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Late locoregional recurrence in rectal carcinoma
EJSO 2002; 28: 716±722 doi:10.1053/ejso.2002.1305, available online at http://www.idealibrary.com on
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Late locoregional recurrence in rectal carcinoma S. Merkel, T. Meyer, J. GoÈhl and W. Hohenberger Department of Surgery, University of Erlangen, Germany
Aims: Locoregional recurrence in rectal carcinoma usually occurs within the first five years of treatment. In recent years we have increasingly diagnosed patients with late locoregional recurrence more than 5 years after primary treatment. Methods: The data of 978 patients with invasive stage I±III rectal carcinoma who underwent curative resection (R0) between 1978 and 1990 were analysed retrospectively. The median follow-up time was 10 years. Results: The earliest locoregional recurrence was observed at 2 months, the latest at 148 months (extramural locoregional recurrence) after primary treatment. Within 1, 2 and 5 years 34, 64 and 91 per cent of all locoregional recurrences had been diagnosed. The 2-, 5- and 10-year locoregional recurrence rates of all patients increased from 11.3 to 16.7 to 18.8 per cent. The time lapse to diagnosis of locoregional recurrence was significantly influenced by the pN category (pN0: later), grading (low grade: later) and tumour cell dissemination (present: earlier). Locoregional recurrence was also diagnosed significantly earlier in patients undergoing regular follow-up. The curative reoperation rate was 22 per cent (n 37), being higher in patients with intramural locoregional recurrence (49 per cent), after primary anterior resection (32 per cent) and in the absence of distant metastases (29 per cent). Conclusion: Long-term follow-up beyond five years demonstrates increasing numbers of late locoregional recurrences. # 2002 Elsevier Science Ltd. All rights reserved. Key words: locoregional recurrence; rectal carcinoma; late recurrence; follow-up.
INTRODUCTION The aim of follow-up programs for patients with resected rectal carcinoma is to identify asymptomatic recurrences (locoregional and distant) at a stage early enough to allow curative reoperation. The effectiveness of such programs has been shown in colorectal carcinoma.1 The nature, frequency and duration of follow-up is under discussion.2±4 Most follow-up programs end 5 years after primary treatment. After this, only screening for second malignancies, including complete colonoscopy every three years, is recommended.5 Published studies on locoregional recurrence in rectal carcinoma rarely specify the reference time interval after primary surgery. In most cases it is probably 5 years. This is important, because recurrence is time dependent. The longer the follow-up time, the Correspondence to: Dr Susanne Merkel, Department of Surgery, University of Erlangen, Krankenhausstr. 12, D-91054 Erlangen, Germany. Tel: 49 9131 853 3107; Fax: 49 9131 853 2769; E-mail: [email protected] 0748±7983/02/$35.00/0
more recurrences will be detected.6 In recent years we have increasingly diagnosed patients with locoregional recurrence more than 5 years after primary treatment. This prompted us to analyse our data, with emphasis on the time interval to locoregional recurrence in rectal carcinoma patients and its relation to tumour-related and treatment-related prognostic factors.
PATIENTS AND METHODS The study was based on data from the Erlangen Registry of Colo-Rectal Carcinoma (ERCRC), Germany. All patients with invasive colorectal carcinoma treated at the Department of Surgery were registered. General epidemiological data, clinical findings, treatment data, histopathological findings and follow-up data were documented using a standard data-collecting system based on the International Documentation System for Colorectal Carcinoma.7,8 We selected 978 consecutive patients who had undergone primary treatment #
2002 Elsevier Science Ltd. All rights reserved.
LATE LOCOREGIONAL RECURRENCE IN RECTAL CARCINOMA between 1978 and 1990, applying the following inclusion criteria: Solitary invasive (invading at least the submucosa) carcinoma of the rectum located 16 cm or less from the anal verge when measured with a rigid sigmoidoscope;7,8 No other previous or synchronous malignant tumour with the exception of squamous or basal cell carcinoma of the skin, and carcinoma in situ of the uterine cervix; Carcinoma not arisen in familial adenomatous polyposis, ulcerative colitis or Crohn's disease; Primary treatment by (low) anterior resection or abdominoperineal excision; No neoadjuvant or adjuvant therapy; Residual tumour classification R0 (clinical and histopathological examination); Stage I±III (no distant metastases); No surgical mortality (54 patients [5.1 per cent] excluded); Tumour status known with respect to locoregional and distant recurrence (22 patients [2.1 per cent] excluded). Patients with primary treatment in the period from 1978-1990 were followed up for a total of 5 years, initially with examination every 3 months (for 2 years), and thereafter every 6 months. In addition to history taking, physical examination and carcinoembryonic antigen (CEA) assay, rectosigmoidoscopy with endosonography, CT scan and, more recently, magnetic resonance imaging (MRI) were used to detect locoregional recurrence. About two-thirds of the patients were followed up in our department. One-third of the patients were followed up by experienced gastroenterologists working outside the university. In the event of incomplete information on life and tumour status of the patient (including cause of death) the family doctor or the patient himself was contacted routinely by post or telephone. Follow-up was considered to be complete when all investigations were correctly carried out (as required by the program +1 month) for 5 years, or until locoregional recurrence was diagnosed. In addition, all recurrence events after completion of the five year follow-up were registered in our database, as was the cause death. Locoregional recurrence was defined as the presence of any anastomotic, pelvic or perineal tumour documented by clinical and/or pathological examination. We distinguished between intramural locoregional recurrence located mainly in the mucosa, submucosa and/or the muscularis propria, and extramural recurrence with location predominantly outside the bowel wall. Late locoregional recurrence was defined as that occurring more than 5 years after primary treatment. Both symptomatic and asymptomatic locoregional recurrences were recorded.
