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Risk factors for postoperative recurrence of Crohn's disease
GASTROENTEROLOGY
198:3:85:917-21
Risk Factors for Postoperative Recurrence of Crohn’s Disease DAVID
B. SACHAR,
ADRIAN ROGER
DAVID
J. GREENSTEIN, STYCZYNSKI,
Departments Mount Sinai
M.
WOLFSON,
JUDITH
and HENRY
Eventual disease recurrence is the most common postoperative complication of Crohn’s disease (1). Consequently, many investigators continue to search for clinical and pathological predictors of postoperative recurrence rates (2,3). In a recent follow-up study of 119 patients with Crohn’s disease who 1982. Accepted April 22, 1983. Address requests for reprints to: David B. Sachar, M.D., Division of Gastroenterology. Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. Dr. Wolfson‘s present address is Maimonides Medical Center. Brooklyn, Nelv York 11219. C 1983 by the American Gastroenterological Association OOlfi-5085:83!$3.00
D. JANOWITZ
of Medicine (Gastroenterology), Surgery, School of Medicine of the City University
To identify potential risk factors that influence postoperative recurrence rates of Crohn’s disease, the postoperative recurrence-free survival of 93 patients who underwent their first resections at The Mount Sinai Hospital between 1964 and 1973 has been examined. Features analyzed individually and jointly were age, sex, anatomic location, operative procedure, and preoperative disease duration. In patients with Crohn’s colitis, recurrence rates appeared somewhat lower among 11 patients with ileostomy than among 5 patients with anastomosis. In the entire series, recurrence rates were lowest in patients with longest preoperative durations (p = 0.02). This same tendency was especially marked among the 68 patients without ileostomies (p = 0.005). Likewise, among the 38 patients with ileitis, the relative risk of recurrence was significantly lowexceeding 10 yr (p er for those with disease duration = 0.01). Relative risk of recurrence in the entire series for patients with 2-yr duration was 1.5 compared with those who had lo-yr duration. This inverse association between preoperative disease duration and postoperative recurrence rate may reflect persisting differences between inherently more aggressive versus more indolent forms of Crohn’s disease.
Received July 6.
GOLDBERG, and Biomathematical Sciences of New York, New York
of the
underwent their first resection at The Mount Sinai Hospital between 1964 and 1973, the effects of six variables on the rates of postoperative recurrence were analyzed: age, sex, anatomic location of disease, operative procedure (anastomosis vs. ileostomy), preoperative duration of disease, and presence or absence of granulomas in the resected surgical specimen (4). Each of these variables was examined individually and jointly for its influence on cumulative postoperative recurrence-free survival. In a previous publication, our findings concerning the influence of granulomas on postoperative recurrence rates of Crohn’s disease were reported in detail (5). It was concluded that the presence or absence of granulomas in resected specimens exerted no independent influence upon recurrence rates. In this paper, the findings are described with respect to each of the five remaining clinical variables that we studied.
Methods As in our previous study (5) we reviewed the charts of 498 patients with Crohn’s disease who were admitted to The Mount Sinai Hospital between 1964 and 1973. Of these patients, 124 had undergone their first completely extirpative resection at the institution in this lime. In five instances the surgical pathologic studies were not available for review. The remaining 119 patients whose slides were available all manifested histopathologic criteria characteristic of Crohn’s disease, as established by LockhartMummery and Morson (6). Clinical follow-up examination was subsequently obtained by contact with patients and their physicians, and whenever possible by review of hospital and office records. Follow-up data were available for 93 patients (78%), who did not differ from the remaining 26 patients in age or sex
distribution,
procedures,
anatomic
preoperative
of granulomas.
The
location duration
results
of disease,
of disease,
reported
here
surgical
or frequency are
based
on
918
SACHAR
ET AL.
