Original article
doi:10.1111/j.1463-1318.2008.01600.x
Transanal endoscopic microsurgery in 143 consecutive patients with rectal adenocarcinoma: results from a Danish multicenter study G. Baatrup*†, B. Breum‡, N. Qvist§, P. Wille-Jørgensen–, H. Elbrønd**, P. Møller¶ and P. Hesselfeldt‡ *Department of Surgery, Haukeland University Hospital, Bergen, †Section for Surgery, Department of Surgical Sciences, University of Bergen, Bergen, Norway, ‡Department of Surgery, Hvidovre University Hospital, Copenhagen, §Department of Surgery, Odense University Hospital, Odense, –Department of Surgery K, Bispebjerg University Hospital, Copenhagen and **Department of Surgery, A˚lborg University Hospital, A˚lborg, Denmark Received 1 January 2008; accepted 21 April 2008
Abstract Objective The long-term results are presented on total survival, cancer-specific survival and recurrence in 143 consecutive patients treated with transanal endoscopic microsurgery (TEM) for adenocarcinoma of the rectum. Method Four Danish centres established in 1995 a database for registration of all TEM procedures. Data were supplemented from pathology reports and death certificates were checked in the Danish patient registry. Data were analysed with multivariance regression and survival analysis. Results The T stage was as follows: T1 50%, T2 33%, T3 14%, and stage unknown 3%. TEM was performed with curative intent in 43%, for compromise in 52% and for palliation in 5%. Five-year total survival was
Introduction Rectal cancer affects the elderly and old, and 25% of the patients are more than 80 years at the time of the diagnosis. Despite improvements in anaesthesia and surgical technique, patients over 80 years still have a considerable 30-day mortality after conventional surgery with a mortality of up to 10%, co-morbidity being a strong risk factor [1,2]. A procedure, which significantly reduces the 30-day mortality rate, might accordingly be acceptable, even though a higher number of recurrences might occur. Local resection by transanal endoscopic microsurgery (TEM) of well or moderately differentiated small T1
Correspondence to: Gunnar Baatrup, Department of Surgery, Haukeland University Hospital, N5021 Bergen, Norway. E-mail:
[email protected]
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66% and 5-year cancer-specific survival 87%. Cancerspecific survival for T1 was 94%. The significant predictors for total survival were age and tumour size. For cancer-specific survival T stage, radical resection, tumour size and recurrence were significant predictors. Eighteen per cent had recurrence and 15% had immediate reoperation. Conclusion The TEM provides good long-term results for pT1 cancers. In old patients and patients with comorbidity TEM may provide acceptable long-term results for T2 cancers. Tumours larger than 3 cm should not be treated with TEM for cure. Keywords Transanal endoscopic microsurgery, cancer, adeno carcinoma, survival
rectum cancers without vascular or lymphatic involvement seems to match those of conventional surgery in terms of long-time survival [3–5]. Adjuvant or neoadjuvant oncological treatment may improve cancer-free survival for patients with high risk T1 and T2 cancers [6–9]. The results of single centre studies are very promising whereas those from multicentre studies are few and more debatable [10–13]. The major problems with TEM include nonradical resection and local recurrence. A 17% rate of nonradical resection for T1 cancers has been reported [8]. The risk of local failure due to involvement of local lymph nodes not resected may be up to 10% in T1 and 25% in T2 tumours. Local recurrence is considerable in tumours with a diameter above 3 cm. Based upon age and physical performance, 10–25% of patients with rectal cancer would profit from a TEM procedure even though more local recurrences could be expected. Additional
2009 The Authors. Journal Compilation 2009 The Association of Coloproctology of Great Britain and Ireland. Colorectal Disease, 11, 270–275
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benefits would be a reduction of complications and longterm side effects, and a reduction in hospital costs. The aim of the present study was to evaluate long-term crude mortality and cancer-associated mortality in patients undergoing TEM in a consecutive series of patients.
