). The 4-year rates of local recurrence, metastases and overall survival for all rectal cancer patients treated for cure according to the four periods are given in Table 3, part (a), and Figs 2–4. The local recurrence rate decreased from 12.9% (95% CI 11.1–14.7) in the first period to 8.1% (95% CI 6.3–9.9) after 2004 (P < 0.001). Simultaneously, there was a continuous increase in survival, from 65.4% (95% CI 63.2–67.6) in the first period to 73.4% (95% CI 70.8–76.0) in the last period (P < 0.001). The rate of distant metastases decreased from 25.2% (95% CI 23.0–27.4) in 1993– 1996 to 18.5% (95% CI 16.1–20.9) in 2004–2006 (P < 0.001).

Similar results were observed for the 5414 rectal cancer patients treated by surgery only [Table 3, part (b)]. Comparing the first and the last periods, local recurrence decreased from 12.2% to 8.1%, distant metastases from 23.3% to 16.5% and overall survival improved from 66.5% to 75.5%. Of the 653 rectal cancer patients treated by preoperative radiochemotherapy 19.6% developed local recurrence in the first period vs 9.6% in the last period [Table 3, part (c)]. In the first period, 33.8% (95% CI 26.2–41.4) developed distant metastases compared with 26.8% (95% CI 22.2–31.4) in the last period. The overall survival increased from 53.3% to 68.5% from the first to the last period. Among the patients with local recurrence, 46.8% also developed distant


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Hazard ratio of death (95% CI shaded)



1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1993 1995 1997 1999 2001 2003 2005 Year of operation

Figure 7 Risk of death by year of operation. The grey area represents the 95% confidence intervals.

metastases, in contrast to 18.9% of the patients without local recurrence (Table 4). Five-year rates of local recurrence, distant metastases and overall survival are presented in Table 5. No difference in the three end-points exists between CRM £ 1 and CRM £ 2 mm. Distal tumours, APR, T3–4, N1–2, low differentiation, inadvertent perforation, as well as short CRM (CRM £ 1 and CRM £ 2 mm) are all associated with poor outcomes in univariable analyses. The risk of local recurrence, distant metastases and death substantially decreased during the study period. After being adjusted for sex, age, operation type, tumour level, N and T stages, differentiation and perforation, by using the first period as a reference the relative risk (hazard ratio) of local recurrence in the last period vs the first period was 0.57 (95% CI 0.45–0.74), for distant metastases it was 0.71 (95% CI 0.60–0.84) and for mortality it was 0.67 (95% CI 0.59–0.77) (Table 6). The risks of local recurrence, distant metastases and death are presented by year of operation in Figs 5–7. APR, T2–4, N1–2, inadvertent perforation, as well as short CRM (both CRM £ 1 and CRM £ 2 mm), were risk factors for development of distant metastases (Table 6).

Discussion Since the initiation of the Norwegian Rectal Cancer Project in 1993 [2], there has been a continuous effort to improve the diagnostics and treatment of rectal cancer. The rate of local recurrence is considered to be the most important marker of standards of care, and following the implementation of TME there has been a considerable reduction in the incidence of local recurrence. The main cause of death is the development of

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Table 4 The association between local recurrence and distant metastases. Distant metastases No n Local recurrence No 4447 Yes 349

Yes %

n

%

P*

81.1 53.2

1036 307

8.9 46.8

< 0.001

*v2test.

distant metastases, which present in 20–40% of rectal cancer patients [6]. This nationwide study including a large number of patients is important as it shows a significant reduction in the rate of distant metastases following the changes within diagnostics and treatment modalities of rectal cancer. A German study that included rectal cancer patients who were treated with surgery alone, and which compared the periods before and after the implementation of TME, found a decrease in local recurrence and improved survival rates [17]. However, the improvements in surgical quality had no impact on the rates of distant metastases, which remained unchanged. There is only one study showing a reduction in the rate of distant metastases by preoperative radiotherapy [18]. This study of 279 patients treated between 1981 and 1989 was conducted before the TME era. The 5-year local recurrence was 40% for patients who had preoperative radiotherapy compared with 50% for patients who had surgery alone, and the rates of distant metastases were 47% and 55% in the two groups, respectively. Thus, this study seems to be more or less anecdotal compared with contemporary treatment. A study by Folkesson et al. [19] that included patients treated with or without preoperative radiotherapy during the late 1980s showed a reduced rate of local recurrence, 9% vs 26%, and an improved survival rate in the radiotherapy group. However, there was no effect on the incidence of distant metastases. A more recent German trial, that started in 1995 and ended in 2002, described rates of local recurrence and distant metastasis of 6% and 36%, respectively, for patients treated with preoperative radiochemotherapy, and 13% and 38%, respectively, for patients treated with postoperative radiochemotherapy [4]. In spite of a significantly reduced rate of local recurrence for patients treated by preoperative radiochemotherapy, the rate of distant metastases still remained high.