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Table 1 Patient and tumour characteristics No. of patients (%) Gender Male Female Age Median/range(years) Location Upper third Middle third Lower third Treatment (Low) anterior resection Abdominoperineal excision Stage Stage I Stage II Stage III
543 (55.5) 435 (44.5) 60 (21±96) 223 (22.8) 381 (39.0) 374 (38.2) 642 (65.2) 336 (34.4) 230 (23.5) 313 (32.0) 435 (44.5)
The actual median follow-up time was 116 months (range 1±275 months), while potential median follow-up was 199 months (range 120±275 months). By the end of the study (1 January 2001) 568 patients (58.1 per cent) had died of their rectal carcinoma. Patient and tumour characteristics are shown in Table 1. Detailed documentation of the histopathological findings permitted classification of patients in accordance with the 5th, 1997 edition of the UICC TNM classification.9 The site of rectal carcinomas was broken down into three groups by distance of the distal margin of the tumour to the anal verge as measured by rigid sigmoidoscopy: lower third: up to ,7.5 cm, middle third: 7.5 to 12 cm, and upper third: 12 to 16 cm.10 Grading was defined in accordance with the WHO recommendations.11 With respect to venous invasion we distinguished no venous invasion or only intramural venous invasion (EVIÿ) from extramural venous invasion (EVI). In 68 patients (6.9 per cent) no data on extramural venous invasion were available. Local tumour cell dissemination (TCD) was defined as iatrogenic disruption of the tumour during mobilization and/or incision into the tumour tissue. The surgeon at our surgical department who treated the largest number of patients with rectal carcinoma between 1978 and 1990 and who had the lowest rate of locoregional recurrences has been identified as `surgeon A'. His results are compared with those of all other surgeons, identified collectively as `surgeon non-A'. (Low) anterior resection and abdominoperineal excision were performed with formal regional lymph node dissection. In 1985 total mesorectal excision (TME) was introduced for carcinomas of the middle and lower thirds.
Statistics The Kaplan±Meier method was used to calculate locoregional recurrence rates. An event was defined as
718 the diagnosis of locoregional recurrence. The survival time of all patients remaining free of locoregional recurrence was censored (n 811). The 95 per cent confidence intervals (95% CI) were calculated in accordance with Greenwood.12 For comparisons the log-rank test was used. Fisher's exact test was used to compare frequencies. A P value , 0.05 was considered statistically significant. In patients with locoregional recurrence we analysed ± separately for each of the potential influencing factors ± the percentages of locoregional recurrences occurring within 1, 2 and 5 years, and the time intervals elapsed until 50 and 90 per cent of the locoregional recurrences had been observed. All analyses were performed using statistical software (SPSS for Windows, version 10; SPSS Inc., Chicago, USA).
RESULTS Locoregional recurrence was observed in 167 out of 978 patients (17.1 per cent) when considering a followup time of ten years. The recurrence rate was significantly influenced by tumour-related factors such as pT category, pN category, grading, extramural venous invasion and tumour site, as well by treatment-related factors such as local tumour cell dissemination, the surgeon and the surgical procedure (Table 2).
Diagnostic time-point of locoregional recurrence The earliest locoregional recurrence was diagnosed 2 months, the latest, an extramural locoregional recurrence, 148 months, after primary treatment. In 2 patients locoregional recurrence was diagnosed at the time of death, 26 and 37 months after primary treatment. Thirtyfour per cent of all locoregional recurrences were observed within 1 year after primary treatment, 64 per cent within 2 years and 91 per cent within 5 years. Nine per cent (15 patients) were diagnosed as having late recurrences after more than 5 years. The locoregional recurrence rate therefore increased from 11.3 per cent at 2 years, to 16.7 per cent at 5 years, to 18.8 per cent at 10 years of follow-up. The increase in locoregional recurrence is represented in Figure 1. Several factors were analysed with respect to the time of diagnosis of locoregional recurrence.
Tumour-related factors (Table 2A) The pN category and grading had a significant influence on the time elapsed to locoregional recurrence; the influence of the pT category was marginal. In patients presenting with unfavourable prognostic factors (pT3, pT4, pN1, pN2, high grade), associated with higher 5-year locoregional recurrence rates, such recurrence was observed earlier, while in patients with more favourable
S. MERKEL ET AL. prognostic factors, associated with lower 5-year rates of locoregional recurrences (pT2, pN0, low grade), such recurrence was diagnosed later. Late locoregional recurrences were observed predominantly in carcinomas of the categories pT2 (22 per cent) and pN0 (18 per cent).
Treatment-related factors (Table 2B) In patients with local tumour cell dissemination during primary treatment, locoregional recurrence was observed significantly earlier. The influence of the surgeon (surgeon A vs surgeon non-A) and the surgical procedure (anterior resection vs abdominoperineal excision) did not reach significance.
Recurrence-related factors (Table 2C) Locoregional recurrence was observed significantly earlier in patients undergoing regular follow-up than in those with reduced, minimal or no follow-up. Neither the location of locoregional recurrent tumour (intramural vs extramural) nor the presence of distant metastases influenced the diagnostic time point of locoregional recurrence. The median number of follow-up examinations prior to diagnosis of locoregional recurrence was 2 (range 0±12). However, not only the number of follow-ups, but also the time interval between the last follow-up with no evidence of locoregional recurrence and the diagnosis of the latter appears to be of importance. This interval ranged from 1 to 94 months (median 5 months). It increased the later locoregional recurrence was diagnosed.
Treatment of locoregional recurrence Thirty-seven patients with locoregional recurrence (22 per cent) underwent curative reoperation (Table 3). In 2 other patients locoregional recurrent tumour was removed, while distant metastases were left untreated. The pT category of the primary tumour, the type of primary treatment, the site of the locoregional recurrence (intramural vs extramural), and the absence or presence of distant metastases significantly influenced the number of curatively reoperated patients. R0resection of recurrent disease was possible mainly in primary pT2 carcinomas, after anterior resection, in cases of intramural locoregional recurrence and in the absence of distant metastases. It was independent of when locoregional recurrence was diagnosed.
