Causes of Death during the First 5 Years of a Randomized Trial of Mass Screening for Colorectal Cancer with Fecal Occult Blood Test 0. KRONRORG, C. FENGER, J . W O R M , S. A . PEDERSEN, J . H E M , K. BEKI'ELSEN & J . SEN *nad Dept. of Pathology. and Institute of Social Medicine, Aarhus University. Arhus. 0
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Odense.
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Kronborg 0, Fcnger C, Worm J , Pederhen SA, Hcm J . Bertelsen K. Olsen J . Causes of death during the first S years of a randomized trial of mass screening for colorectal canccr with fecal occult blood test. Scand J Gastroenterol 1992. 27. 47-52 G h e main purpose of population screening for colorectal cancer is to reduce mortality from the disease. The criteria of death from colorectal canccr are defined in the present randomized trial 0161,938 persons between 45 and 74 years old. and the need for an impartial dcath review committee was demonstrated. Causes of death within the first 5 years are described within subgroups of the test group and compared with those in the control group. Death rates wcrc higher among non-responders to screening than among controls and among thosc in whom Hemoccult-I1 had been performed at least once. Persons with negative Hemoccult-I1 had a lowcr death rate than controls. The overall autopsy rate was 32%. Lethal complications from treatment of colorectal neoplasia were evaluated per se. Death from colorectal cancer occurred in 74 pcrsons in the total screening group and In 91 among controls. Sources of bias are discussed. A method of evaluating possible benetit to those being screened is suggested. Final results cannot be expected hefore 1996
J
Kev words: Colonoscopy; colorcctal adcnoma; colorectal cancer; fecal occult blood test; population study; randomized trial; screening Ole Kronhorg, M . D., Dept. of Surgicul Gastroenterology K , Odeiise Uniriersity Hospital, D K-5000 Odense C', Denmark
Four ongoing European trials (1-3) are attempting to evaluate a possible reduction in mortality from colorectal cancer by screening for fecal occult blood. The trials include more than 300,000 asymptomatic persons. Causes of death during the first 5 years of The Danish Population Study are presented in an intermediate evaluation of the screening program. The criteria used for death from colorectal cancer are discussed. The final evaluation will not be made until 1996. SUBJECTS A N D METHODS Initial screening with Hemoccult-I1 (H-11)began in 1985 (5), allocating 30,970 persons at random to screening and 30,968 to il control group in a population of 140,000 between 45 and 74 years old on the island of Funen. The two samples were generated from linkage of two E D P files: The Central Person Register (CPR) and the Patient File of The County of Funen, the latter to exclude from randomization patients with diagnosed colorectal cancer, colorectal adenoma, and distant spread from all types of cancer. The two samples were generated on 1 January 1985, but the screening was not initiated until August 1985. Besides the original test group of 30,970 persons and the control group of 30,968,
two equal samples were drawn at random among the persons (in the population of 140,000) excluded from initial randomization because of the above-mentioned three diagnoses. Adding these samples to the test group and control group will make it possible to compare prevalent figures, representative for the whole population. in the final evaluation. These extended groups are presented in Table VI. The screening procedures with H-I1 have been described in detail previously (4-6). Three screenings were completed from 1985 to 1990 with intervals of 2 years (Table I). Persons who had accepted previous invitations were invited for rescreening biannually. Those with positive H-I1 were invited for full colonoscopy. A double-contrast barium enema was done when colonoscopy was incomplete or when the person refused colonoscopy. New diagnoses of colorectal cancer and adenoma and death certificates are obtained continuously for all persons in the study by means of the E D P system. The death certificates are evaluated blindly with regard to to which group the persons belong. Criteria of death from colorectal cancer are presented in Table 11. Histologic diagnoses may be obtained by biopsy, laparotomy, or autopsy. Clinical diagnoses were based on physical signs, radiologic findings including ultrasound and other scannings, and laboratory