GASTROENTEROLOGY
analyses of these 93 cases with follow-up ranging from 1 to 15 yr. Recurrence was defined radiologically and/or surgically. Symptoms alone were not sufficient to establish a diagnosis of recurrence without objective documentation, so as not to confuse nonspecific symptoms of bile salt diarrhea, food intolerance, motor disturbance, postoperative adhesions, etc., with true recurrence of Crohn’s disease. Criteria for recurrence were identical to those in our most recent study (5) and were essentially the same as those applied for the original diagnosis (6). Although all symptomatic patients were investigated, there was no systematic effort to screen for asymptomatic recurrence, so that recurrence rates may be artifactually somewhat inflated by ascertainment bias favoring selection of symptomatic patients in a data. Cumulative recurstudy with only 78% follow-up rence rates were calculated as in our previous studies (1,5). Patients were considered as remaining at risk from the time of initial resection until the onset of symptoms proved to be due to disease recurrence, or if no recurrence was documented, then until the date of last follow-up examination. Patients in different subgroups defined by age, sex, location of disease, surgical procedure, and preoperative disease duration were compared with respect to the other clinical characteristics using cross-tabulation methods. Postoperative recurrence-free survival curves were compared using Gehan’s generalized Wilcoxon procedure
Table
1. Age at Operation
Vol.
85, No. 4
Disease
by Preoperative
Duration Duration
Age (yr)
52
(yr)
2-10
Total
>lO
523 23-40 >40
10” 5 7
36” 13 27
17" 28 8
61b 72 31
1" 6 11
4" 15 42
28" 39 26
100" 100 100
Total
2.2
24
53
57
18
20
93
100
(1Number
of patients.
b Percent
of total
in that age group.
(Breslow’s extension) (7) and Mantel-Cox logrank procedures (8). All calculations were performed with computer program PlL (9). Multivariate methods including logrank procedures and Cox regression models for censored data (10) were then used to examine the joint effects of these clinical features upon recurrence rates.
Results Sex There study group. men (median 7 yr), and 30 postoperative recurrence-free and women
were 45 men and 48 women in the There were 24 recurrences among the postoperative recurrence-free survival recurrences among the women (median recurrence-free survival 4 yr). The survival curves were similar for men (logrank x2’ = 1.6, p = 0.2).
IO-
4
0
& 0@
Age
0.8-
5 $ 0.62: 5$0435
0.2-
00-
2
4
6 YEARS
Figure
8
IO
12
14
16
AFTER OPERATION
1. Cumulative postoperative recurrence-free survival in 93 patients with Crohn’s disease as a function of age at time of operation. Closed circles represent the proportion surviving without a recurrence at each year in which some recurrence was noted. In this and all succeeding figures, the numbers below the abscissa indicate, for each year of follow-up study, the numbers of recurrences within the preceding year over the number of patients who were still at risk during that year. The recurrence rates are lowest in the 26 patients over 40 yr old (13 recurrences), intermediate in the 39 patients between 23 and 40 yr old (21 recurrences], and highest in the 28 patients 23 yr old or younger (19 recurrences], but the differences among the three curves are not statistically significant (Wilcoxon x2’ = 1.3, p = 0.53; logrank xzz = 2.2, p = 0.34).
The median age at time of initial resection was 30 yr. Cumulative recurrence rates were calculated for three age groups (Figure 1): patients over 40 yr (the oldest quartile), those under 23 yr (the youngest quartile), and those between 23 and 40 yr. The recurrence rates were similar for the three age groups (logrank xz” = 2.2, p = 0.34). However, those patients who were older at the time of surgery had longer preoperative durations of disease (Table 1). Duration of disease rather than age appeared to exert the stronger influence on recurrence rates in this series.
Anatomical
Distribution
Anatomical distributions of disease were similar to those reported in most other series (11): 38 patients with ileitis (41%), 39 with ileocolitis (42%), 16 with colitis (17%). Recurrence rates appeared similar among these subgroups (Figure 2).
Ileostomy
versus
Anastomosis
Ileostomies were performed in 25 patients and anastomoses in 68 patients. No patient with ileitis
October
RECURRENCE
1983
“+,__.
‘.
‘..
‘S,
,....