Data of patients with late locoregional recurrence In 15 patients locoregional recurrence was diagnosed more than 60 months after primary treatment. These patients had only pT2 and pT3 tumours (i.e. no pT4), 9 patients had no lymph node metastases (i.e. only
No. of patients
5 year LR-Rate (95% CI)
All
978
(A) Tumour-related factors pT1 pT2 pT3 pT4 pN0 pN1 pN2 Low grade High grade EVI ÿ EVI Upper third Middle third Lower third
49 240 629 60 543 243 192 829 148 716 194 223 381 374
(B) Treatment-related factors No TCD TCD Surgeon A Surgeon non-A Anterior resection Abdominoperineal excision
922 56 302 676 642 336
(C) Recurrence-related factors Reduced FU Regular FU Intramural LR Extramural LR No distant metastases Previous or synchronous distant metastases
P*
LR (n)
LR 1 year (%)
LR 2 years (%)
16.7 (14.3±19.1)
167
34
64
6.1 20.6 35.7 8.1 21.9 36.7 15.0 27.6 11.9 17.7 11.1 14.5 22.5
0 (3.0±9.2) (17.3±24.0) (22.6±48.8) (5.8±10.5) (16.5±27.4) (29.2±44.3) (12.5±17.5) (19.5±35.6) (9.4±14.3) (10.8±24.5) (6.8±15.3) (10.8±18.1) (18.1±27.0)
18 130 19 51 53 63 131 36 92 49 27 59 81
39 32 42 28 23 49 30 50 29 39 30 37 33
15.1 45.0 10.5 19.5 14.1 21.9
(12.7±17.5) (30.7±59.3) (6.8±14.1) (16.4±22.6) (11.3±16.8) (17.2±26.5)
145 22 34 133 93 74 82 81 49 111 113 54
,0.0001 ,0.0001 0.0004 ,0.0001 0.0034
,0.0001 0.0009 0.0026
LR 5 years n (%)
Late LR n (%)
LR 50 (months)
LR 90 (months)
152 (91)
15 (9)
18
56
44 65 79 55 53 81 62 72 58 65 59 71 61
14 (78) 119 (92) 19 (100) 42 (82) 49 (93) 61 (97) 117 (89) 35 (97) 80 (87) 47 (96) 23 (85) 52 (88) 77 (95)
4 (22) 11 (8) 0 9 (18) 4 (7) 2 (3) 14 (11) 1 (3) 12 (13) 2 (4) 4 (15) 7 (12) 4 (5)
31 18 17 22 23 12 21 13 21 18 21 19 17
91 56 37 74 57 38 65 45 74 51 74 76 49
33 41 27 36 40 27
63 68 53 67 74 51
130 (90) 22 (100) 29 (85) 123 (92) 85 (91) 67 (91)
15 (10) 0 5 (15) 10 (8) 8 (9) 7 (9)
19 14 23 18 17 22
64 36 72 53 57 60
29 40 39 33 35 31
55 74 78 59 63 67
71 77 44 101 102 50
11 (13) 4 (5) 5 (10) 10 (9) 11 (10) 4 (7)
21 16 17 19 19 17
76 48 69 56 62 60
(87) (95) (90) (91) (90) (93)
0.071 0.0002 0.016 0.10 0.17
0.036 0.20 0.27
0.0099 0.43 0.44
719
LR 1 year: Percentage of locoregional recurrences observed within 1 year of follow-up. LR 2 years: Percentage of locoregional recurrences observed within 2 years of follow-up. LR 5 years: Percentage of locoregional recurrences observed within 5 years of follow-up. Late LR: Late locoregional recurrence observed more than 5 years after primary treatment. LR 50: Time to detecting of 50 of all locoregional recurrences. LR 90: Time to detecting of 90 of all locoregional recurrences. * Log rank test. EVI: extramural venous invasion; TCD: tumour cell dissemination; FU: follow-up; LR: locoregional recurrence.
P*
LATE LOCOREGIONAL RECURRENCE IN RECTAL CARCINOMA
Table 2 Locoregional recurrence rates and time of diagnosis
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S. MERKEL ET AL.
Figure 1 Locoregional recurrence at 1, 2, 5 years of follow-up and the time points of diagnosis of 50 and 90 per cent of all locoregional recurrences (167 locoregional recurrences in 978 patients).
Table 3 Results of treatment (R0-resection) in patients with locoregional recurrence, n 167 R0 resection of recurrence n (%) All Findings on primary treatment pT2 pT3 pT4 pN0 pN1 pN2 Low grade High grade Anterior resection Abdominoperineal excision Findings on locoregional recurrence Intramural LR Extramural LR No synchronous distant metastases Synchronous distant metastases Early locoregional recurrence diagnosis 12 months diagnosis .12 to 24 months diagnosis .24 to 36 months diagnosis .36 to 60 months Late locoregional recurrence (diagnosis .60 months)
P*
37/167 (22) 8/18 (44) 27/130 (21) 2/19 (11) 13/51 (25) 13/53 (25) 11/63 (17) 31/131 (24) 6/36 (17) 30/93 (32) 7/74 (9) 23/49 (47) 13/111 (12) 34/118 (29) 3/49 (6) 33/152 (22) 16/57 (28) 8/50 (16) 5/22 (23) 4/23 (17) 4/15 (27)
0.042 0.51 0.50 ,0.001 ,0.001 0.001
0.75
*Fisher's extract test.
6 patients had lymph node metastases) and 14 had low grade tumours (i.e. only one high grade tumour). Seven of these patients had no evidence of disease on conclusion of their 5-year follow-up program. Four patients stopped attending for follow-up examination after 54 to
56 months. Four other patients already stopped attending after 28, 41, 50 and 51 months, and might otherwise have been diagnosed earlier. There were more extramural locoregional recurrences (n 10) than intramural recurrences (n 5). But R0-resection of the recurrent
LATE LOCOREGIONAL RECURRENCE IN RECTAL CARCINOMA lesion was possible in 3 intramural and only in one extramural recurrence.
Comparison with the period from 1991 to 1995 To investigate the question whether late locoregional recurrence may be expected to increase in the future, a separate analysis of 200 patients with the same inclusion criteria but treated between 1991 and 1995 was done (data not shown). During this period the 5-year locoregional recurrence rate was 8.4 per cent. In 15 out of 20 patients locoregional recurrence was diagnosed within 5 years. The other 5 patients with locoregional recurrent lesions (25 per cent) were diagnosed as late recurrence. (This percentage may increase during ongoing follow-up over the next few years.) These figures show that the percentage of late recurrences has already increased from 9 per cent in 1978±1990 to 25 per cent in 1991±1995.