4x
0. Kronborg et al.
'Table I. The three screenings with Hemoccult-I1
(96)
Cancers detected per 1000 screened
20.672
I .o
I .8
18,779
0.8
0.7
17.284
0.9
1.4
No. of persons
Allocated to scrccning Performed 1st screening Perfornicd 2nd screening Performed 3rd scrccning
Positive H-I1
30,970
from colorectal cancer is not significantly less frequent in the test group than in controls ( p = 0.24). All causes of death were more frequent among controls than among persons screened at least once, including death from colorectal cancer. Non-responders had higher death rates from all major diseases ( p < 0.001) except colorectal cancer ( p = 0.16) compared with controls. Causes of death may also be compared between persons being screened at least once and a subgroup of controls constructed by subtracting (Non-responders + Before invitation (10,298)) from controls (30,968). This makes it possible to evaluate a possible reduction in mortality among those being screened. So far, 35 have died of colorectal cancer among the latter, compared with 91 - (34 5) = 52 in the constructed control group. Age at the time of death did not differ between the test and control groups (median, 70 years; range, 49-79 years in both groups). The risk of dying of colorectal cancer increased with age in both groups. The extent to which criteria of death from colorectal cancer were fulfilled in all groups is similar. distant spread being present in most of the patients (Table V). The death review committee stated that death from colorectal cancer could not be excluded in 31 patients (19 in the test group). However. none of the patients fulfilled any of the criteria in Table 11. Complications after surgery for colorectal cancer accounted for eight deaths in the test group and three among controls (Table V). Lethal complications wcre peritonitis and pulmonary embolism. The rates did not differ significantly between the test group (8 of 243) and controls (3 of 217). Deaths within 30 days of surgery are not presented because they were partly due to surgical complications and partly due to universal cancer spread or spread to vital organs. Most of the 19 patients (12 + 7) dying of causes other than complications and colorectal cancer (Table V) had no spread from the cancer (Dukes A in 10, Dukes B in 7, no surgery in 2). Complications from surgical removal of colorectal adenomas were lethal in two patients: pulmonary embolism after sigmoid resection for adenoma detected during the second screening and an anastomotic leakage after low anterior resection for adenoma in an interval case (7). Suicide did not occur among persons with screen-detected colorectal cancer, but one person with a positive H-I1 and no cancer committed suicide 29 months later. This is the only suicide among persons with false-positive H-I1 (451 persons). The total number of deaths among persons with false-positive tests (24 of 451 = 5.3%) did not differ from that in controls (8.9%) and was similar to that in all persons being screened (5.6%) (Table Ill). Suicide caused death in 62 persons in the test group and in 62 persons among controls, none of these 124 persons having known colorectal cancer. Suicide tended to be commoner among non-responders than among screened persons ( p = 0.11).
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+
findings. No more than one of thc criteria in Table I1 needs to be satisfied to claim death from colorectal cancer in patients in whom a colorectal cancer has been demonstrated previously or at the time of death and in whom no other cancer has been found. Dcath from complications after radical surgery for colorectal cancer have been reported separately (Table V). Whenever doubt exists, an impartial death review committee decides whether a person has died of colorectal cancer. All persons who die with clinically or histologically demonstrated distant spread from an unrecognized primary cancer are evaluated by the committee, which includes a pathologist, an oncologist, a general practitioner, a surgeon, and an internist (authors 2 to 6). The statistics included the chi-square test. Statistical significance was set at the 0.05 level. RESULTS Deaths from all causes are presented in Table 111. There were 106 more deaths among the controls. Autopsy rates are similar in the test and control groups. The table gives a detailed description of all the subgroups within the test group. The cumulative mortality among non-responders (1,322/1,322 8,771) is higher than among the controls (2,775/2,775 + 28,191) ( p < 0.001) and higher than in those who had ti-II performed at least once ( p < 0.001). The various causes of death are listed in Table IV. Death
+
Table 11. Criteria of death from colorectal cancer in patients with a previous diagnosis o f colorectal cancer ~~
~~~
~-
1. Histologically or clinically demonstrated distant rnetastascs.
2. Histologically o r clinically demonstrated carcinomatosis. 3. Histologically or clinically demonstratcd invasion of neighboring organs. 4. Unrescctable colorectal cancer as evaluated by thc surgeon. 5 . Colorectal cancer with perforation causing peritonitis.
Mass Screening for Colorectal Cancer
49
Table 111. Deaths from all causes, 1985-90 ~~~
Test group Positive Hemoccult-I1
No. of deaths Autopsy in % Still alive
1st screen
2nd screen
3rd screen
23 34 192
12 25 144
4 0 145
Negative Hemoccult-I1
1st screening only 585 30 1,164
All three Nonscreenings responders
1st and 2nd screening only 449 31 939
92 21 16,923
1,322 31 8,771
Before invitation*
Total
Control group
182 38 21
2,669 31 28,299
2,775 32 28,191
* Persons allocated to screening but dying or having colorectal neoplasia before invitation could be effectuated.
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Table IV. The various causes of death, 1985-90 Test group
Cardiovascular disease Lung disease Other disease and traumas Colorectal cancer Other cancer Total no. of deaths
Screened (20,672)
Non-responders (10,095)
Before invitation (203)
Total
488 144 217 35 281 1,165
518 200 287 34 283 1,322
66 24 57 5 30 182
1,072 368 561 74 594 2,669
Control group (30,968) 1,067 413 569 91 635 2,775
Tablc V. Deaths in patients with colorectal cancer, diagnosed from 1985 to 1990 ~
Test group
Fulfillment of death criterion No. 1 No. 2 No. 3 No. 4 No. 5 Death from colorectal cancer cannot be excluded Death from complications after surgery Death from other causes
*
Positive H-I1
Negative H-11
Nonresponders
Before invitation
6
21 4 3 1 0
4 0
I
27 3 2 (+1)* 0 (+I) 1 12
3
2
2
2
0 0 0 0 0
Total
Control group 65 7
0
58 7 6 2 1 19
3
0
8
3
5
3
12
7
0 0 0
II 4 4 12
($-1) = person with positive H-I1 who refused colorectal examination
Comparison of prevalent figures. adding the two groups that were initially excluded (Table VI), still shows a tendency towards fewer deaths from colorectal cancer in the ‘extended’ test group than in the controls. Cause of death could not be established for 258 persons in the test group and for 257 among controls. Proportions of unknown cause within subgroups of the test group did not differ. Complete agreement between the physician producing the
death certificate and the committee was obtained in 10 patients with colorectal cancer (Table VII). Death from colorectal cancer as stated on the death certificate was changed by the committee to death from other causes in 10 (1 + 9) of 26 patients, whereas death from colorectal cancer could not be completely excluded in 6. Death from colorectal cancer was excluded by the committee in 9 of 33 patients, in whom the death certificate suggested colorectal cancer as a possible cause. Twelve
