Chapter 9

Chapter 9

DECISION ANALYSIS IN THE SURGICAL TREATMENT OF FAMILIAL ADENOMATOUS POLYPOSIS: A DUTCH-SCANDINAVIAN COLLABORATIVE STUDY ON 659 POLYPOSIS PATIENTS

H.F.A. Vasen , P. van Duijvendijk1, E. Buskens1, C. Bülow"1, J. Bjork§, H. Jarvinnen0, S. Bülow11 From the Netherlands Foundation for the Detection of Hereditary Tumours and the Department of Gastroenterology, Leiden University Medical Center, The Netherlands', The Department of Surgery, Academic Medical Center, Amsterdam, The Department of Clinical Epidemiology, University Hospital Utrecht, The Netherlands1, Hvidovre University Hospital, Copenhagen, Denmark^, Department of Surgery, University of Lund, Sweden8, Department of Surgery, University of Helsinki, Finland0

CH.M'ÏI-:R v

Abstract Backgroud/Aims: The choice of surgery in patients with familial adenomatous polyposis lies between the morbidity of proctocolectomy and ileum pouch-anal anastomosis (IPAA) and the mortality from rectal carcinoma after total colectomy and ileorectal anastomosis (IRA). The aims of the present study were: (1) to assess the risk of dying from rectal carcinoma after IRA, (2) to compare the life expectancy between patients with an IRA and those with an IPAA and (3) to investigate whether regular endoscopic examination leads to detection of carcinoma at an earlier stage. Methods: Clinical and pathological data on 659 patients who underwent total colectomy and ileorectal anastomosis were collected from four National Polyposis Registries, i.e., in Denmark, Finland, Sweden and the Netherlands. The data were analyzed using survival analysis methods. Decision analysis was used to compare the life expectancy between patients with an IRA and those with an IPAA. Results: A total of 47 patients developed rectal carcinoma after IRA. The risk of dying from rectal carcinoma was 12.5 percent (CI: 7.1-17.9%) by age 65. Compared to IRA, IPAA would lead to an increase in life expectancy of 1.8 years. Seventy-five percent of the patients with rectal carcinoma had a negative endoscopy within 12 month before diagnosis. Conclusions: IRA is associated with a substantial mortality due to rectal carcinoma. Follow up examinations of the rectum do not guarantee early detection of rectal carcinoma.

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Introduction Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by the development of numerous adenomas in the colorectum and various other extracolonic manifestations such as adenomas in the upper GI tract, desmoids and retinal lesions. 1 The syndrome is caused by mutations in the APC (Adenomatous Polyposis Coli) gene.2-3 Most patients develop colorectal adenomas in their second decade of life. If they are not timely treated, they will develop colorectal carcinoma in the third and fourth decade of life. 1 The establishment of Polyposis Registries in various countries encouraged genealogical studies in FAP families and, consequently, the identification of family members at risk for the disease.4 These activities led to the detection of polyposis at an earlier, often pre-malignant stage5'6 and to improvement of the prognosis.7 Although medical treatment, e.g. sulindac is effective in reducing the number and /or size of the adenomas,8"10 the only curative treatment of colonic polyposis is still surgical. Until a decade ago, colectomy with an ileorectal anastomosis (IRA) was the most frequently applied surgical procedure for patients with polyposis. This surgical option is attractive because it is a relatively simple procedure with good functional results. A major disadvantage of the procedure, however, is the need for continuous endoscopic follow up and the risk of rectal carcinoma that increases over time.11'12 In addition, in about half of the cases a secondary proctectomy is needed because of uncontrollable polyps. These disadvantages might be the reason that an increasing number of patients is treated with the alternative surgical option, i.e., a proctocolectomy and ileoanal anastomosis (IPAA). However, this surgical procedure has also various disadvantages including a risk of severe postoperative complications, in the worst case necessitating removal of the pouch and construction of an ileostomy. Another disadvantage is the inferior functional outcome as compared to that after IRA.13 For patients with a large number of rectal adenomas or rectal carcinoma and patients that will not comply to follow up examinations after IRA, an IPAA seems the procedure of first choice. There is, however, no agreement about the best surgical option for patients with only a few or no rectal adenomas. In the decision making between the two procedures the risk of developing rectal carcinoma after IRA is important but even more crucial is the risk of dying of rectal carcinoma. The aims of the present study are, therefore, to assess the risk of dying from rectal carcinoma in a large series of IRA patients, and to find out whether frequent follow up of the rectum leads to the detection of rectal carcinoma at an early stage. In addition, using the technique of decision analysis, we evaluated