Table 5 Five-year rates of local recurrence, distant metastases and overall survival for 6501 rectal cancer patients. Local recurrence % Tumour level 12–15 cm 9 6–11 cm 12.5 0–5 cm 14.1 Type of resection AR 10.2 APR 14.8 Hartmann 17.5 Tumour stage (T) 1 3.1 2 6.0 3 14.8 4 27.2 Nodal stage (N) 0 8.0 1 16.0 2 30.4 Differentiation High 8.6 Moderate 11.3 Low 18.6 Perforation No 10.4 Yes 28.3 CRM ‡ 3 mm 9.5 £ 2 mm 25.5 R-stage R0 10.0 R1 28.7

Metastases

Survival

95% CI

P*

%

95% CI

P*

%

95% CI

P*

7.6–10.4 11.1–13.9 12.3–15.9

< 0.001

22.4 22.8 26.8

20.2–24.6 21.0–24.6 24.6–29.0

0.016

67.2 68.7 56.9

65.0–69.4 67.1–70.3 54.5–59.3

< 0.001

9.2 –11.2 13.0–16.6 13.1–21.9

< 0.001

21.9 28.1 25.5

20.5–23.3 25.7–30.5 20.3–30.7

< 0.001

65.7 65.1 48.4

60.9–70.5 63.7–66.5 44.4–52.4

< 0.001

1.3–4.9 4.8–7.2 13.4–16.2 21.8–32.2

< 0.001

6.6 12.4 30.4 43.0

4.2–9.0 10.8–14.0 28.8–32.0 38.5–47.8

< 0.001

83.0 74.0 58.1 39.8

79.4–86.6 71.8–76.2 56.5–59.7 34.8–44.8

< 0.001

7.0–9.0 13.8–18.2 26.0–34.8

< 0.001

15.4 33.1 59.0

14.2–16.6 30.3–35.9 54.6–63.4

< 0.001

70.5 55.9 34.3

69.1–71.9 53.3–58.5 30.5–38.5

< 0.001

5.6–11.6 10.3–12.3 15.2–22.0

< 0.001

18.1 22.7 37.1

13.9–22.3 21.5–23.9 32.9–41.3

< 0.001

65.7 65.1 48.4

60.9–70.5 63.7–66.5 44.0–52.4

< 0.001

9.0–11.0 23.3–32.9

< 0.001

22.8 34.7

21.6–24.0 29.9–39.5

< 0.001

65.1 45.6

63.7–66.5 41.2–50.0

< 0.001

8.5–10.5 21.7–29.3

< 0.001

21.9 44.5

20.3–23.5 40.3–48.7

< 0.001

66.8 43.2

65.2–68.4 39.6–46.8

< 0.001

9.0–11.0 23.9–33.5

< 0.001

22.8 48.5

21.2–24.4 43.5–53.5

< 0.001

65.6 40.0

63.9–67.2 36.0–44.0

< 0.001

AR, anterior resection; APR, abdominoperineal excision; CRM, circumferential resection margin. *Kaplan–Meier, log-rank test.

Thus, although TME surgery has been shown to reduce the rate of local recurrence and to improve survival, a cohort study has never found a reduction in the rate of distant metastases, even when in combination with radiochemotherapy, neither as a preoperative regimen nor as a postoperative regimen. In the present study, MRI was not performed in the first period, but the use of MRI increased from 2.9% to 81.1% from the second to the last period. Most probably, improvements in staging were important for the increase in use of preoperative radiochemotherapy, from 4.5% to 19.9%, from the first to the last period. The rate of T4 tumours was reduced from 7.8% to 4.9%, and T3 tumours from 57.7% to 55.3%. The downstaging was probably a result of the increased use of preoperative radiochemotherapy observed towards

the last study period, as staging was based on the reports from pathologists. It has previously been found that inadvertent perforation increases the risk of local recurrence and death [20]. In the present study, inadvertent perforation also increased the risk of distant metastases. Increased use of radiochemotherapy and possibly improved preoperative planning and surgery during the last period might have contributed to the reduction in inadvertent perforations from 10.0% to 6.7% from the third to the last period. This reduction might also have influenced the reduced risk of distant metastases. Reporting of CRM distance has been incomplete, although increasing from 53% to 84% from the first to the last study period. During the first years many pathologists only reported free lateral margins without


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Table 6 Risk factors for local recurrence, distant metastases and mortality in rectal cancer patients. Local recurrence

Tumour level 12–15 cm 6–11 cm 0–5 cm Type of resection AR APR Hartmann Tumour stage (T) 1 2 3 4 Nodal stage (N) 0 1 2 Differentiation High Moderate Low Perforation No Yes Periods 1993–1997 1998–2000 2001–2003 2004–2006 CRM ‡ 3 mm £ 2 mm R stage R0 R1