*.__._-_---____ *_-------------__.
lleltlr
____
._-.
lleocolltls
O/--1 TIME
Figure
IN YEARS
(follow-up)
2. Cumulative postoperative recurrence-free survival for each anatomic category of Crohn’s disease. Recurrence rates are shown for the 39 patients with ileocolitis (21 recurrences), for the 38 with ileitis (23 recurrences), and for the 16 with colitis (7 recurrences). The differences among the curves are not statistically significant (Wilcoxon xLZ = 0.7. )I = 0.70; logrank xe’ = 1.0, p = 0.60).
underwent ileostomy. Among the 39 ileocolitis patients, recurrence rates in the 14 patients with ileostomy (seven recurrences) and in the 25 patients with (17 recurrences] were comparable (loganastomosis rank x1’ = 0.39, p = 0.53). The different operations, however, may have been associated with different recurrence rates among the 16 patients with Crohn’s disease limited to the colon. Although the numbers were very small, recurrence rates appeared somewhat lower in the 11 patients with ileostomy (three recurrences) than among the 5 patients with anastomosis [four recurrences) (Wilcoxon x1’ = 2.5, p = 0.11; logrank x1’ = 3.2, p = 0.08). In the combined colitis and ileocolitis groups, patients with ileostomy again had a somewhat lower risk of recurrence than did patients with anastomosis (logrank x1’ = 2.7, p = 0.10).
Preoperative
RATES
IN CROHN’S
DISEASE:
919
durations (Figure 3), (Wilcoxon x1’ = 5.5, p = 0.02; of logrank x1’ = 5.3, p = 0.02). This influence disease duration was observed even within the younger age groups, although the numbers were small. We further estimated the relative risk of recurrence from a Cox model analyzing the effect of disease duration as either a discrete or a continuous variable. In the entire series, the relative risk of recurrence for patients with 2-yr duration was 1.5 compared with patients with 10 yr of disease, either with or without adjustment for age. This same effect of preoperative duration was especially clear among the 68 patients without ileostomies (Figure 4) (Wilcoxon x1’ = 6.4, p = 0.004; logrank x1’ = 8.0, p = 0.005). The cumulative 5-yr postoperative recurrence rate in this group was -65’% for patients with up to lo-yr duration, versus only 23% for patients with >lO-yr duration. Similarly, among the 38 ileitis patients, none of whom had ileostomies, the relative risk of recurrence over a 15-yr follow-up period was significantly greater for patients with preoperative disease duration of 510 yr (21 recurrences among 29 patients) than among patients with duration >lO yr (two recurrences among 9 patients) (logrank x1’ = 6.0, p = 0.01). This apparent influence of preoperative disease duration could theoretically be confounded by associated influences of age, sex, and location of disease. For example, as we have already seen [Table l), the proportion of patients with long preoperative disease durations increases with older ages at time of operation. Yet from a series of Cox models using age, sex, anatomic location, and preoperative duration, as
Duration
Preoperative duration of disease appeared to exert an important influence on recurrence rates. Recurrence-free survival was significantly lengthened in patients with longer preoperative duration. Preoperative duration of disease, as judged by onset of characteristic symptoms, was 52 yr in 22 patients, 2-10 yr in 53 patients, and >lO yr in 18 patients. The recurrence-free survival curves were different for these three groups (Wilcoxon xz2 = 5.95, p = 0.05). This difference was due primarily to the recurrence rates in patients with disease duration >lO yr being lower than the rates in the patients with shorter
Figure
3. Cumulative postoperative recurrence-free survival as a function of preoperative duration of Crohn’s disease. The recurrence rate is significantly lower in the 18 patients with >lO yr of disease (6 recurrences) than in the 75 patients with 510 yr of disease before operation (48 recurrences). (Wilcoxon ,yIL = 5.5. p = 0.02; logrank x,’ = 5.3, p = t1.02.)
920
SACHAR
ET AL
I
I.0 - *\‘\
sQ
I
I
I
I
I
I
I
-
- ---t
??
k;
0.8-
8;
0.6-
r
Figure
GASTROENTEROLOGY
‘\,.__., ?? \ .
‘\ .__.--_____------. >lOyrs
\
4. Cumulative postoperative recurrence-free survival among 68 Crohn’s disease patients who underwent resection and anastomosis. The recurrence rate is significantly lower among the 14 patients with >lO-yr preoperative disease duration (4 recurrences) than among the 54 patients whose duration was 210 yr (40 recurrences). (Wilcoxon x1 ’ = 8.4, p = 0.004; logrank x,2 = 8.0, p = 0.005.)
well as age-duration interactions, both individually and jointly, only disease duration made a statistically significant contribution to the model to explain the observed data.