50
0. Kronborg et al.
Table VI. Death from all causes in the population selected for evaluation of screening, and number of patients with colorectal cancer 1985-90
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Death from colorectal cancer Death from othcr causes Diagnosed colorectal cancer
Extended test group (31,440)
Extended control group (31,430)
109
132
2,691
2,781
406
376
patients with a certificate stating other causes of death than colorectal cancer were evaluated by the committee, who considered colorectal cancer to be the cause of death in one patient and the possible cause of death in four others. Three patients in all were considered to have died with, but not of, colorectal cancer. DISCUSSION Deaths from all causes were more frequent among nonresponders than among those screened and also among controls, confirming the results of the two first screenings in the Gothenburg study (8). A previous analysis of the Danish study showed that 34% of non-responders had severe disease other than colorectal cancer, and 6% thought that they were too old to be screened (6). This high morbidity may explain the higher mortality in non-responders. We d o not know the morbidity rate among persons with negative H-11,but no more than 23% of the 525 persons with positive H-I1 had severe diseases. The lower mortality among screened persons than among controls is probably due to self-selection, the non-responders having more severe diseases than those accepting screening. The design only allowed for exclusion of patients with neoplastic disease with spread. Diagnoses of cardiopulmonary diseases could be obtained from the EDP tiles, but the degree of severity of disease could not be stated, making it impossible to exclude beforehand those considered unsuitable for population screening. Most of the
non-significant difference in number of deaths between the whole test group and controls was due to more deaths from lung disease and cancer other than colorectal in the control group. The most frequent cause of death in all groups was cardiovascular disease (Table IV). Construction of the fictive subgroup of controls, subtracting non-responders and those who were never invited for screening in spite of being allocated to screening, was done to evaluate possible reduction in mortality for persons being screened at least once, and not for the whole test group representing the population between 45 and 74 years. The figures obtained are consistent with a reduced mortality in persons who are screened and may to some extent justify recommendation of screening to those who want to be screened. Many clinical diagnoses appear false at autopsy (9). but colorectal cancer has been underestimated as a cause of death in no more than 5% of the cases in previous autopsy studies (10, 11). The present criteria of death from colorectal cancer may also underestimate the real figures. This bias was reduced by having the committee evaluate all deaths in patients with distant spread without any known primary cancer. Most of these patients had no previous colorectal symptoms, making death from colorectal cancer unlikely, but the colon and rectum had not been examined. Death from complications following treatment of colorectal cancer was not considered a death from colorectal cancer, when the cancer had been removed. Nevertheless these deaths must be added to the deaths from colorectal cancer when possible benefits from screening are evaluated. Most operations for colorectal cancer detected after a positive H-I1 were performed in the university department, but most surgery in both the test and the control group was performed in hospitals of various sizes, with the distribution being representative for the whole country. It was agreed on beforehand that cancers detected by screening should be treated at the university hospital, when local surgery was considered for radical purposes including polypectomy . Fewer lethal complications were expected among persons with screen-detected cancers, because the tumors are smaller and are treated with local surgery more often than those among controls. The present small numbers could not con-
Table VII. Deaths revicwed by the death review committee Death review committee
Death certificate Death from colorectal cancer Death from colorectal cancer cannot be excluded Death from other cause
Death from colorectal cancer
Death from colorectal cancer cannot be excluded
Death with, but not from, colorectal cancer
Death from other cause
Total
10 0
6
24
1 0
9 9
26 33
1
4
2
5
12
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Mass Screening for Colorectal Cancer
firm this assumption (Table V); one of the deaths occurred after colonoscopic polypectomy for an early cancer ( 5 ) . The overall postoperative mortality did not differ from that for other large series. The expected lower age at death from colorectal cancer among controls could not be demonstrated so far, but no more than six patients have died of colorectal cancer among those with a positive H-11. No bias was apparent from fulfillment of different criteria of death from colorectal cancer in the subgroups (Table V). The figures were small except for patients fulfilling the first criterion (distant spread). The older literature has also suggested that distant spread is the commonest cause of death, whereas local recurrence alone, causing intestinal or ureteral obstruction or pelvic sepsis, is an infrequent cause of death (12). However, intestinal perforation and obstruction are frequent causes of death when cancer is diagnosed at autopsy alone (10). Unfortunately, the tendency towards more deaths from surgical complications and from other causes in patients with colorectal cancer favors the control group (Table V), but the figures are rather small. The figures lend no support to the assumption of more