DISCUSSION Twenty years ago the rate of locoregional recurrence in our rectal carcinoma patients was 26 per cent with 88 per cent being diagnosed within 2 years. Ten years ago a new analysis showed a locoregional recurrence rate of 17 per cent, with 71 per cent diagnosed within 2 years (unpublished data of the ERCRC). In the present analysis with a potential follow-up time of at least 10 years, only 63 per cent of all locoregional recurrences were diagnosed within 2 years. Late locoregional recurrences (more than 5 years after primary treatment) were observed in 9 per cent (n 15) of patients with locoregional recurrence (n 167). Seven of these patients had no evidence of disease at the end of their 5year follow-up programme. Four patients stopped attending for follow-up examinations after 54 to 56 months and 4 patients had already stopped after 28, 41, 50 and 51 months. Some of these patients might have been diagnosed earlier if they had regularly attended for follow-up. However, it is hard to believe that the diagnosis would have been made 7 years earlier in the patient with locoregional recurrence diagnosed 149 months after primary treatment. According to data in the literature13 the rate of locoregional recurrence is significantly influenced by the pT and pN category, grading, extramural venous invasion, local tumour cell dissemination, tumour site, and the surgeon. The time to diagnosis of locoregional recurrence was significantly influenced by such tumourrelated factors as pN category and grading, by such treatment-related factors as intraoperative tumour cell dissemination, and by the constancy of follow-up. But also a lower pT category, absence of extramural venous invasion, and treatment by surgeon A (the surgeon with
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the lowest rate of locoregional recurrences) were associated with a trend towards later diagnosis of locoregional recurrence. Favourable prognostic factors of the primary tumour and optimized surgery with a low risk for locoregional recurrence were associated with a higher percentage of late locoregional recurrences. Three questions arise: (1) Is late locoregional recurrence likely to increase in the current setting of optimised surgery? Probably. The factors that influenced the rate of locoregional recurrence also influenced the time point of diagnosis of locoregional recurrence (not always significantly). Favourable prognostic factors of the primary tumour and tumours treated by surgeon A were associated with a higher proportion of late locoregional recurrences. With optimised surgery (total mesorectal excision in carcinomas of the middle and lower third of the rectum, formal regional lymphadenectomy) and adjuvant therapy when indicated,5,14 the rate of locoregional recurrence decreases. As a result the percentage of late locoregional recurrences may increase in the future. This is suggested by the results of our separate analysis of 200 patients treated between 1991 and 1995. The 5-year locoregional recurrence rate was only 8.4 per cent, but 5 out of 20 patients (25 per cent) with locoregional recurrence were diagnosed as having a late locoregional recurrence. This represents an increase in late locoregional recurrences from 9 per cent in 1978±1990 to 25 per cent in 1991±1995. (2) Will we need longer follow-up in the future? The constancy of follow-up influenced the time point at which locoregional recurrence was diagnosed. In patients attending for follow-up examinations regularly locoregional recurrence was observed significantly earlier, but there were also patients with late locoregional recurrence 5 years after primary treatment despite regular follow-up. However, prolonged follow-up is expensive, and does not guarantee an R0-resection of the recurrence. This is a problem given the present financial constraints on public health funding. In contrast to prolonged follow-up, the current guidelines of the German Cancer Society recommend a reduced and more individualised follow-up programme4 than that used in this study. In stage I patients undergoing radical resection only two follow-ups with history taking, physical examination and colonoscopy after 2 and 5 years are recommended. In stage II and III patients follow-up is recommended every 6 months for two years and thereafter every 12 months for a further 3 years. Rectoscopy is recommended 6, 12, and 18 months, and colonoscopy 24 and 60 months, after conclusion of primary treatment. Additional rectoscopy after 36 and 48 months is recommended only for patients receiving adjuvant radio/chemotherapy, in whom a later onset of locoregional recurrence is expected. (3) Which patients with locoregional recurrence have a chance of a curative reoperation? Only 22 per cent of
722 our patients with locoregional recurrence were treatable by curative reresection. This value is similar to data of the literature.15,16 In patients with primary pT2 rectal carcinoma the 5-year locoregional recurrence rate was low (6.5 per cent), but the number of curative reoperations for locoregional recurrence was 44 per cent, possibly influenced by the primary surgical procedure, which has an important impact on the chances for curative reoperation in the event of a locoregional recurrence. In patients undergoing primary anterior resection the rate of curative reoperation was 32 per cent, as compared with 9 per cent in those undergoing abdominoperineal excision. In addition, the chance of a repeat curative operation was clearly higher for intramural than for extramural locoregional recurrence (49 per cent vs 10 per cent). In patients with/ without synchronous distant metastases the relevant figures were 6 and 29 per cent, respectively. However, there was no difference in the number of curative reoperations between early and late locoregional recurrence. In summary, late locoregional recurrence may increase with present optimised surgery. It is not clear whether long-term follow-up is of benefit to rectal carcinoma patients in terms of early detection of locoregional recurrence. Therefore, especially in clinical studies, longer follow-up is needed. In addition it is important to consider the possibility of late recurrence in all patients with a history of rectal carcinoma.
NOTE ADDED IN PROOF The 10-year-rate of locoregional recurrence in the text (17.1%) seems to be in contradiction to the recurrence rate in Fig. 1 (18.8%). This is caused by two different methods of calculation: 17.1% is the number of patients with local recurrence observed within 10 years divided by the number of patients followed for at least one month (167/978). Patients who had already died after a few months (or years) of observation and had no local recurrence were analysed like patients never developing local recurrence during 10 years of follow-up. In contrast the Kaplan±Meier method calculates all diagnosed local recurrences in proportion to all patients being currently observed at the time of calculation. The rate of locoregional recurrence increases not only by every new local recurrence but also by the decreasing number of observed patients (patients died who never had a local recurrence). Therefore the 10-year-rate (18.8%) is related to the number of patients who either