85, No. 4
patients with shorter preoperative disease duration has also been noted in many other centers (Is--19), although an opposite trend has been suggested (20). We are not proposing that there is any intrinsic influence of preoperative duration per se on recurrence rates. To the contrary, it seems likely that differences in preoperative duration are reflections in turn of different “clinical patterns” of disease (21) and hence of different indications for surgery. It may well be these patterns themselves, rather than preoperative durations per se, that determine recurrence rates. In other words, inherently aggressive instances of Crohn’s disease, which bring their victims to surgery early, may recur early; while more indolent cases, which lead to operation later, may recur later. Besides, there are other potentially important determinants of recurrence rate which we have not investigated at all, such as radicalness of resection, regarding the influence of which some controversy still exists (20,22-26). The point remains, however, that studies of recurrence rates in Crohn’s disease should not focus exclusively on single determinants like location of disease (31, without considering the potential influences of other related variables such as operative procedure and especially preoperative duration of disease.
References
Discussion The two principal conclusions arising from this study are [a) that recurrence rates appear lower in Crohn’s colitis patients after ileostomy than after anastomosis and (b) that at least in patients without ileostomy, rates of recurrence are lowest in those patients with the longest preoperative durations of disease. With respect to the difference between ileostomy and anastomosis, our numbers are too small to achieve statistical significance, but the finding has been repeatedly made before. For example, the Birmingham group have demonstrated that for Crohn’s disease involving the colon, recurrence rates are lower after panproctocolectomy and ileostomy than after any other operative procedure (12). Glotzer (13) has recently reviewed the evidence that Crohn’s disease recurs relatively infrequently after total colectomy and ileostomy. Of course, these differences in recurrence rates could reflect different disease characteristics providing different indications for ileostomy versus anastomosis. Nothing in these data suggests, therefore, that ileostomy is a “better” choice than anastomosis for any given patient. Moreover, many other considerations besides recurrence rates alone must enter into choice of operation (14). The tendency toward higher recurrence rates in
Vol.
1. Greenstein
2.
3.
4.
5.
6.
7. 8.
9. 10. 11.
AJ, Sachar DB, Paternack BS, Janowitz HD. Reoperation and recurrence in Crohn’s colitis and ileocolitis: crude and cumulative rates. N Engl J Med 1975;293:685-90. Mekhjian HS, Switz DM, Watts HD, Deren JJ, Katon RM, Beman FM. National Cooperative Crohn’s Disease Study: factors determining recurrence of Crohn’s disease after surgery. Gastroenterology 1979;77:907-13. Lock MR, Farmer RG, Fazio VW, Jagelman DG, Lavery IC, Weakley FL. Recurrence and reoperation for Crohn’s disease: the role of disease location in prognosis. N Engl J Med 1981;304:1586-8. Wolfson DM, Sachar DB, Cohen A, et al. Do granulomas affect recurrence rates in Crohn’s disease? (abstr). Gastroenterologp 1981;80:1319. Wolfson DM, Sachar DB, Cohen A, et al. Granulomas do not affect postoperative recurrence rates in Crohn’s disease. Gastroenterology 1982;83:405-9. Lockhart-Mummery HE, Morson BC. Crohn’s disease (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1960;1:87-105. Gehan EA. A general Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 1965;52:203-23. Peto R, Rike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation. II: analysis and examples. Br J Cancer 1977;35:1-39. Dixon WJ, ed. BMDP statistical software 1981. Berkeley: University of California Press, 1981. Cox DR. Regression models and life tables. J Roy Stat Sot B 1972;34:187-200. Janowitz HD, Sachar DB. Clinical, laboratory and certain differential diagnostic features of noncolitic Crohn’s disease.