Method Four Danish TEM centres covering a population of 2 million inhabitants established a database in January 1996 for the prospective registration of all TEM procedures performed for adenocarcinoma of the rectum. Questionnaires were collected in October 2005 and systematically cross-checked in the national disease register. All death certificates were collected for determination of the cause of death, and all pathology reports for checking and supplementing histological features were reviewed. The database contained information on demographics, preoperative staging and characterization, indications for TEM, procedure-related factors, postoperative complications, pathological features, supplementary treatment and follow up. Short-term results and accuracy of the preoperative staging have been published previously [13]. Age and gender, indication for TEM, T stage, distance from the dentate line and concurrent disease were all recorded. The indications for TEM were curative (all stage T1 cancer, less than 3 cm), for compromise (high age, concurrent disease and stage T2, or diameter > 3 cm), and palliative (T2 or more and major surgery contraindicated). Concurrent disease was not specified other than being serious enough to influence the decision. The maximal diameter of the tumour was measured with a rigid sigmoideoscope. Histological T stage and information concerning resection margins were obtained from the pathology report. An R0 resection (radical TEM) was defined as microscopically recognizable normal tissue in all circumferential and lateral margins of the resected specimen. Data on histological features such as differentiation or involvement of lymphatics or veins were available in less than 50% of cases and were consequently omitted from the study. Preoperative radiation therapy and postoperative rescue surgery (within 4 weeks) were registered together with treatment for recurrence including re-TEM, radiation therapy, electrocautery or argon beam. The cause of death was obtained from the death certificates and defined as death from the rectal cancer or death from other causes. Patients who died from other causes such as pneumonia, other infections, pulmonary embolism, cerebral infarction, age or cachexia, and who also had recurrence of the rectal cancer, were entered as having died from rectal
cancer. Patients with recurrence who died from small intestinal obstruction, from volvulus, arteriosclerotic gangrene of the lower extremities, leukaemia, disseminated ovarian cancer, or from accidents, were regarded as having died from other causes. A total of 149 procedures were registered. Two patients were excluded since histology on preoperative biopsies and the TEM specimen was initially benign, and one patient was excluded because of a carcinoid tumour. Thus 146 procedures for cancer in 143 patients were registered. One case excluded in an earlier publication as a carcinoid [10] was re-entered on the basis of revised information from the pathology report stating that the tumour was actually an adeno-carcinoma. The three re-TEM procedures were excluded leaving 143 procedures for analysis. The four hospitals performed between 22 and 47 operations each. The data were collected in an Access 2000 database (Microsoft Corporation, Seattle, WA, USA), which was imported into a SPSS version 14 database (SPSS Inc. Chicago, IL, USA).
Statistics The data were controlled for nonsense figures and missing data manually and by frequency analysis. For tumour diameter there were 20 missing figures, for distance from anal verge four figures were missing. Fisher’s exact test and Mann–Whitney U-test were performed to analyse for possible correlation between independent variables and death, cancer-specific death and recurrence. Possible candidates as independent variables were entered in a Cox multivariate regression analysis for survival. Parameters with P-values of less than 0.65 were accepted for further analysis. Missing data were not replaced. The analysis was performed both with and without the variables of diameter of tumour and distance from the anal verge, to test for possible influence of missing data. Only one P-value changed from 0.008 to 0.003. Survival was obtained from a Kaplan–Meier analysis. Intervals are given as 95% confidence limits. Pvalues for age, diameter of tumour and distance from anus were analysed for continuous numbers, but were, presented graphically as interval groups. The Cox analysis is based upon events during the observation period whereas 5-year survival figures were calculated in the Kaplan–Meier equation. Ethics
The study was conducted in accordance with the Helsinki Declaration. The Danish Data Protection Agency (file 2001-41-0575, Datatilsynet, Denmark) approved the database.
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Results
Table 2 Cox analysis of possible correlation between selected independent variables and total mortality and cancer-specific mortality during the observation period.
Survival
The total 5-year survival was 66% and the total 3-year survival 71%. The cancer-specific survival was 87% after 5 years and 90% after 3 years (Table 1).