S. MERKEL ET AL. developed locoregional recurrence or lived for at least 10 years free of local recurrence.
REFERENCES 1. Bruinvels DJ, Stiggelbout AM, Kievit J, van Houwelingen HC, Habbema JD, van de Velde CJ. Follow-up of patients with colorectal cancer. A meta-analysis. Ann Surg 1994; 219: 174±82. 2. Schoemaker D, Black R, Giles L, Toouli J. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998; 114: 7±14. 3. Castells A, Bessa X, Daniels M, Ascaso C, Lacy AM, Garcia-Valdecasas JC, Gargallo L, Novell F, Astudillo E, Filella X, Pique JM. Value of postoperative surveillance after radical surgery for colorectal cancer: results of a cohort study. Dis Colon Rectum 1998; 41: 714±23. 4. Secco GB, Fardelli R, Rovida S, Gianquinto D, Baldi E, Bonfante P, Derchi L, Ferraris R. Is intensive follow-up really able to improve prognosis of patients with local recurrence after curative surgery for rectal cancer? Ann Surg Oncol 2000; 7: 32±7. 5. Hermanek P (ed) QualitaÈtssicherung in der Onkologie. Diagnose und Therapie maligner Erkrankungen. Kurzgefasste InterdisziplinaÈre Leitlinien 2000. Deutsche Krebsgesellschaft e.V. MuÈnchen: Zuckschwerdt, 2000: 139±55. 6. Bokey EL, Ojerskog B, Chapuis PH, Dent OF, Newland RC, Sinclair G. Local recurrence after curative excision of the rectum for cancer without adjuvant therapy: role of total anatomical dissection. Br J Surg 1999; 86: 1164±70. 7. Fielding LP, Arsenault PA, Chapuis PH, Dent O et al. Clinicopathological staging for colorectal cancer: an International Documentation System (IDS) and an International Comprehensive Anatomical Terminology (ICAT). J Gastroenterol Hepatol 1991; 6: 325±44. 8. Soreide O, Norstein J, Fielding LP, Silen W. International standardization and documentation of the treatment of rectal cancer. In: Soreide O, Norstein J (eds). Rectal cancer surgery. Optimisation±standardisation±documentation. Berlin: Springer, 1997: 405±45. 9. Sobin LH, Wittekind CHd (eds). UICC TNM classification of malignant tumours. International Union Against Cancer (UICC). 5th edn New York: John Wiley & Sons, Inc., 1997. 10. Wagner G, Hermanek P. Organspezifische Tumordokumentation. Berlin, Heidelberg New York: Springer, 1995: 17±27. 11. Jass JR, Sobin LH. Histological Classification of Tumours. 2nd edn WHO International Histological Classification of Tumours. Berlin: Springer, 1989. 12. Greenwood M. The Natural Duration of Cancer. Report on public health and medicine. Subject no. 33. London: HM Stationery Office, 1926. 13. Hermanek P, Sobin LH. Colorectal carcinoma. In: Hermanek P, Gospodarowicz MK, Henson DE, Hutter RVP, Sobin LH (eds). Prognostic factors in cancer. International Union Against Cancer (UICC). Berlin, Heidelberg, New York: Springer, 1995: 64±79. 14. Junginger Th, Hossfeld DK, Sauer R, Hermanek P. Adjuvante und neoadjuvante Therapie bei Kolon- und Rektumkarzinom. Dtsch AÄrztebl 1999; 96A: 698±700. 15. Manfredi S, Benhamiche AM, Meny B, Cheynel N, Rat P, Faivre J. Population-based study of factors influencing occurrence and prognosis of local recurrence after surgery for rectal cancer. Br J Surg 2001; 88: 1221±7. 16. Wiggers T, de Vries MR, Veeze-Kuypers B. Surgery for local recurrence of rectal carcinoma. Dis Colon Rectum 1996; 39: 323±8. Accepted for publication 15 April 2002
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Late locoregional recurrence in rectal carcinoma S. Merkel, T. Meyer, J. GoÈhl and W. Hohenberger Department of Surgery, University of Erlangen, Germany
Aims: Locoregional recurrence in rectal carcinoma usually occurs within the first five years of treatment. In recent years we have increasingly diagnosed patients with late locoregional recurrence more than 5 years after primary treatment. Methods: The data of 978 patients with invasive stage I±III rectal carcinoma who underwent curative resection (R0) between 1978 and 1990 were analysed retrospectively. The median follow-up time was 10 years. Results: The earliest locoregional recurrence was observed at 2 months, the latest at 148 months (extramural locoregional recurrence) after primary treatment. Within 1, 2 and 5 years 34, 64 and 91 per cent of all locoregional recurrences had been diagnosed. The 2-, 5- and 10-year locoregional recurrence rates of all patients increased from 11.3 to 16.7 to 18.8 per cent. The time lapse to diagnosis of locoregional recurrence was significantly influenced by the pN category (pN0: later), grading (low grade: later) and tumour cell dissemination (present: earlier). Locoregional recurrence was also diagnosed significantly earlier in patients undergoing regular follow-up. The curative reoperation rate was 22 per cent (n 37), being higher in patients with intramural locoregional recurrence (49 per cent), after primary anterior resection (32 per cent) and in the absence of distant metastases (29 per cent). Conclusion: Long-term follow-up beyond five years demonstrates increasing numbers of late locoregional recurrences. # 2002 Elsevier Science Ltd. All rights reserved. Key words: locoregional recurrence; rectal carcinoma; late recurrence; follow-up.
INTRODUCTION The aim of follow-up programs for patients with resected rectal carcinoma is to identify asymptomatic recurrences (locoregional and distant) at a stage early enough to allow curative reoperation. The effectiveness of such programs has been shown in colorectal carcinoma.1 The nature, frequency and duration of follow-up is under discussion.2±4 Most follow-up programs end 5 years after primary treatment. After this, only screening for second malignancies, including complete colonoscopy every three years, is recommended.5 Published studies on locoregional recurrence in rectal carcinoma rarely specify the reference time interval after primary surgery. In most cases it is probably 5 years. This is important, because recurrence is time dependent. The longer the follow-up time, the Correspondence to: Dr Susanne Merkel, Department of Surgery, University of Erlangen, Krankenhausstr. 12, D-91054 Erlangen, Germany. Tel: 49 9131 853 3107; Fax: 49 9131 853 2769; E-mail: [email protected] 0748±7983/02/$35.00/0
more recurrences will be detected.6 In recent years we have increasingly diagnosed patients with locoregional recurrence more than 5 years after primary treatment. This prompted us to analyse our data, with emphasis on the time interval to locoregional recurrence in rectal carcinoma patients and its relation to tumour-related and treatment-related prognostic factors.
PATIENTS AND METHODS The study was based on data from the Erlangen Registry of Colo-Rectal Carcinoma (ERCRC), Germany. All patients with invasive colorectal carcinoma treated at the Department of Surgery were registered. General epidemiological data, clinical findings, treatment data, histopathological findings and follow-up data were documented using a standard data-collecting system based on the International Documentation System for Colorectal Carcinoma.7,8 We selected 978 consecutive patients who had undergone primary treatment #
2002 Elsevier Science Ltd. All rights reserved.
LATE LOCOREGIONAL RECURRENCE IN RECTAL CARCINOMA between 1978 and 1990, applying the following inclusion criteria: Solitary invasive (invading at least the submucosa) carcinoma of the rectum located 16 cm or less from the anal verge when measured with a rigid sigmoidoscope;7,8 No other previous or synchronous malignant tumour with the exception of squamous or basal cell carcinoma of the skin, and carcinoma in situ of the uterine cervix; Carcinoma not arisen in familial adenomatous polyposis, ulcerative colitis or Crohn's disease; Primary treatment by (low) anterior resection or abdominoperineal excision; No neoadjuvant or adjuvant therapy; Residual tumour classification R0 (clinical and histopathological examination); Stage I±III (no distant metastases); No surgical mortality (54 patients [5.1 per cent] excluded); Tumour status known with respect to locoregional and distant recurrence (22 patients [2.1 per cent] excluded). Patients with primary treatment in the period from 1978-1990 were followed up for a total of 5 years, initially with examination every 3 months (for 2 years), and thereafter every 6 months. In addition to history taking, physical examination and carcinoembryonic antigen (CEA) assay, rectosigmoidoscopy with endosonography, CT scan and, more recently, magnetic resonance imaging (MRI) were used to detect locoregional recurrence. About two-thirds of the patients were followed up in our department. One-third of the patients were followed up by experienced gastroenterologists working outside the university. In the event of incomplete information on life and tumour status of the patient (including cause of death) the family doctor or the patient himself was contacted routinely by post or telephone. Follow-up was considered to be complete when all investigations were correctly carried out (as required by the program +1 month) for 5 years, or until locoregional recurrence was diagnosed. In addition, all recurrence events after completion of the five year follow-up were registered in our database, as was the cause death. Locoregional recurrence was defined as the presence of any anastomotic, pelvic or perineal tumour documented by clinical and/or pathological examination. We distinguished between intramural locoregional recurrence located mainly in the mucosa, submucosa and/or the muscularis propria, and extramural recurrence with location predominantly outside the bowel wall. Late locoregional recurrence was defined as that occurring more than 5 years after primary treatment. Both symptomatic and asymptomatic locoregional recurrences were recorded.