suicides among patients with colorectal cancer than among those without the disease, which is in accordance with recently published figures from Sweden (13). The one suicide among persons with false-positive H-I1 could not be related to the test result 29 months before and does not support the hypothesis of an increased risk of suicide in these persons (14). The initial exclusion of persons with known colorectal adenomas may be important when comparing the present results with those of other screening trials in which this has not been done. A higher number of colorectal cancers must be expected in trials in which these persons have been included. A substantial but similar number of deaths from unknown causes occurred in both groups; this possible source of bias is impossible to evaluate, but there is no reason to believe that more deaths from colorectal cancer should be present in one or the other. Another possible bias is the lack of autopsy in more than two-thirds of all the subjects, but again this drawback was not more pronounced in any of the subgroups. The need for a review committee is shown in Table VII; it is obvious that the general practitioner claims colorectal cancer as a cause of death more often than justified, the only reason being a previously treated colorectal cancer. This overestimation was also found in the Minnesota study (15). The present criteria of death from cancer may be too strict, but in principle they are similar t o those used in another large population trial of breast cancer screening (16). SOfar, nothing has been published about causes of death in the English and French study of screening for colorectal cancer. A possible underestimation of numbers of death from
51
colorectal cancer is difficult to evaluate; the total number of deaths is too great to be considered for evaluation by the review committee, and it will more than double (17) before the trial can end. In conclusion, the many sources of bias in deciding cause of death underlines the need for randomized trials to evaluate possible benefits from screening for colorectal cancer. We must estimate number of deaths from colorectal cancer and from complications following treatment of the disease and its possible precursors both in the test group and in the control group. In the present design at least 5 more years are needed before a final analysis can be made, comparing possible gain in years of survival with costs as measured in economic terms and by morbidity following the screening procedures.
ACKNOWLEDGEMENTS Thanks are due to Ole S ~ n d e r g a a r dand Ruth Johansen for technical assistance and to Darley Petersen and Kirsten Grinsted for secretarial assistance. Support was given by The Danish Cancer Society, T h e County of Funen, Sygekassernes Helsefond, Astrid Thaysens Foundation, The Danish Medical Research Council, and others. REFERENCES 1. Kcwenter J, Bjork S, Haglind E, Svanvik J, AhrCn C. Screening and rescreening for colorectal cancer. A controlled trial of fecal occult blood testing in 27,700 subjects. Cancer 19x8, 62, 64.565 1 2. Hardcastle JD, Chamberlain J , Sheffield J, et al. Randomised, controlled trial of faecal occult blood screening for colorectal cancer. Results for first 107,349 subjects. Lancet 1988, 1, 116& 1164 3. Faivre J . Preliminary results of a mass screening programme for colorcctal cancer in France. In: Hardcastle JD, editor. Screening for colorectal cancer. Nordrned Verlag, Englewood, N.J., 1989, 94101 4. Kronborg 0, Fenger C, Olsen J , Bech K, Sondergaard 0. Repeated screening for colorectal cancer with fecal occult blood test. A prospective randomized study at Funen, Denmark. Scand J Gastroenterol 1989, 24, 599-606 5. Kronborg 0, Fenger C, Sondegaard 0, Pcdersen KM, Olsen J . Initial mass screening for colorectal Cancer with fecal occult blood test. Scand J Gastroenterol 1987, 22, 677-686 6. Klaaborg K, Madsen MS, Sondergaard 0, Kronborg 0. Participation in mass screening for colorectal cancer with fecal occult blood test. Scand J Gastroenterol 1986, 21. 118CL1184 7. Bech K , Kronborg 0, Fenger C. Adenomas and hyperplastic polyps in screening studies. World J Surg 1991, 15, 7-13 8. Lindholm E, Berglund B, Gustavsson K, Haglind E, Kewenter J. Death causes among subjects in a randomised trial for early detection of colorectal cancer. World Congresses of Gastroenterology. The Medicine Group (UK) Ltd, Publishing House, Abingdon, 1990, abstract PP 2029 9. Britton M. Diagnostic errors discovercd at autopsy. Acta Med Scand 1974, 196, 203-210 10. Vellacott KD, Ferro MA. Cause of death and accuracy of certification of colorectal cancer. J Roy Soc Med 1984, 77, 2225 11. Armstrong CP, Whitelaw SJ. Death from unsuspected colorcctal cancer. Ann R Coll Surg Engl 1989, 71, 2CL22 12. Welch JP, Donaldson GA. The clinical correlation of an autopsy
52
0. Krnnborg ef 01
study of recurrent colorectal cancer. Ann Surg 1979, 189, 4 9 6 502 13. Eriksson A , Gezelius C. Malignant diseases at forensic investigations of the cause of death. Nord Med 1990, 105, 264265 14. Erichsen GGA. Mammographical screening for cancer mammae-a cost-benefit analysis. Nord Med 1990, 105, 64-66 15. Mandel JS, Bond J , Snover D, et al. The University of Minnesota’s Colon Cancer Control Study: design and progress to
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Received 29 April 1991 Accepted 9 August 1991
date. In: Chamberlain J, Miller AB, editors. Screening for gastrointestinal cancer. Hans Huber Publishers, Toronto, 1988, 17-24 16. Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two county trials of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health 1989, 43, 107-114 17. Winawer S , Schottenfeld D, Sherlock P. Screening for colorectal cancer: the issues. Gastroenterology 1985, 88, 841-844
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b m -
Odense.