Dead during the observation period n ⁄ N (%)
Death from the cancer during the observation period
P-values n ⁄ N (%)
P-values
Multivariate analysis and patient-related factors
The dependent variables were death, death from cancer and recurrence. Independent variables tested in univariant analysis for possible correlation included age, gender, indication for TEM, histopathological T-stage, radicality, diameter of tumour, area of tumour, distance from anal verge, closure of the defect, recurrence and immediate reoperation. On the basis of these analyses, the parameters listed in Table 2 were entered in the Cox regression analysis. Values for age, tumour diameter, and distance from the anal verge were entered as continuous values in the test and are depicted in the table as groups, for descriptive purposes. The age ranged from 28 to 94 years (median 77), 75 ⁄ 143 were female, 69 (48 %) patients had severe co morbidity and 64 (45 %) patients were 80 years or older. Sixty-one procedures were for cure (median age: 73 years), 75 for compromise (median 81 years) and seven for palliation (median 83 years). No correlation was found between indications for TEM and total or cancerspecific mortality. Multivariate analysis and tumour-related factors
There were 72 pT1 cancers, 47 pT2 cancers, and 20 pT3 cancers. In four cases, the pT stage could not be determined due to a fragmented resection. Significant correlation was found between pT stage and cancerspecific mortality, but not between pT stage and total mortality. The mean diameter of the tumours was 3.8 cm
Table 1 Five-year cancer-specific and total survival after TEM including adjuvant and salvage treatment and treatment of recurrences. 5-year survival
T stage
Deaths
Survival (%)
Cancer specific
T1 T2 T3 T1 T2 T3
4 ⁄ 72 8 ⁄ 47 6 ⁄ 20 17 ⁄ 72 20 ⁄ 47 12 ⁄ 20
94 83 70 76 57 40
Total
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T-stage 1 21 ⁄ 72 (29) 2 21 ⁄ 47 (45) 3 13 ⁄ 20 (65) X 2 ⁄ 4 (50) Indication For cure 16 ⁄ 61 (26) Compromise 37 ⁄ 75 (49) Palliation 4 ⁄ 7 (57) Radicality Yes 35 ⁄ 99 (35) No 17 ⁄ 32 (53) Undetermined 5 ⁄ 12 (42) Diameter (cm) < 3.1 12 ⁄ 57 (21) 3.1–5 12 ⁄ 46 (28) > 5.0 8 ⁄ 20 (40) Recurrence Yes 12 ⁄ 26 (46) No 45 ⁄ 117 (38) Reoperation Yes 4 ⁄ 23 (17) No 53 ⁄ 120 (44) Distance from anus (cm) 0–5 24 ⁄ 60 (40) 5.1–10 20 ⁄ 63 (32) 10.1–15 2 ⁄ 16 (13) Age (years) > 85 19 ⁄ 29 (66) 76–85 33 ⁄ 60 (55) < 75 15 ⁄ 54 (28)
ns
4 ⁄ 72 (6) 8 ⁄ 27 (30) 7 ⁄ 20 (35) 1 ⁄ 4 (25)
ns
5 ⁄ 61 (8) 24 ⁄ 75 (32) 2 ⁄ 7 (29)
ns
9 ⁄ 99 (10) 7 ⁄ 32 (22) 4 ⁄ 12 (33)
0.02
7 ⁄ 57 (12) 6 ⁄ 46 (13) 6 ⁄ 20 (30)
0.01
ns
11 ⁄ 26 (43) 9 ⁄ 117 (8)
0.003
ns
3 ⁄ 23 (13) ns 17 ⁄ 120 (14)
0.008
ns
0.009
0.03
ns
9 ⁄ 60 (15) 8 ⁄ 63 (13) 1 ⁄ 16 (6)
ns
4 ⁄ 30 (13) 11 ⁄ 66 (17) 5 ⁄ 57 (9)
ns
P-values < 0.05 were significant. Data on diameter of tumour are missing in 20 patients and on distance from the anal verge to the tumour in four patients.
(range: 0.8–10 cm). In 57 patients the cancer was less than 3 cm in diameter. For these small tumours, the cancer-specific mortality was 12% and total mortality was 21%. The mean diameter of the tumour in patients who died from cancer was 4.6 cm, and for those alive 3.4 cm. The mean diameter of pT1 cancers was 3.4 cm (3.7– 5.4 cm) for pT2 3.9 cm (3.3–4.6 cm) and for pT3 5.0 cm (4.1–5.8 cm). Significant correlation was demonstrated between diameter and total and cancerspecific mortality (Fig. 1).