717
Table 1 Patient and tumour characteristics No. of patients (%) Gender Male Female Age Median/range(years) Location Upper third Middle third Lower third Treatment (Low) anterior resection Abdominoperineal excision Stage Stage I Stage II Stage III
543 (55.5) 435 (44.5) 60 (21±96) 223 (22.8) 381 (39.0) 374 (38.2) 642 (65.2) 336 (34.4) 230 (23.5) 313 (32.0) 435 (44.5)
The actual median follow-up time was 116 months (range 1±275 months), while potential median follow-up was 199 months (range 120±275 months). By the end of the study (1 January 2001) 568 patients (58.1 per cent) had died of their rectal carcinoma. Patient and tumour characteristics are shown in Table 1. Detailed documentation of the histopathological findings permitted classification of patients in accordance with the 5th, 1997 edition of the UICC TNM classification.9 The site of rectal carcinomas was broken down into three groups by distance of the distal margin of the tumour to the anal verge as measured by rigid sigmoidoscopy: lower third: up to ,7.5 cm, middle third: 7.5 to 12 cm, and upper third: 12 to 16 cm.10 Grading was defined in accordance with the WHO recommendations.11 With respect to venous invasion we distinguished no venous invasion or only intramural venous invasion (EVIÿ) from extramural venous invasion (EVI). In 68 patients (6.9 per cent) no data on extramural venous invasion were available. Local tumour cell dissemination (TCD) was defined as iatrogenic disruption of the tumour during mobilization and/or incision into the tumour tissue. The surgeon at our surgical department who treated the largest number of patients with rectal carcinoma between 1978 and 1990 and who had the lowest rate of locoregional recurrences has been identified as `surgeon A'. His results are compared with those of all other surgeons, identified collectively as `surgeon non-A'. (Low) anterior resection and abdominoperineal excision were performed with formal regional lymph node dissection. In 1985 total mesorectal excision (TME) was introduced for carcinomas of the middle and lower thirds.
Statistics The Kaplan±Meier method was used to calculate locoregional recurrence rates. An event was defined as
718 the diagnosis of locoregional recurrence. The survival time of all patients remaining free of locoregional recurrence was censored (n 811). The 95 per cent confidence intervals (95% CI) were calculated in accordance with Greenwood.12 For comparisons the log-rank test was used. Fisher's exact test was used to compare frequencies. A P value , 0.05 was considered statistically significant. In patients with locoregional recurrence we analysed ± separately for each of the potential influencing factors ± the percentages of locoregional recurrences occurring within 1, 2 and 5 years, and the time intervals elapsed until 50 and 90 per cent of the locoregional recurrences had been observed. All analyses were performed using statistical software (SPSS for Windows, version 10; SPSS Inc., Chicago, USA).
RESULTS Locoregional recurrence was observed in 167 out of 978 patients (17.1 per cent) when considering a followup time of ten years. The recurrence rate was significantly influenced by tumour-related factors such as pT category, pN category, grading, extramural venous invasion and tumour site, as well by treatment-related factors such as local tumour cell dissemination, the surgeon and the surgical procedure (Table 2).
Diagnostic time-point of locoregional recurrence The earliest locoregional recurrence was diagnosed 2 months, the latest, an extramural locoregional recurrence, 148 months, after primary treatment. In 2 patients locoregional recurrence was diagnosed at the time of death, 26 and 37 months after primary treatment. Thirtyfour per cent of all locoregional recurrences were observed within 1 year after primary treatment, 64 per cent within 2 years and 91 per cent within 5 years. Nine per cent (15 patients) were diagnosed as having late recurrences after more than 5 years. The locoregional recurrence rate therefore increased from 11.3 per cent at 2 years, to 16.7 per cent at 5 years, to 18.8 per cent at 10 years of follow-up. The increase in locoregional recurrence is represented in Figure 1. Several factors were analysed with respect to the time of diagnosis of locoregional recurrence.
Tumour-related factors (Table 2A) The pN category and grading had a significant influence on the time elapsed to locoregional recurrence; the influence of the pT category was marginal. In patients presenting with unfavourable prognostic factors (pT3, pT4, pN1, pN2, high grade), associated with higher 5-year locoregional recurrence rates, such recurrence was observed earlier, while in patients with more favourable
S. MERKEL ET AL. prognostic factors, associated with lower 5-year rates of locoregional recurrences (pT2, pN0, low grade), such recurrence was diagnosed later. Late locoregional recurrences were observed predominantly in carcinomas of the categories pT2 (22 per cent) and pN0 (18 per cent).
Treatment-related factors (Table 2B) In patients with local tumour cell dissemination during primary treatment, locoregional recurrence was observed significantly earlier. The influence of the surgeon (surgeon A vs surgeon non-A) and the surgical procedure (anterior resection vs abdominoperineal excision) did not reach significance.
Recurrence-related factors (Table 2C) Locoregional recurrence was observed significantly earlier in patients undergoing regular follow-up than in those with reduced, minimal or no follow-up. Neither the location of locoregional recurrent tumour (intramural vs extramural) nor the presence of distant metastases influenced the diagnostic time point of locoregional recurrence. The median number of follow-up examinations prior to diagnosis of locoregional recurrence was 2 (range 0±12). However, not only the number of follow-ups, but also the time interval between the last follow-up with no evidence of locoregional recurrence and the diagnosis of the latter appears to be of importance. This interval ranged from 1 to 94 months (median 5 months). It increased the later locoregional recurrence was diagnosed.