Scand J Gastroenterol Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
Kronborg 0, Fcnger C, Worm J , Pederhen SA, Hcm J . Bertelsen K. Olsen J . Causes of death during the first S years of a randomized trial of mass screening for colorectal canccr with fecal occult blood test. Scand J Gastroenterol 1992. 27. 47-52 G h e main purpose of population screening for colorectal cancer is to reduce mortality from the disease. The criteria of death from colorectal canccr are defined in the present randomized trial 0161,938 persons between 45 and 74 years old. and the need for an impartial dcath review committee was demonstrated. Causes of death within the first 5 years are described within subgroups of the test group and compared with those in the control group. Death rates wcrc higher among non-responders to screening than among controls and among thosc in whom Hemoccult-I1 had been performed at least once. Persons with negative Hemoccult-I1 had a lowcr death rate than controls. The overall autopsy rate was 32%. Lethal complications from treatment of colorectal neoplasia were evaluated per se. Death from colorectal cancer occurred in 74 pcrsons in the total screening group and In 91 among controls. Sources of bias are discussed. A method of evaluating possible benetit to those being screened is suggested. Final results cannot be expected hefore 1996
J
Kev words: Colonoscopy; colorcctal adcnoma; colorectal cancer; fecal occult blood test; population study; randomized trial; screening Ole Kronhorg, M . D., Dept. of Surgicul Gastroenterology K , Odeiise Uniriersity Hospital, D K-5000 Odense C', Denmark
Four ongoing European trials (1-3) are attempting to evaluate a possible reduction in mortality from colorectal cancer by screening for fecal occult blood. The trials include more than 300,000 asymptomatic persons. Causes of death during the first 5 years of The Danish Population Study are presented in an intermediate evaluation of the screening program. The criteria used for death from colorectal cancer are discussed. The final evaluation will not be made until 1996. SUBJECTS A N D METHODS Initial screening with Hemoccult-I1 (H-11)began in 1985 (5), allocating 30,970 persons at random to screening and 30,968 to il control group in a population of 140,000 between 45 and 74 years old on the island of Funen. The two samples were generated from linkage of two E D P files: The Central Person Register (CPR) and the Patient File of The County of Funen, the latter to exclude from randomization patients with diagnosed colorectal cancer, colorectal adenoma, and distant spread from all types of cancer. The two samples were generated on 1 January 1985, but the screening was not initiated until August 1985. Besides the original test group of 30,970 persons and the control group of 30,968,
two equal samples were drawn at random among the persons (in the population of 140,000) excluded from initial randomization because of the above-mentioned three diagnoses. Adding these samples to the test group and control group will make it possible to compare prevalent figures, representative for the whole population. in the final evaluation. These extended groups are presented in Table VI. The screening procedures with H-I1 have been described in detail previously (4-6). Three screenings were completed from 1985 to 1990 with intervals of 2 years (Table I). Persons who had accepted previous invitations were invited for rescreening biannually. Those with positive H-I1 were invited for full colonoscopy. A double-contrast barium enema was done when colonoscopy was incomplete or when the person refused colonoscopy. New diagnoses of colorectal cancer and adenoma and death certificates are obtained continuously for all persons in the study by means of the E D P system. The death certificates are evaluated blindly with regard to to which group the persons belong. Criteria of death from colorectal cancer are presented in Table 11. Histologic diagnoses may be obtained by biopsy, laparotomy, or autopsy. Clinical diagnoses were based on physical signs, radiologic findings including ultrasound and other scannings, and laboratory