October
1983
In: Kirsner JB. Shorter RG, eds. Inflammatory bowel disease, 2nd ed. Philadelphia: Lea & Febiger 1980:150-65. 12. Allan R, Steinberg DM, Alexander Williams J, Cooke WT. Crohn’s disease involving the colon: an audit of clinical management. Gastroenterology 1977:73:723-32. 13. Glotzer DJ. Recurrence in Crohn’s colitis: the numbers game. World J Surg 1980:4:173-9. 14. Meyers S, Walfish JS, Sachar DB, Greenstein AJ, Hill AG, Janowitz HD. Quality of life after surgery for Crohn’s disease: a psychosocial survey. Gastroenterology 1980;78:1-6. 15. de Dombal FT, Burton I, Goligher JC. Recurrence of Crohn’s disease after primary excisional surgery. Gut 1971;12:519-27. 16. Higgens CS. Allan RN. Crohn’s disease of the distal ileum. Gut 1980;21:933-40. 17. Vender RJ, Rickert RR, Spiro HM. The outlook after total colectomy in patients with Crohn’s colitis and ulcerative colitis. J Clin Gastroenterol 1979;1:209-17. 18. Lennard-Jones JE, Staider GA. Prognosis after resection of chronic regional ileitis. Gut 1967;8:332-6. 19. Kyle J, Prognosis after ileal resection for Crohn’s disease. Br J Surg 1971;58:735-7.
RECURRENCE
RATES
IN (:ROHN’S
DISEASE
921
20. Trnka YM, Glotzer DJ, Kasdon EJ. Goldman H, Steer ML. Goldman LD. The long-term outcome of restorative operation in Crohn’s disease: influence of location, prognostic factors and surgical guidelines. Ann Surg 1982;196:345-54. 21. Farmer RG, Hawk WA, Turnbull RB Jr. Clinical patterns in Crohn’s disease: a statistical study of 615 cases. Gastroenterology 1975;68:627-35. 22. Nygaard K, Fausa 0. Crohn’s disease. Recurrence after surgical treatment. Stand J Gastroenterol 1977:12:577-84. 23. Pennington L, Hamilton S, Bayless TM, et al. Surgical management of Crohn’s disease: influence of disease at margin of resection. Ann Surg 1980;192:311-8. 24. Hamilton SR, Boitnott JK, Morson BC. Relationships of disease extent and margin length to recrudescence of Crohn’s disease after ileocolonic anastomosis (abstr). Gastroenterology 1981;80:1166. 25. Karesen R, Serch-Hanssen A, Thoresen 130. Hertzberg J. Crohn’s disease: long-term results of surgical treatment. Stand J Gastroenterol 1981;16:57-64. 26. Lee ECG, Papaioannou N. Recurrences following surgery for Crohn’s disease. Clin Gastroenterol 1980:9:419-38.
198:3:85:917-21
Risk Factors for Postoperative Recurrence of Crohn’s Disease DAVID
B. SACHAR,
ADRIAN ROGER
DAVID
J. GREENSTEIN, STYCZYNSKI,
Departments Mount Sinai
M.
WOLFSON,
JUDITH
and HENRY
Eventual disease recurrence is the most common postoperative complication of Crohn’s disease (1). Consequently, many investigators continue to search for clinical and pathological predictors of postoperative recurrence rates (2,3). In a recent follow-up study of 119 patients with Crohn’s disease who 1982. Accepted April 22, 1983. Address requests for reprints to: David B. Sachar, M.D., Division of Gastroenterology. Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. Dr. Wolfson‘s present address is Maimonides Medical Center. Brooklyn, Nelv York 11219. C 1983 by the American Gastroenterological Association OOlfi-5085:83!$3.00
D. JANOWITZ
of Medicine (Gastroenterology), Surgery, School of Medicine of the City University
To identify potential risk factors that influence postoperative recurrence rates of Crohn’s disease, the postoperative recurrence-free survival of 93 patients who underwent their first resections at The Mount Sinai Hospital between 1964 and 1973 has been examined. Features analyzed individually and jointly were age, sex, anatomic location, operative procedure, and preoperative disease duration. In patients with Crohn’s colitis, recurrence rates appeared somewhat lower among 11 patients with ileostomy than among 5 patients with anastomosis. In the entire series, recurrence rates were lowest in patients with longest preoperative durations (p = 0.02). This same tendency was especially marked among the 68 patients without ileostomies (p = 0.005). Likewise, among the 38 patients with ileitis, the relative risk of recurrence was significantly lowexceeding 10 yr (p er for those with disease duration = 0.01). Relative risk of recurrence in the entire series for patients with 2-yr duration was 1.5 compared with those who had lo-yr duration. This inverse association between preoperative disease duration and postoperative recurrence rate may reflect persisting differences between inherently more aggressive versus more indolent forms of Crohn’s disease.