Treatment of locoregional recurrence Thirty-seven patients with locoregional recurrence (22 per cent) underwent curative reoperation (Table 3). In 2 other patients locoregional recurrent tumour was removed, while distant metastases were left untreated. The pT category of the primary tumour, the type of primary treatment, the site of the locoregional recurrence (intramural vs extramural), and the absence or presence of distant metastases significantly influenced the number of curatively reoperated patients. R0resection of recurrent disease was possible mainly in primary pT2 carcinomas, after anterior resection, in cases of intramural locoregional recurrence and in the absence of distant metastases. It was independent of when locoregional recurrence was diagnosed.
Data of patients with late locoregional recurrence In 15 patients locoregional recurrence was diagnosed more than 60 months after primary treatment. These patients had only pT2 and pT3 tumours (i.e. no pT4), 9 patients had no lymph node metastases (i.e. only
No. of patients
5 year LR-Rate (95% CI)
All
978
(A) Tumour-related factors pT1 pT2 pT3 pT4 pN0 pN1 pN2 Low grade High grade EVI ÿ EVI Upper third Middle third Lower third
49 240 629 60 543 243 192 829 148 716 194 223 381 374
(B) Treatment-related factors No TCD TCD Surgeon A Surgeon non-A Anterior resection Abdominoperineal excision
922 56 302 676 642 336
(C) Recurrence-related factors Reduced FU Regular FU Intramural LR Extramural LR No distant metastases Previous or synchronous distant metastases
P*
LR (n)
LR 1 year (%)
LR 2 years (%)
16.7 (14.3±19.1)
167
34
64
6.1 20.6 35.7 8.1 21.9 36.7 15.0 27.6 11.9 17.7 11.1 14.5 22.5
0 (3.0±9.2) (17.3±24.0) (22.6±48.8) (5.8±10.5) (16.5±27.4) (29.2±44.3) (12.5±17.5) (19.5±35.6) (9.4±14.3) (10.8±24.5) (6.8±15.3) (10.8±18.1) (18.1±27.0)
18 130 19 51 53 63 131 36 92 49 27 59 81
39 32 42 28 23 49 30 50 29 39 30 37 33
15.1 45.0 10.5 19.5 14.1 21.9
(12.7±17.5) (30.7±59.3) (6.8±14.1) (16.4±22.6) (11.3±16.8) (17.2±26.5)
145 22 34 133 93 74 82 81 49 111 113 54
,0.0001 ,0.0001 0.0004 ,0.0001 0.0034
,0.0001 0.0009 0.0026
LR 5 years n (%)
Late LR n (%)
LR 50 (months)
LR 90 (months)
152 (91)
15 (9)
18
56
44 65 79 55 53 81 62 72 58 65 59 71 61
14 (78) 119 (92) 19 (100) 42 (82) 49 (93) 61 (97) 117 (89) 35 (97) 80 (87) 47 (96) 23 (85) 52 (88) 77 (95)
4 (22) 11 (8) 0 9 (18) 4 (7) 2 (3) 14 (11) 1 (3) 12 (13) 2 (4) 4 (15) 7 (12) 4 (5)
31 18 17 22 23 12 21 13 21 18 21 19 17
91 56 37 74 57 38 65 45 74 51 74 76 49
33 41 27 36 40 27
63 68 53 67 74 51
130 (90) 22 (100) 29 (85) 123 (92) 85 (91) 67 (91)
15 (10) 0 5 (15) 10 (8) 8 (9) 7 (9)
19 14 23 18 17 22
64 36 72 53 57 60
29 40 39 33 35 31
55 74 78 59 63 67
71 77 44 101 102 50
11 (13) 4 (5) 5 (10) 10 (9) 11 (10) 4 (7)
21 16 17 19 19 17
76 48 69 56 62 60
(87) (95) (90) (91) (90) (93)
0.071 0.0002 0.016 0.10 0.17
0.036 0.20 0.27
0.0099 0.43 0.44
719
LR 1 year: Percentage of locoregional recurrences observed within 1 year of follow-up. LR 2 years: Percentage of locoregional recurrences observed within 2 years of follow-up. LR 5 years: Percentage of locoregional recurrences observed within 5 years of follow-up. Late LR: Late locoregional recurrence observed more than 5 years after primary treatment. LR 50: Time to detecting of 50 of all locoregional recurrences. LR 90: Time to detecting of 90 of all locoregional recurrences. * Log rank test. EVI: extramural venous invasion; TCD: tumour cell dissemination; FU: follow-up; LR: locoregional recurrence.
P*
LATE LOCOREGIONAL RECURRENCE IN RECTAL CARCINOMA
Table 2 Locoregional recurrence rates and time of diagnosis
720
S. MERKEL ET AL.
Figure 1 Locoregional recurrence at 1, 2, 5 years of follow-up and the time points of diagnosis of 50 and 90 per cent of all locoregional recurrences (167 locoregional recurrences in 978 patients).
Table 3 Results of treatment (R0-resection) in patients with locoregional recurrence, n 167 R0 resection of recurrence n (%) All Findings on primary treatment pT2 pT3 pT4 pN0 pN1 pN2 Low grade High grade Anterior resection Abdominoperineal excision Findings on locoregional recurrence Intramural LR Extramural LR No synchronous distant metastases Synchronous distant metastases Early locoregional recurrence diagnosis 12 months diagnosis .12 to 24 months diagnosis .24 to 36 months diagnosis .36 to 60 months Late locoregional recurrence (diagnosis .60 months)
P*
37/167 (22) 8/18 (44) 27/130 (21) 2/19 (11) 13/51 (25) 13/53 (25) 11/63 (17) 31/131 (24) 6/36 (17) 30/93 (32) 7/74 (9) 23/49 (47) 13/111 (12) 34/118 (29) 3/49 (6) 33/152 (22) 16/57 (28) 8/50 (16) 5/22 (23) 4/23 (17) 4/15 (27)
0.042 0.51 0.50 ,0.001 ,0.001 0.001
0.75
*Fisher's extract test.
6 patients had lymph node metastases) and 14 had low grade tumours (i.e. only one high grade tumour). Seven of these patients had no evidence of disease on conclusion of their 5-year follow-up program. Four patients stopped attending for follow-up examination after 54 to
56 months. Four other patients already stopped attending after 28, 41, 50 and 51 months, and might otherwise have been diagnosed earlier. There were more extramural locoregional recurrences (n 10) than intramural recurrences (n 5). But R0-resection of the recurrent
LATE LOCOREGIONAL RECURRENCE IN RECTAL CARCINOMA lesion was possible in 3 intramural and only in one extramural recurrence.