4x
0. Kronborg et al.
'Table I. The three screenings with Hemoccult-I1
(96)
Cancers detected per 1000 screened
20.672
I .o
I .8
18,779
0.8
0.7
17.284
0.9
1.4
No. of persons
Allocated to scrccning Performed 1st screening Perfornicd 2nd screening Performed 3rd scrccning
Positive H-I1
30,970
from colorectal cancer is not significantly less frequent in the test group than in controls ( p = 0.24). All causes of death were more frequent among controls than among persons screened at least once, including death from colorectal cancer. Non-responders had higher death rates from all major diseases ( p < 0.001) except colorectal cancer ( p = 0.16) compared with controls. Causes of death may also be compared between persons being screened at least once and a subgroup of controls constructed by subtracting (Non-responders + Before invitation (10,298)) from controls (30,968). This makes it possible to evaluate a possible reduction in mortality among those being screened. So far, 35 have died of colorectal cancer among the latter, compared with 91 - (34 5) = 52 in the constructed control group. Age at the time of death did not differ between the test and control groups (median, 70 years; range, 49-79 years in both groups). The risk of dying of colorectal cancer increased with age in both groups. The extent to which criteria of death from colorectal cancer were fulfilled in all groups is similar. distant spread being present in most of the patients (Table V). The death review committee stated that death from colorectal cancer could not be excluded in 31 patients (19 in the test group). However. none of the patients fulfilled any of the criteria in Table 11. Complications after surgery for colorectal cancer accounted for eight deaths in the test group and three among controls (Table V). Lethal complications wcre peritonitis and pulmonary embolism. The rates did not differ significantly between the test group (8 of 243) and controls (3 of 217). Deaths within 30 days of surgery are not presented because they were partly due to surgical complications and partly due to universal cancer spread or spread to vital organs. Most of the 19 patients (12 + 7) dying of causes other than complications and colorectal cancer (Table V) had no spread from the cancer (Dukes A in 10, Dukes B in 7, no surgery in 2). Complications from surgical removal of colorectal adenomas were lethal in two patients: pulmonary embolism after sigmoid resection for adenoma detected during the second screening and an anastomotic leakage after low anterior resection for adenoma in an interval case (7). Suicide did not occur among persons with screen-detected colorectal cancer, but one person with a positive H-I1 and no cancer committed suicide 29 months later. This is the only suicide among persons with false-positive H-I1 (451 persons). The total number of deaths among persons with false-positive tests (24 of 451 = 5.3%) did not differ from that in controls (8.9%) and was similar to that in all persons being screened (5.6%) (Table Ill). Suicide caused death in 62 persons in the test group and in 62 persons among controls, none of these 124 persons having known colorectal cancer. Suicide tended to be commoner among non-responders than among screened persons ( p = 0.11).
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findings. No more than one of thc criteria in Table I1 needs to be satisfied to claim death from colorectal cancer in patients in whom a colorectal cancer has been demonstrated previously or at the time of death and in whom no other cancer has been found. Dcath from complications after radical surgery for colorectal cancer have been reported separately (Table V). Whenever doubt exists, an impartial death review committee decides whether a person has died of colorectal cancer. All persons who die with clinically or histologically demonstrated distant spread from an unrecognized primary cancer are evaluated by the committee, which includes a pathologist, an oncologist, a general practitioner, a surgeon, and an internist (authors 2 to 6). The statistics included the chi-square test. Statistical significance was set at the 0.05 level. RESULTS Deaths from all causes are presented in Table 111. There were 106 more deaths among the controls. Autopsy rates are similar in the test and control groups. The table gives a detailed description of all the subgroups within the test group. The cumulative mortality among non-responders (1,322/1,322 8,771) is higher than among the controls (2,775/2,775 + 28,191) ( p < 0.001) and higher than in those who had ti-II performed at least once ( p < 0.001). The various causes of death are listed in Table IV. Death
+
Table 11. Criteria of death from colorectal cancer in patients with a previous diagnosis o f colorectal cancer ~~
~~~
~-
1. Histologically or clinically demonstrated distant rnetastascs.
2. Histologically o r clinically demonstrated carcinomatosis. 3. Histologically or clinically demonstratcd invasion of neighboring organs. 4. Unrescctable colorectal cancer as evaluated by thc surgeon. 5 . Colorectal cancer with perforation causing peritonitis.
Mass Screening for Colorectal Cancer
49
Table 111. Deaths from all causes, 1985-90 ~~~
Test group Positive Hemoccult-I1
No. of deaths Autopsy in % Still alive
1st screen
2nd screen
3rd screen
23 34 192
12 25 144
4 0 145
Negative Hemoccult-I1
1st screening only 585 30 1,164
All three Nonscreenings responders
1st and 2nd screening only 449 31 939
92 21 16,923
1,322 31 8,771
Before invitation*
Total
Control group
182 38 21
2,669 31 28,299
2,775 32 28,191
* Persons allocated to screening but dying or having colorectal neoplasia before invitation could be effectuated.
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Table IV. The various causes of death, 1985-90 Test group
Cardiovascular disease Lung disease Other disease and traumas Colorectal cancer Other cancer Total no. of deaths
Screened (20,672)
Non-responders (10,095)
Before invitation (203)
Total
488 144 217 35 281 1,165
518 200 287 34 283 1,322
66 24 57 5 30 182
1,072 368 561 74 594 2,669
Control group (30,968) 1,067 413 569 91 635 2,775
Tablc V. Deaths in patients with colorectal cancer, diagnosed from 1985 to 1990 ~
Test group
Fulfillment of death criterion No. 1 No. 2 No. 3 No. 4 No. 5 Death from colorectal cancer cannot be excluded Death from complications after surgery Death from other causes
*
Positive H-I1
Negative H-11
Nonresponders
Before invitation
6
21 4 3 1 0
4 0
I
27 3 2 (+1)* 0 (+I) 1 12
3
2
2
2
0 0 0 0 0
Total
Control group 65 7
0
58 7 6 2 1 19
3
0
8
3
5
3
12
7
0 0 0
II 4 4 12
($-1) = person with positive H-I1 who refused colorectal examination
Comparison of prevalent figures. adding the two groups that were initially excluded (Table VI), still shows a tendency towards fewer deaths from colorectal cancer in the ‘extended’ test group than in the controls. Cause of death could not be established for 258 persons in the test group and for 257 among controls. Proportions of unknown cause within subgroups of the test group did not differ. Complete agreement between the physician producing the
death certificate and the committee was obtained in 10 patients with colorectal cancer (Table VII). Death from colorectal cancer as stated on the death certificate was changed by the committee to death from other causes in 10 (1 + 9) of 26 patients, whereas death from colorectal cancer could not be completely excluded in 6. Death from colorectal cancer was excluded by the committee in 9 of 33 patients, in whom the death certificate suggested colorectal cancer as a possible cause. Twelve