Received July 6.
GOLDBERG, and Biomathematical Sciences of New York, New York
of the
underwent their first resection at The Mount Sinai Hospital between 1964 and 1973, the effects of six variables on the rates of postoperative recurrence were analyzed: age, sex, anatomic location of disease, operative procedure (anastomosis vs. ileostomy), preoperative duration of disease, and presence or absence of granulomas in the resected surgical specimen (4). Each of these variables was examined individually and jointly for its influence on cumulative postoperative recurrence-free survival. In a previous publication, our findings concerning the influence of granulomas on postoperative recurrence rates of Crohn’s disease were reported in detail (5). It was concluded that the presence or absence of granulomas in resected specimens exerted no independent influence upon recurrence rates. In this paper, the findings are described with respect to each of the five remaining clinical variables that we studied.
Methods As in our previous study (5) we reviewed the charts of 498 patients with Crohn’s disease who were admitted to The Mount Sinai Hospital between 1964 and 1973. Of these patients, 124 had undergone their first completely extirpative resection at the institution in this lime. In five instances the surgical pathologic studies were not available for review. The remaining 119 patients whose slides were available all manifested histopathologic criteria characteristic of Crohn’s disease, as established by LockhartMummery and Morson (6). Clinical follow-up examination was subsequently obtained by contact with patients and their physicians, and whenever possible by review of hospital and office records. Follow-up data were available for 93 patients (78%), who did not differ from the remaining 26 patients in age or sex
distribution,
procedures,
anatomic
preoperative
of granulomas.
The
location duration
results
of disease,
of disease,
reported
here
surgical
or frequency are
based
on
918
SACHAR
ET AL.
GASTROENTEROLOGY
analyses of these 93 cases with follow-up ranging from 1 to 15 yr. Recurrence was defined radiologically and/or surgically. Symptoms alone were not sufficient to establish a diagnosis of recurrence without objective documentation, so as not to confuse nonspecific symptoms of bile salt diarrhea, food intolerance, motor disturbance, postoperative adhesions, etc., with true recurrence of Crohn’s disease. Criteria for recurrence were identical to those in our most recent study (5) and were essentially the same as those applied for the original diagnosis (6). Although all symptomatic patients were investigated, there was no systematic effort to screen for asymptomatic recurrence, so that recurrence rates may be artifactually somewhat inflated by ascertainment bias favoring selection of symptomatic patients in a data. Cumulative recurstudy with only 78% follow-up rence rates were calculated as in our previous studies (1,5). Patients were considered as remaining at risk from the time of initial resection until the onset of symptoms proved to be due to disease recurrence, or if no recurrence was documented, then until the date of last follow-up examination. Patients in different subgroups defined by age, sex, location of disease, surgical procedure, and preoperative disease duration were compared with respect to the other clinical characteristics using cross-tabulation methods. Postoperative recurrence-free survival curves were compared using Gehan’s generalized Wilcoxon procedure
Table
1. Age at Operation
Vol.
85, No. 4
Disease
by Preoperative
Duration Duration
Age (yr)
52
(yr)
2-10
Total
>lO
523 23-40 >40
10” 5 7
36” 13 27
17" 28 8
61b 72 31
1" 6 11
4" 15 42
28" 39 26
100" 100 100
Total
2.2
24
53
57
18
20
93
100
(1Number
of patients.
b Percent
of total
in that age group.
(Breslow’s extension) (7) and Mantel-Cox logrank procedures (8). All calculations were performed with computer program PlL (9). Multivariate methods including logrank procedures and Cox regression models for censored data (10) were then used to examine the joint effects of these clinical features upon recurrence rates.
Results Sex There study group. men (median 7 yr), and 30 postoperative recurrence-free and women
were 45 men and 48 women in the There were 24 recurrences among the postoperative recurrence-free survival recurrences among the women (median recurrence-free survival 4 yr). The survival curves were similar for men (logrank x2’ = 1.6, p = 0.2).