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whether there is a difference in life expectancy between the two surgical procedures. Patients and Methods Four national polyposis registries, i.e., in Finland, Denmark, Sweden and The Netherlands participated in the study. Clinical information was collected on 659 patients who underwent a colectomy with an ileorectal anastomosis for FAP between 1940 and 1997. The registered data included information on the mode of diagnosis, the age at diagnosis, pathology, age at surgery, type of surgery, age at death and causes of death. Hundred-ninety-three of the 659 patients (29%) presented with symptoms and 418 patients (63%) were identified by family screening. For the remaining patients the mode of diagnosis is not known. For risk assessment, patients who underwent an IRA were studied with respect to their risk of dying due to rectal carcinoma. The data were analyzed using survival analysis methods. Observation time was from the date of surgery up to the date of last contact, death, the date of rectal excision for other reasons or closing date of the study, i.e., the first of januari 1997. life expectancy (years)

risk proctectomy rectal cancer

risk =s? proctectomy other reason

25 yrs

•

0.005 Is'

risk

surgical death

^ \ 0.995

successful operation

risk metastatic cancer

11 30

\ ^ 0.995

successful operation

45 45

***s _' U

risk surgical death

\ . successful 0.995 operation no operation

43

/-\'

risk surgical death

no operation

risk excision pouch

risk local cancer

O

old patient

20

O

0

45

45

Figure J: Decision tree for comparing life expectancy between patients with an IRA and those with an IPAA.

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DECISION ANALYSIS IN SURGICAL TREATMENT OF FAP

A decision model was developed to estimate the potential health effects (life expectancy) of the two surgical options. The calculations were applied to a hypothetical polyposis patient aged 25 years who was found to have hundreds of adenomas in the colon and only a few in the rectum. The age of 25 years was chosen because the mean age at surgery is about this age. The first step was to identify the outcomes of both surgical options and to construct a decision tree displaying these events in their proper time sequence. The decision model for both strategies is shown in Figure 1. Points where the tree branches ("nodes") are indicated by a square when they are under the control of the physician and by a round symbol when they are not. The software program "Decision maker" was used to calculate the life expectancies. Results Table 1: Mortality observed in patients with IRA Cause Rectal carcinoma after IRA Non FAP-related Duodenal carcinoma Other carcinoma Postoperatieve complications Metastatic primary colorectal carcinoma Unknown

Screen-detected N 10 6 4 4 2 1 2

group % 34 21 14 14 7 3 7

Total group N 21 20 17 18 8 8 10 10 4 4 29 30 8 8

Ninety-seven patients died at a mean age of 48 years (21-80 yrs). The main cause of death in the total group of patients was metastatic colorectal carcinoma. In the screen-detected group rectal carcinoma was the main cause of death. The causes of death are listed in Table 1. A total of 47 patients developed rectal carcinoma after IRA. The mean age at diagnosis of rectal carcinoma was 44.5 (range: 21-46 years). The Dukes stages of the tumors are shown in Table 2. Table 2: Comparison of Dukes stages between patients with rectal carcinoma after IRA and patients with sporadic colorectal carcinoma. Sporadic colorectal carcinoma 26 Rectal carcinoma after Dukes stages IRA A B C Distant metstases Unknown

N 8 19 12 5 3

% 17 40 25 11 6

% 8 43 22 12 13

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Dukes A cancinomas were more frequently observed among patients with rectal carcinoma after an IRA than in patients with sporadic colorectal carcinoma registered at the Dutch Cancer Registry. Seventy-five percent of the patients had a negative endoscopic examination within one year before diagnosis of the carcinoma. The majority of these patients (19 out of 28) had Dukes stage A or B colorectal carcinoma (Table 3). Table 3:

Interval since last negative endoscopy in patients diagnosed with rectal carcerinoma

Months

No. of patients (%) 13*(35%) 15**(40%) 5(13%) 1 (3%)

0-6 6-12 12-18 18-24 >24 Unknown Total

3 (8%) 10 47

Two Dukes A, eight Dukes B, one Dukes C carcinomas and two colorectal carcinomas with distant metastases; ** Two Dukes A, seven Dukes B, four Dukes C and two colorectal carcinomas with distant metastases.

The 10 years survival according to the various pathological stages is shown in Figure 2. The risk of dying from rectal carcinoma was 8% by age 55, 9% by age 60 and 12.5% (CI: 7.1%-17.9%) by age 65. The probabilities of dying from rectal carcinoma for patients operated before and after 1980 were 7% and 6% at 10 years after surgery, respectively.

0

10

20

30

40

Years after IRA

Figure 2: Survival of patients with rectal carcinoma according to Dukes' stages A-D.