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two for palliation. In 12 patients radicality could not be determined. Radical resection correlated with cancerspecific survival. Local recurrence occurred in 26 (18%) of the 143 cases. These were nine (13%) of 72 pT1 cancers, 12 (26%) of 47 pT2 cancers and five of five pT3 cancers. Recurrence significantly influenced cancer-specific survival, but not total survival.
Crude survival in age groups
(a) 1.0
< 75 years 0.8
Cum survival
76–85 years 0.6
Multivariate analysis and treatment-related factors
> 85 years 0.4
The frequency of pT1 cancers treated in the four hospitals ranged from 22% to 68%. Closure of the rectal wall (72 cases) or not (61 cases) did not influence survival or recurrence. Total mortality was 34% and 31% for closure and nonclosure and cancer-specific mortality was 15% and 13% respectively.
0.2
0.0 0.0
(b)
1
2 Years
3
4
5
Immediate reoperation and treatment of local recurrence
Crude survival and diameter of tumour
1.0
Cum survival
0.8
< 3.1 cm 3.1–5.0 cm
0.6
0.4
> 5.0 cm
0.2
0.0 0.0
1
2 3 Years
4
5
Figure 1 Significant predictors for total survival. (a) Correlation between age and total 5-year survival. Patients younger than 75 years (1). Patients 76–85 years of age (2), and patients older than 85 years (3). (b) Correlation between tumour diameter and total 5-year survival. Tumours 3 cm or less (1). Tumours larger than 3 cm and up to 5 cm (2), and tumours larger than 5 cm (3).
The mean distance from the anal verge to the tumour was 6.5 cm. One hundred and ten (77%) tumours were placed in the lower two-thirds (10 cm) of the rectum. The distance from the anal verge did not significantly influence survival. In 32 (22%) cases, the resection was not radical. Ten of these were resections for cure, 20 for compromise and
Immediate reoperation was performed in 23 cases. In all cases the procedure was performed within 4 weeks of TEM. The procedures were low anterior resections or abdomino-perineal resections (18), re-TEM (1) and postoperative radiation therapy (4). The original T stage was pT1 4, pT2 9, pT3 7 and pTx 3. Four (21%) of these had died, three from cancer. Thirty-two (24%) patients had a histological R1 resection. In 12 cases the radicality could not be determined due to piecemeal resection or poor handling of the specimen. Of these 32 cases, four were palliative procedures, 18 were for compromise and 11 for cure. The reoperation rate was nine of the 11 TEM resections for cure, two of the 18 R1 resections for compromise and zero of three palliative procedures. Thus 12 of 99 reoperations were performed after radical resection. These were patients who preoperatively were judged to be nonmalignant (seven patients) or where the T stage was higher than expected (five patients). Twenty-six patients had local recurrence. Low anterior resection or abdomino-perineal resection was performed in seven cases (three are dead), re-TEM in six cases (three of which were combined with radiation) (two are dead), radiation therapy in six cases (four are dead) and three patients with electrocautery or argon beam (three are dead). Four patients received no treatment. Mean time to recurrence was 10.7 months (4–33 months). The number of recurrences was too small for subgroup analysis but recurrence occurred in five of 20 T3, 12 of 47 T2 and nine of 72 T1 cancers.