IO-
4
0
& 0@
Age
0.8-
5 $ 0.62: 5$0435
0.2-
00-
2
4
6 YEARS
Figure
8
IO
12
14
16
AFTER OPERATION
1. Cumulative postoperative recurrence-free survival in 93 patients with Crohn’s disease as a function of age at time of operation. Closed circles represent the proportion surviving without a recurrence at each year in which some recurrence was noted. In this and all succeeding figures, the numbers below the abscissa indicate, for each year of follow-up study, the numbers of recurrences within the preceding year over the number of patients who were still at risk during that year. The recurrence rates are lowest in the 26 patients over 40 yr old (13 recurrences), intermediate in the 39 patients between 23 and 40 yr old (21 recurrences], and highest in the 28 patients 23 yr old or younger (19 recurrences], but the differences among the three curves are not statistically significant (Wilcoxon x2’ = 1.3, p = 0.53; logrank xzz = 2.2, p = 0.34).
The median age at time of initial resection was 30 yr. Cumulative recurrence rates were calculated for three age groups (Figure 1): patients over 40 yr (the oldest quartile), those under 23 yr (the youngest quartile), and those between 23 and 40 yr. The recurrence rates were similar for the three age groups (logrank xz” = 2.2, p = 0.34). However, those patients who were older at the time of surgery had longer preoperative durations of disease (Table 1). Duration of disease rather than age appeared to exert the stronger influence on recurrence rates in this series.
Anatomical
Distribution
Anatomical distributions of disease were similar to those reported in most other series (11): 38 patients with ileitis (41%), 39 with ileocolitis (42%), 16 with colitis (17%). Recurrence rates appeared similar among these subgroups (Figure 2).
Ileostomy
versus
Anastomosis
Ileostomies were performed in 25 patients and anastomoses in 68 patients. No patient with ileitis
October
RECURRENCE
1983
“+,__.
‘.
‘..
‘S,
,....
*.__._-_---____ *_-------------__.
lleltlr
____
._-.
lleocolltls
O/--1 TIME
Figure
IN YEARS
(follow-up)
2. Cumulative postoperative recurrence-free survival for each anatomic category of Crohn’s disease. Recurrence rates are shown for the 39 patients with ileocolitis (21 recurrences), for the 38 with ileitis (23 recurrences), and for the 16 with colitis (7 recurrences). The differences among the curves are not statistically significant (Wilcoxon xLZ = 0.7. )I = 0.70; logrank xe’ = 1.0, p = 0.60).
underwent ileostomy. Among the 39 ileocolitis patients, recurrence rates in the 14 patients with ileostomy (seven recurrences) and in the 25 patients with (17 recurrences] were comparable (loganastomosis rank x1’ = 0.39, p = 0.53). The different operations, however, may have been associated with different recurrence rates among the 16 patients with Crohn’s disease limited to the colon. Although the numbers were very small, recurrence rates appeared somewhat lower in the 11 patients with ileostomy (three recurrences) than among the 5 patients with anastomosis [four recurrences) (Wilcoxon x1’ = 2.5, p = 0.11; logrank x1’ = 3.2, p = 0.08). In the combined colitis and ileocolitis groups, patients with ileostomy again had a somewhat lower risk of recurrence than did patients with anastomosis (logrank x1’ = 2.7, p = 0.10).