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DECISION ANAL YSIS IN SURGICAL TREA TMENT OF FAP

A summary of the data used in the decision analysis is shown in Table 4. The assessment of the risk of developing rectal carcinoma or the risk of a secondary proctectomy for other reasons is subject of a recent study from our group. The estimated risk of a secondary proctectomy because of rectal carcinoma found in this study is 26% by age 65 years and the estimated risk of a secondary proctectomy for other reasons was 34% by age 65 years. The mean age of the patients in this study at time of proctectomy because of rectal carcinoma or because of other reasons was 45 respectively 36 years. Table 4: Data used for the decision analysis risk proctectomy rectal carcinoma by age 65 = 26% risk proctectomy other reasons by age 65 = 34% mean age proctectomy rectal carcinoma = 45 years mean age proctectomy for other reasons = 36 years peri-operative mortality = 0.005" risk metastatic rectal carcinoma = 0.39 10-yrs survival local rectal carcinoma = 90% 10-yrs survival metastatic disease = 25% life expectancy 25-years-old FAP patient = 45 years The life expectancy of males and females at birth in the Netherlands and the Scandinavian countries is 75 and 80 years, respectively (on average 77 years). We assumed that the life expectancy of a patient with polyposis is shortened by 7 years because of death due to extracolonic lesions such as desmoid tumors and duodenal carcinomas. Hence, the life expectancy of a hypothetical 25 years-old polyposis patient is 45 years. As reports on development of carcinoma after IPAA are very rare, we assumed that this risk might be neglected. If all parameters are entered in the decision model, an increase of life expectancy of 1.8 years is found for a proctocolectomy followed by IPAA. Discussion The present study revealed that patients with an IRA have a substantial higher risk of dying from rectal carcinoma than has been suggested earlier.'' In contrast with studies, 1516 that showed that desmoid tumors and duodenal carcinomas are the most frequent causes of death in screen-detected cases, in the present study rectal carcinoma was the most frequent cause of death in this group. The development of rectal carcinoma can not be attributed to failure of compliance as 75 percent of the patients had an endoscopic examination within 12 months before the diagnosis of rectal carcinoma. Although periodic examination led to detection of more Dukes A carcinomas, it certainly did not prevent the

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development of advanced stages of rectal carcinoma. Using decision analysis we found that IPAA led to increase of life expectancy by 1.8 years. We did not adjust the life expectancies for quality of life as a recent study from our group did not reveal any differences in quality of life between IRA and IPAA.17 For the analysis we assumed that the risk of developing carcinoma from residual rectal mucosa after IPAA might be neglected. In this respect, it should be noticed that a recent international collaborative study revealed that patients with an IPAA have a significant risk of adenoma especially after a double stapled procedure. Reports of carcinomas that developed after IPAA in the literature are very 10

iq

•*

rare, ' but the follow up after this surgical procedure is still short (15-20 years). In addition, adenomas in the pouch have been reported.20 One study reported adenomas in the ileal pouch in 11 (42%) out of 26 patients.21 The current study included patients who underwent surgery over a long period of time (1940-1997). In the course of time, indications for surgery might have been changed. Patients with a moderate number of rectal polyps will currently be selected for an IPAA procedure while in the past such patients might probably have been selected for IRA instead of the only alternative at that time, i.e., proctocolectomy with an ileostomy. As a consequence the risk of carcinoma in patients that nowadays are selected for IRA might be lower than the risk in patients selected for an IRA 20 years ago. A subanalysis, however, showed no significant difference in risk of dying from rectal carcinoma between patients who underwent surgery before and those with surgery after 1980 (the time since IPAA is widely applied). An alarming finding in the present study is that follow up examinations and polypectomies do not guarantee early detection of rectal carcinoma. The question is how the effectiveness of endoscopic surveillance in this group of patients can be improved. Nugent suggested in selected cases to shorten the interval between examinations from six to four months.22 Another possibility is to use the technique of fluorescence endoscopic imaging to identify nonpolypoid adenomatous areas in the rectal mucosa.23 Several studies showed that sulindac treatment lead to disappearance or reduction in size of rectal adenomas. On the other hand patients have been reported that developed carcinoma under sulindac treatment.24,25 Long-term follow up studies are, therefore, needed to assess whether also the risk of carcinoma development is decreased. Until such studies are available frequent follow up of the rectum should continue also in patients in which the adenomas disappeared after sulindac treatment. The results of the present study can be used in the decision making of surgical management. The finding of a significant risk of dying from rectal carcinoma and the shortened life expectancy can be considered as arguments against performing

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IRA in patients also in those with a moderate or low number of rectal adenomas. Probably the remaining appropriate indication for an IRA procedure is a patient with a few or no rectal adenomas from a family with a similar mild phenotype of the disease. References 1.