50
0. Kronborg et al.
Table VI. Death from all causes in the population selected for evaluation of screening, and number of patients with colorectal cancer 1985-90
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Death from colorectal cancer Death from othcr causes Diagnosed colorectal cancer
Extended test group (31,440)
Extended control group (31,430)
109
132
2,691
2,781
406
376
patients with a certificate stating other causes of death than colorectal cancer were evaluated by the committee, who considered colorectal cancer to be the cause of death in one patient and the possible cause of death in four others. Three patients in all were considered to have died with, but not of, colorectal cancer. DISCUSSION Deaths from all causes were more frequent among nonresponders than among those screened and also among controls, confirming the results of the two first screenings in the Gothenburg study (8). A previous analysis of the Danish study showed that 34% of non-responders had severe disease other than colorectal cancer, and 6% thought that they were too old to be screened (6). This high morbidity may explain the higher mortality in non-responders. We d o not know the morbidity rate among persons with negative H-11,but no more than 23% of the 525 persons with positive H-I1 had severe diseases. The lower mortality among screened persons than among controls is probably due to self-selection, the non-responders having more severe diseases than those accepting screening. The design only allowed for exclusion of patients with neoplastic disease with spread. Diagnoses of cardiopulmonary diseases could be obtained from the EDP tiles, but the degree of severity of disease could not be stated, making it impossible to exclude beforehand those considered unsuitable for population screening. Most of the
non-significant difference in number of deaths between the whole test group and controls was due to more deaths from lung disease and cancer other than colorectal in the control group. The most frequent cause of death in all groups was cardiovascular disease (Table IV). Construction of the fictive subgroup of controls, subtracting non-responders and those who were never invited for screening in spite of being allocated to screening, was done to evaluate possible reduction in mortality for persons being screened at least once, and not for the whole test group representing the population between 45 and 74 years. The figures obtained are consistent with a reduced mortality in persons who are screened and may to some extent justify recommendation of screening to those who want to be screened. Many clinical diagnoses appear false at autopsy (9). but colorectal cancer has been underestimated as a cause of death in no more than 5% of the cases in previous autopsy studies (10, 11). The present criteria of death from colorectal cancer may also underestimate the real figures. This bias was reduced by having the committee evaluate all deaths in patients with distant spread without any known primary cancer. Most of these patients had no previous colorectal symptoms, making death from colorectal cancer unlikely, but the colon and rectum had not been examined. Death from complications following treatment of colorectal cancer was not considered a death from colorectal cancer, when the cancer had been removed. Nevertheless these deaths must be added to the deaths from colorectal cancer when possible benefits from screening are evaluated. Most operations for colorectal cancer detected after a positive H-I1 were performed in the university department, but most surgery in both the test and the control group was performed in hospitals of various sizes, with the distribution being representative for the whole country. It was agreed on beforehand that cancers detected by screening should be treated at the university hospital, when local surgery was considered for radical purposes including polypectomy . Fewer lethal complications were expected among persons with screen-detected cancers, because the tumors are smaller and are treated with local surgery more often than those among controls. The present small numbers could not con-
Table VII. Deaths revicwed by the death review committee Death review committee
Death certificate Death from colorectal cancer Death from colorectal cancer cannot be excluded Death from other cause
Death from colorectal cancer
Death from colorectal cancer cannot be excluded
Death with, but not from, colorectal cancer
Death from other cause
Total
10 0
6
24
1 0
9 9
26 33
1
4
2
5
12
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Mass Screening for Colorectal Cancer
firm this assumption (Table V); one of the deaths occurred after colonoscopic polypectomy for an early cancer ( 5 ) . The overall postoperative mortality did not differ from that for other large series. The expected lower age at death from colorectal cancer among controls could not be demonstrated so far, but no more than six patients have died of colorectal cancer among those with a positive H-11. No bias was apparent from fulfillment of different criteria of death from colorectal cancer in the subgroups (Table V). The figures were small except for patients fulfilling the first criterion (distant spread). The older literature has also suggested that distant spread is the commonest cause of death, whereas local recurrence alone, causing intestinal or ureteral obstruction or pelvic sepsis, is an infrequent cause of death (12). However, intestinal perforation and obstruction are frequent causes of death when cancer is diagnosed at autopsy alone (10). Unfortunately, the tendency towards more deaths from surgical complications and from other