Preoperative
RATES
IN CROHN’S
DISEASE:
919
durations (Figure 3), (Wilcoxon x1’ = 5.5, p = 0.02; of logrank x1’ = 5.3, p = 0.02). This influence disease duration was observed even within the younger age groups, although the numbers were small. We further estimated the relative risk of recurrence from a Cox model analyzing the effect of disease duration as either a discrete or a continuous variable. In the entire series, the relative risk of recurrence for patients with 2-yr duration was 1.5 compared with patients with 10 yr of disease, either with or without adjustment for age. This same effect of preoperative duration was especially clear among the 68 patients without ileostomies (Figure 4) (Wilcoxon x1’ = 6.4, p = 0.004; logrank x1’ = 8.0, p = 0.005). The cumulative 5-yr postoperative recurrence rate in this group was -65’% for patients with up to lo-yr duration, versus only 23% for patients with >lO-yr duration. Similarly, among the 38 ileitis patients, none of whom had ileostomies, the relative risk of recurrence over a 15-yr follow-up period was significantly greater for patients with preoperative disease duration of 510 yr (21 recurrences among 29 patients) than among patients with duration >lO yr (two recurrences among 9 patients) (logrank x1’ = 6.0, p = 0.01). This apparent influence of preoperative disease duration could theoretically be confounded by associated influences of age, sex, and location of disease. For example, as we have already seen [Table l), the proportion of patients with long preoperative disease durations increases with older ages at time of operation. Yet from a series of Cox models using age, sex, anatomic location, and preoperative duration, as
Duration
Preoperative duration of disease appeared to exert an important influence on recurrence rates. Recurrence-free survival was significantly lengthened in patients with longer preoperative duration. Preoperative duration of disease, as judged by onset of characteristic symptoms, was 52 yr in 22 patients, 2-10 yr in 53 patients, and >lO yr in 18 patients. The recurrence-free survival curves were different for these three groups (Wilcoxon xz2 = 5.95, p = 0.05). This difference was due primarily to the recurrence rates in patients with disease duration >lO yr being lower than the rates in the patients with shorter
Figure
3. Cumulative postoperative recurrence-free survival as a function of preoperative duration of Crohn’s disease. The recurrence rate is significantly lower in the 18 patients with >lO yr of disease (6 recurrences) than in the 75 patients with 510 yr of disease before operation (48 recurrences). (Wilcoxon ,yIL = 5.5. p = 0.02; logrank x,’ = 5.3, p = t1.02.)
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GASTROENTEROLOGY
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4. Cumulative postoperative recurrence-free survival among 68 Crohn’s disease patients who underwent resection and anastomosis. The recurrence rate is significantly lower among the 14 patients with >lO-yr preoperative disease duration (4 recurrences) than among the 54 patients whose duration was 210 yr (40 recurrences). (Wilcoxon x1 ’ = 8.4, p = 0.004; logrank x,2 = 8.0, p = 0.005.)
well as age-duration interactions, both individually and jointly, only disease duration made a statistically significant contribution to the model to explain the observed data.
85, No. 4
patients with shorter preoperative disease duration has also been noted in many other centers (Is--19), although an opposite trend has been suggested (20). We are not proposing that there is any intrinsic influence of preoperative duration per se on recurrence rates. To the contrary, it seems likely that differences in preoperative duration are reflections in turn of different “clinical patterns” of disease (21) and hence of different indications for surgery. It may well be these patterns themselves, rather than preoperative durations per se, that determine recurrence rates. In other words, inherently aggressive instances of Crohn’s disease, which bring their victims to surgery early, may recur early; while more indolent cases, which lead to operation later, may recur later. Besides, there are other potentially important determinants of recurrence rate which we have not investigated at all, such as radicalness of resection, regarding the influence of which some controversy still exists (20,22-26). The point remains, however, that studies of recurrence rates in Crohn’s disease should not focus exclusively on single determinants like location of disease (31, without considering the potential influences of other related variables such as operative procedure and especially preoperative duration of disease.
References
Discussion The two principal conclusions arising from this study are [a) that recurrence rates appear lower in Crohn’s colitis patients after ileostomy than after anastomosis and (b) that at least in patients without ileostomy, rates of recurrence are lowest in those patients with the longest preoperative durations of disease. With respect to the difference between ileostomy and anastomosis, our numbers are too small to achieve statistical significance, but the finding has been repeatedly made before. For example, the Birmingham group have demonstrated that for Crohn’s disease involving the colon, recurrence rates are lower after panproctocolectomy and ileostomy than after any other operative procedure (12). Glotzer (13) has recently reviewed the evidence that Crohn’s disease recurs relatively infrequently after total colectomy and ileostomy. Of course, these differences in recurrence rates could reflect different disease characteristics providing different indications for ileostomy versus anastomosis. Nothing in these data suggests, therefore, that ileostomy is a “better” choice than anastomosis for any given patient. Moreover, many other considerations besides recurrence rates alone must enter into choice of operation (14). The tendency toward higher recurrence rates in
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