Bussey HJR. Family studies, histopathology, differential diagnosis and results of treatment. In: Familial polyposis coli. Baltimore: The Johns Hopkins University Press, 1975: 2. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66:589-600. 3. Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 1991;251:1366-1370. 4. Biilow S, Burn J, Neale K, Northover J, Vasen HFA. The establishment of a polyposis register. Int J Colorectal Dis 1993; 8:34-38. 5. Vasen HF, Griffioen G, Offerhaus GJ, den Hartog Jager FC, Van Leeuwen-Cornelisse IS, Meera Khan P, et al. The value of screening and central registration of families with familial adenomatous polyposis. A study of 82 families in The Netherlands. Dis Colon Rectum 1990;33:227-230. 6. Jarvinen H. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33:357-360. 7. Biilow S, Biilow C, Nielsen TF, Karlsen L, Moesgaard F. Centralized registration, prophylactic examination, and treatment results in improved prognosis in familial adenomatous polyposis. Results from the Danish Polyposis Register. Scand J Gastroenterol 1995;30:989-993. 8. Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991; 101:635-639. 9. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Eng J Med 1993;328:1313-1316. 10. Winde G, Schmid KW, Schlegel W, Fischer R, Osswald H, Bunte H. Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas exceeding 33 months. Dis Colon Rectum 1995; 38:813-830. 11. De Cosse JJ, Biilow S, Neale KF, Jarvinen H, Aim T, Hultcrantz R, et al. Rectal cancer risk in patients treated for familial adenomatous polyposis. Br J Surg 1992; 79:1372-1375. 12. Vasen HFA, van der Luijt RB, Slors JFM, Buskens E, de Ruiter P, Baeten CG, et al. Molecular genetic tests as a guide to surgical management of familial adenomatous polyposis. Lancet 1996; 348:433-435.

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13. van Duijvendijk P. Slors JFM, Taat CW, Oosterveld P, Vasen HFA. Functional outcome after colectomy and ileorectal anastomosis compared to proctocolectomy and ileal pouchanal anastomosis in familial adenomatous polyposis. Ann Surg 1999; 230:648-654. 14. Biilow C, Vasen HFA, Jarvinen H, et al. The rectum after colectomy and ileorectal anastomosis in patients with familial adenomatous polyposis: Analysis of risk factors for rectal cancer and secondary proctectomy. Submitted 2000; In press. 15. Arvanitis ML, Jagelman DG, Fazio VW, Lavery IC, McGannon, F. Mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 1990; 33:639-642. 16. Nugent KP, Spigelman AD, Phillips RK. Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Dis Colon Rectum 1993; 36:1059-1062. 17. van Duijvendijk P, Slors JFM, Taat CW, Oosterveld P, Sprangers MA, Obertop H, et al. Quality of life after total colectomy with ileorectal or proctocolectomy and ileoanal anastomosis for familial adenomatous polyposis. Submitted 2000. 18. Hoehner JC, Metcalf AM. Development of invasive adenocarcinoma following colectomy with ileoanal anastomosis for familial polyposis coli. Report of a case. Dis Colon Rectum 1994;37:824-828. 19. von Herbay A, Stern J, Herfarth C. Pouch-anal cancer after restorative proctocolectomy for familial adenomatous polyposis. Am J Surg Pathol 1996; 20:995-999. 20. Nugent KP, Spigelman AD, Nicholls RJ, Talbot 1C, Neale KF, Phillips RK. Pouch adenomas in patients with familial adenomatous polyposis. Br J Surg 1993; 80:1620 21. Wu JS, Mcgannon EA, Church JM. Incidence of neoplastic polyps in the ileal pouch of patients with familial adenomatous polyposis after restorative proctocolectomy. Dis Colon Rectum 1998;41:552-556. 22. Nugent KP, Phillips RK. Rectal cancer risk in older patients with familial adenomatous polyposis and an ileorectal anastomosis: a cause for concern. Br J Surg 1992; 79:1204-1206. 23. Wang TD, Van Dam J, Crawford JM, Preisinger EA, Wang Y, Feld MS. Fluorescence endoscopic imaging of human colonic adenomas. Gastroenterology 1996; 111:1182-1191. 24. Lynch HT, Thorson AG, Smyrk T. Rectal cancer after prolonged sulindac chemoprevention. A case report. Cancer 1995; 75:936-938. 25. Niv Y, Fraser GM. Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy. Gastroenterology 1994; 107:854-857. 26. The Netherlands Cancer Registry. Visser O, Coebergh JWW, Schouten LJ, van Dijck JAAM, editors. Incidence of cancer in the Netherlands 1995. Seventh report of the Netherlands cancer registry. 7th ed. Utrecht: Vereniging van Integrale Kankercentra, 1998:24-43. 27. Nugent KP, Northover J. Total colectomy and ileorectal anastomosis. In: Philips RKS, Spigelman AD, Thomson JPS, editors. Familial adenomatous polyposis. London: Edward Arnold, 1994:79-91.

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