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Discussion This patient series indicates a restrictive attitude to TEM in cancer patients. The patients were old and comorbidity was frequent. The number of procedures performed for compromise and the proportion of tumours greater than T1 was high when compared with previous single centre series. This explains the poor total survival rate. The discrimination between death from cancer or dead with cancer but from other causes is problematic, but necessary because of the poor performance of the patients. Due to high age and co morbidity, follow-up was incomplete or missing in a high proportion of the patients. Data on recurrence free survival and local recurrence free survival could not be obtained. The information from the death certificates concerning immediate cause of death, secondary cause of death and other diseases with possible influence on death is often difficult to interpret since the immediate cause of death could be ‘acute heart failure’ in a patient with disseminated disease. Only 22 patients with cancer, however, died from other causes, and the distinction was obvious in 16 cases. We therefore consider the data for cancer-specific death to be accurate. The cancer-specific death rate is very good in T1 tumours and in tumours with a diameter of 3 cm or less and comparable to results from conventional surgery. The total survival of patients with tumours greater than 3 cm was significantly lower than that of patients with smaller tumours and TEM should in these cases be used as a compromise or for palliation. However, the final conclusion on the use of TEM as a palliative procedure cannot be deduced from our data. The decision to perform reoperation is complex and depends upon histopathology and the physical performance of the patient. If the initial indication for TEM was curative, reoperation was performed if histopathology showed a T stage higher than T1 or if the resection was not radical. If the intent was for compromise, reoperation was performed if the histopathology showed nonradical resection or a T stage higher than that anticipated preoperatively. The number of patients subjected to immediate reoperation was relative small, but the results were acceptable even for T2 and T3 cancers. Poor preoperative staging can be compensated for by early reoperation, and compete with primary major procedures in terms of long-term survival. More data are required, however, to be sure of this conclusion. If recurrence is entered as the independent variable in the Cox analysis, T-stage was significantly correlated to this, as was diameter of tumour and radicality of the resection. The results from intended curative surgery for recurrence are in this series not comparable with primary radical surgery, but TEM and surgery for recurrence might still be a
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feasible strategy since the patients who did not get a recurrence avoided a major surgical procedure with higher 30-day mortality. The number of recurrences is, however, too small for any firm conclusions. The strongest predictors for overall death were age and diameter of the tumour. Large tumours are more advanced as diameter and T stage were closely related, but large tumours also result in more incomplete resections. Therefore tumour diameter is the diseaserelated variable which best predicts outcome and is related to the fact that a nonradical procedure is a significant predictor of cancer-specific death. Tumours with a diameter of 3–5 cm, however, show 5-year survival only slightly worse than the smallest tumours. The patient’s age is the strongest predictor of total survival, but is not correlated to cancer-specific survival. This also indicates that in patients with high age and co morbidity, TEM is a good alternative to conventional surgery not only in terms of complications, long-term side effects and hospital costs, but also of survival. This study began in 1996. Today the preoperative assessment may be more accurate, and fewer TEM procedures will be performed on patients with T2 and T3 cancers in well fitted patients. TEM for cure should be considered only in T1, sm1 or sm2 cancers smaller than 3 cm as has been previously recommended [14]. The results from early rescue surgery, however, and perhaps from later reoperation for recurrence may cure more than 50% of those patients. TEM may therefore be considered in old and co-morbid patients with high short-term postoperative mortality risk. Healthy persons of 85 years have an expected life span of 6 years. Patients with rectal cancer who have recurrence after 1 or 2 years can be treated with radiation or re-resection and chemotherapy. A considerable proportion of these patients will die from other causes before they die from the cancer and TEM may come out favourably on long-term survival analysis even in T3 cancers in old, high-risk patients. It might be possible from the POSSUM score estimate of the 30-day mortality and the expected residual life time based upon age, to calculate the long-term survival after TEM and after radical surgery on an individual basis. More careful patient selection based upon tumour size and development of better staging procedures may improve the long-term results of TEM further. The high rate of R1 resection of 24% is probably due to the very large size of the tumours included in this series, as large size and nonradicality are closely correlated. The R1 rate is comparable to that found in the Norwegian multi centre study [10]. Further studies are needed to compare the results of TEM with radical surgery for patients matched for age, co morbidity, T stage and intention to treat. Also needed are
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studies on TEM as a palliative procedure as compared to radiation needs further studies. Our results in terms of short-term and long-term complications, survival, immediate reoperation and treatment of recurrence is comparable to earlier published single centre [3,4] and multi centre studies [11]. Randomized trials between TEM and standard resection for smaller cancers seem justified in fit patients, but inclusion of sufficient numbers of patients may not be feasible.
Acknowledgements Professor Asgaut Viste is acknowledged for statistical advice. Ann Marie Jørgensen, Anita Anfindsen is thanked for database management. The study was financed by ‘‘The General Medical Research Foundation’’, University of Bergen.
Conflicts of interest None.
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