Metastases P*

HR

95% CI

1.0 1.42 1.53

1.16–1.74 1.13–2.01

1.0 1.04 1.23

0.79–1.35 0.92–1.66

1.0 1.84 3.71 6.69

1.05–3.22 2.17–6.35 3.77–11.88

1.0 1.77 3.30

1.47–2.13 2.68–4.05

1.0 1.15 1.28

0.79–1.66 0.84–1.95

1.0 2.33

1.89–2.86

1.0 0.88 0.66 0.57

0.72–1.07 0.54–0.81 0.45–0.74

1.0 1.54

1.24–1.93

1.0 1.79

1.41–2.27

0.002

0.376

< 0.001

< 0.001

0.452

< 0.001

< 0.001

< 0.001

< 0.001

HR

95% CI

1.0 1.05 1.00

0.91–1.20 0.89–1.37

1.0 1.29 1.12

1.07–1.56 0.89–1.42

1.0 1.77 3.71 5.60

1.97–2.61 2.55–5.40 3.73–8.43

1.0 2.15 4.25

1.89–2.44 3.68–4.91

1.0 1.03 1.22

0.80–1.32 0.92–1.62

1.0 1.23

1.03–1.46

1.0 0.77 0.85 0.71

0.66–0.89 0.74–0.98 0.60–0.84

1.0 1.48

1.27–1.73

1.0 1.60

1.35–1.90

Mortality P*

0.638

0.031

< 0.001

< 0.001

0.093

0.024

< 0.001

< 0.001

< 0.001

HR

95% CI

1.0 1.11 1.14

1.00–1.21 0.99–1.31

1.0 1.19 1.41

1.05–1.35 1.24–1.60

1.0 1.23 1.77 2.80

1.03–1.47 1.49–2.10 2.28–3.43

1.0 1.41 2.56

1.29–1.54 2.30–2.85

1.0 0.95 1.19

0.82–1.10 1.00–1.42

1.0 1.40

1.25–1.57

1.0 0.79 0.80 0.67

0.72–0.87 0.73–0.88 0.59–0.77

1.0 1.38

1.23–1.54

1.0 1.39

1.23–1.58

P*

0.069

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

HR, hazard ratio; AR, anterior resection; APR, abdominoperineal excision; CRM, circumferential resection margin. *Cox regression multivariable analysis. Analysed together with all independent variables. CRM and R stage analysed separately from each other.

measuring the exact distance between the tumour and the plane of dissection. Such slow implementation of new histopathological variables and incomplete registration of major prognostic factors might represent a bias. In order to evaluate any such possibility, patients with unknown CRM and patients with known CRM were analysed, showing that patients with unknown CRM had similar rates of local recurrence, distant metastases and overall survival to patients with CRM ‡ 3 mm (data not given). During the study periods, a short CRM was

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observed less often, as 15.5% of the patients had CRM £ 1 mm in 1993–1997 compared with 8.2% in 2004–2006, and the rate of CRM £ 2 mm was 22.5% and 12.7% in the same two periods. The decrease in the proportion of patients with a short or an involved margin is probably related to improved standards of surgery and the tailored use of preoperative radiochemotherapy. This is in contrast with the results from a single centre study in Oxford, where increased preoperative MRI diagnostics and neoadjuvant treatment did not




reduce the incidence of short CRM, nor local recurrence [21]. The present study as well as previous Norwegian reports on national cohorts have confirmed that a short CRM is a major prognostic factor, not only for local recurrence and survival but also for distant metastases, whether neoadjuvant treatment is given or not [16,22]. Thus, most certainly the decrease in the proportion of patients with a short margin in the present study has played an important role by reducing the rate of distant metastases. Despite a tendency towards improvement for distant metastases from the first to the last two periods among the patients having neoadjuvant treatment, no significant level of difference was observed, most probably because very few patients had neoadjuvant treatment in the first two periods (type II error). Towards the end of the 1980s, the local recurrence rate in Norway was 28%. Among the patients who developed local recurrence, 47% also had distant metastases [1]. Similarly, in the present study, 46.8% of the patients with local recurrence had distant metastases, in contrast to the 18.9% of the patients without local recurrence. There is obviously a strong association between development of local recurrence and distant metastases. Local recurrence and distant metastases are two expressions of advanced disease and ⁄ or failed therapy, given by the nature of the primary tumour (T status, N status, differentiation, MRI based CRM, venous and neural invasion etc.), and of the quality of the treatment, given by the neoadjuvant radiochemotherapy and the surgery (TME, inadvertent perforation, involved margin etc.). As the present study has an observational design, one has to interpret the causes and outcome with caution. The strengths of these analyses are related to the population-based design, and demonstrate that nationwide strategic changes can improve outcome within a few years also within a routine treatment setting. In conclusion, steps taken at a national level to improve diagnostics and treatment of rectal cancer, initially focusing on better local control and overall survival, have also reduced the incidence of distant metastases.

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Acknowledgements

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The authors thank Liv Marit Dørum and Ingunn Aune for all their efforts in collecting data and securing the quality of the Norwegian rectal cancer database.

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Conflict of interest There are no conflicts of interest.

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