Comparison with the period from 1991 to 1995 To investigate the question whether late locoregional recurrence may be expected to increase in the future, a separate analysis of 200 patients with the same inclusion criteria but treated between 1991 and 1995 was done (data not shown). During this period the 5-year locoregional recurrence rate was 8.4 per cent. In 15 out of 20 patients locoregional recurrence was diagnosed within 5 years. The other 5 patients with locoregional recurrent lesions (25 per cent) were diagnosed as late recurrence. (This percentage may increase during ongoing follow-up over the next few years.) These figures show that the percentage of late recurrences has already increased from 9 per cent in 1978±1990 to 25 per cent in 1991±1995.
DISCUSSION Twenty years ago the rate of locoregional recurrence in our rectal carcinoma patients was 26 per cent with 88 per cent being diagnosed within 2 years. Ten years ago a new analysis showed a locoregional recurrence rate of 17 per cent, with 71 per cent diagnosed within 2 years (unpublished data of the ERCRC). In the present analysis with a potential follow-up time of at least 10 years, only 63 per cent of all locoregional recurrences were diagnosed within 2 years. Late locoregional recurrences (more than 5 years after primary treatment) were observed in 9 per cent (n 15) of patients with locoregional recurrence (n 167). Seven of these patients had no evidence of disease at the end of their 5year follow-up programme. Four patients stopped attending for follow-up examinations after 54 to 56 months and 4 patients had already stopped after 28, 41, 50 and 51 months. Some of these patients might have been diagnosed earlier if they had regularly attended for follow-up. However, it is hard to believe that the diagnosis would have been made 7 years earlier in the patient with locoregional recurrence diagnosed 149 months after primary treatment. According to data in the literature13 the rate of locoregional recurrence is significantly influenced by the pT and pN category, grading, extramural venous invasion, local tumour cell dissemination, tumour site, and the surgeon. The time to diagnosis of locoregional recurrence was significantly influenced by such tumourrelated factors as pN category and grading, by such treatment-related factors as intraoperative tumour cell dissemination, and by the constancy of follow-up. But also a lower pT category, absence of extramural venous invasion, and treatment by surgeon A (the surgeon with
721
the lowest rate of locoregional recurrences) were associated with a trend towards later diagnosis of locoregional recurrence. Favourable prognostic factors of the primary tumour and optimized surgery with a low risk for locoregional recurrence were associated with a higher percentage of late locoregional recurrences. Three questions arise: (1) Is late locoregional recurrence likely to increase in the current setting of optimised surgery? Probably. The factors that influenced the rate of locoregional recurrence also influenced the time point of diagnosis of locoregional recurrence (not always significantly). Favourable prognostic factors of the primary tumour and tumours treated by surgeon A were associated with a higher proportion of late locoregional recurrences. With optimised surgery (total mesorectal excision in carcinomas of the middle and lower third of the rectum, formal regional lymphadenectomy) and adjuvant therapy when indicated,5,14 the rate of locoregional recurrence decreases. As a result the percentage of late locoregional recurrences may increase in the future. This is suggested by the results of our separate analysis of 200 patients treated between 1991 and 1995. The 5-year locoregional recurrence rate was only 8.4 per cent, but 5 out of 20 patients (25 per cent) with locoregional recurrence were diagnosed as having a late locoregional recurrence. This represents an increase in late locoregional recurrences from 9 per cent in 1978±1990 to 25 per cent in 1991±1995. (2) Will we need longer follow-up in the future? The constancy of follow-up influenced the time point at which locoregional recurrence was diagnosed. In patients attending for follow-up examinations regularly locoregional recurrence was observed significantly earlier, but there were also patients with late locoregional recurrence 5 years after primary treatment despite regular follow-up. However, prolonged follow-up is expensive, and does not guarantee an R0-resection of the recurrence. This is a problem given the present financial constraints on public health funding. In contrast to prolonged follow-up, the current guidelines of the German Cancer Society recommend a reduced and more individualised follow-up programme4 than that used in this study. In stage I patients undergoing radical resection only two follow-ups with history taking, physical examination and colonoscopy after 2 and 5 years are recommended. In stage II and III patients follow-up is recommended every 6 months for two years and thereafter every 12 months for a further 3 years. Rectoscopy is recommended 6, 12, and 18 months, and colonoscopy 24 and 60 months, after conclusion of primary treatment. Additional rectoscopy after 36 and 48 months is recommended only for patients receiving adjuvant radio/chemotherapy, in whom a later onset of locoregional recurrence is expected. (3) Which patients with locoregional recurrence have a chance of a curative reoperation? Only 22 per cent of
722 our patients with locoregional recurrence were treatable by curative reresection. This value is similar to data of the literature.15,16 In patients with primary pT2 rectal carcinoma the 5-year locoregional recurrence rate was low (6.5 per cent), but the number of curative reoperations for locoregional recurrence was 44 per cent, possibly influenced by the primary surgical procedure, which has an important impact on the chances for curative reoperation in the event of a locoregional recurrence. In patients undergoing primary anterior resection the rate of curative reoperation was 32 per cent, as compared with 9 per cent in those undergoing abdominoperineal excision. In addition, the chance of a repeat curative operation was clearly higher for intramural than for extramural locoregional recurrence (49 per cent vs 10 per cent). In patients with/ without synchronous distant metastases the relevant figures were 6 and 29 per cent, respectively. However, there was no difference in the number of curative reoperations between early and late locoregional recurrence. In summary, late locoregional recurrence may increase with present optimised surgery. It is not clear whether long-term follow-up is of benefit to rectal carcinoma patients in terms of early detection of locoregional recurrence. Therefore, especially in clinical studies, longer follow-up is needed. In addition it is important to consider the possibility of late recurrence in all patients with a history of rectal carcinoma.
NOTE ADDED IN PROOF The 10-year-rate of locoregional recurrence in the text (17.1%) seems to be in contradiction to the recurrence rate in Fig. 1 (18.8%). This is caused by two different methods of calculation: 17.1% is the number of patients with local recurrence observed within 10 years divided by the number of patients followed for at least one month (167/978). Patients who had already died after a few months (or years) of observation and had no local recurrence were analysed like patients never developing local recurrence during 10 years of follow-up. In contrast the Kaplan±Meier method calculates all diagnosed local recurrences in proportion to all patients being currently observed at the time of calculation. The rate of locoregional recurrence increases not only by every new local recurrence but also by the decreasing number of observed patients (patients died who never had a local recurrence). Therefore the 10-year-rate (18.8%) is related to the number of patients who either
S. MERKEL ET AL. developed locoregional recurrence or lived for at least 10 years free of local recurrence.
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