causes in patients with colorectal cancer favors the control group (Table V), but the figures are rather small. The figures lend no support to the assumption of more suicides among patients with colorectal cancer than among those without the disease, which is in accordance with recently published figures from Sweden (13). The one suicide among persons with false-positive H-I1 could not be related to the test result 29 months before and does not support the hypothesis of an increased risk of suicide in these persons (14). The initial exclusion of persons with known colorectal adenomas may be important when comparing the present results with those of other screening trials in which this has not been done. A higher number of colorectal cancers must be expected in trials in which these persons have been included. A substantial but similar number of deaths from unknown causes occurred in both groups; this possible source of bias is impossible to evaluate, but there is no reason to believe that more deaths from colorectal cancer should be present in one or the other. Another possible bias is the lack of autopsy in more than two-thirds of all the subjects, but again this drawback was not more pronounced in any of the subgroups. The need for a review committee is shown in Table VII; it is obvious that the general practitioner claims colorectal cancer as a cause of death more often than justified, the only reason being a previously treated colorectal cancer. This overestimation was also found in the Minnesota study (15). The present criteria of death from cancer may be too strict, but in principle they are similar t o those used in another large population trial of breast cancer screening (16). SOfar, nothing has been published about causes of death in the English and French study of screening for colorectal cancer. A possible underestimation of numbers of death from
51
colorectal cancer is difficult to evaluate; the total number of deaths is too great to be considered for evaluation by the review committee, and it will more than double (17) before the trial can end. In conclusion, the many sources of bias in deciding cause of death underlines the need for randomized trials to evaluate possible benefits from screening for colorectal cancer. We must estimate number of deaths from colorectal cancer and from complications following treatment of the disease and its possible precursors both in the test group and in the control group. In the present design at least 5 more years are needed before a final analysis can be made, comparing possible gain in years of survival with costs as measured in economic terms and by morbidity following the screening procedures.
ACKNOWLEDGEMENTS Thanks are due to Ole S ~ n d e r g a a r dand Ruth Johansen for technical assistance and to Darley Petersen and Kirsten Grinsted for secretarial assistance. Support was given by The Danish Cancer Society, T h e County of Funen, Sygekassernes Helsefond, Astrid Thaysens Foundation, The Danish Medical Research Council, and others. REFERENCES 1. Kcwenter J, Bjork S, Haglind E, Svanvik J, AhrCn C. Screening and rescreening for colorectal cancer. A controlled trial of fecal occult blood testing in 27,700 subjects. Cancer 19x8, 62, 64.565 1 2. Hardcastle JD, Chamberlain J , Sheffield J, et al. Randomised, controlled trial of faecal occult blood screening for colorectal cancer. Results for first 107,349 subjects. Lancet 1988, 1, 116& 1164 3. Faivre J . Preliminary results of a mass screening programme for colorcctal cancer in France. In: Hardcastle JD, editor. Screening for colorectal cancer. Nordrned Verlag, Englewood, N.J., 1989, 94101 4. Kronborg 0, Fenger C, Olsen J , Bech K, Sondergaard 0. Repeated screening for colorectal cancer with fecal occult blood test. A prospective randomized study at Funen, Denmark. Scand J Gastroenterol 1989, 24, 599-606 5. Kronborg 0, Fenger C, Sondegaard 0, Pcdersen KM, Olsen J . Initial mass screening for colorectal Cancer with fecal occult blood test. Scand J Gastroenterol 1987, 22, 677-686 6. Klaaborg K, Madsen MS, Sondergaard 0, Kronborg 0. Participation in mass screening for colorectal cancer with fecal occult blood test. Scand J Gastroenterol 1986, 21. 118CL1184 7. Bech K , Kronborg 0, Fenger C. Adenomas and hyperplastic polyps in screening studies. World J Surg 1991, 15, 7-13 8. Lindholm E, Berglund B, Gustavsson K, Haglind E, Kewenter J. Death causes among subjects in a randomised trial for early detection of colorectal cancer. World Congresses of Gastroenterology. The Medicine Group (UK) Ltd, Publishing House, Abingdon, 1990, abstract PP 2029 9. Britton M. Diagnostic errors discovercd at autopsy. Acta Med Scand 1974, 196, 203-210 10. Vellacott KD, Ferro MA. Cause of death and accuracy of certification of colorectal cancer. J Roy Soc Med 1984, 77, 2225 11. Armstrong CP, Whitelaw SJ. Death from unsuspected colorcctal cancer. Ann R Coll Surg Engl 1989, 71, 2CL22 12. Welch JP, Donaldson GA. The clinical correlation of an autopsy
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0. Krnnborg ef 01
study of recurrent colorectal cancer. Ann Surg 1979, 189, 4 9 6 502 13. Eriksson A , Gezelius C. Malignant diseases at forensic investigations of the cause of death. Nord Med 1990, 105, 264265 14. Erichsen GGA. Mammographical screening for cancer mammae-a cost-benefit analysis. Nord Med 1990, 105, 64-66 15. Mandel JS, Bond J , Snover D, et al. The University of Minnesota’s Colon Cancer Control Study: design and progress to
Scand J Gastroenterol Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
Received 29 April 1991 Accepted 9 August 1991
date. In: Chamberlain J, Miller AB, editors. Screening for gastrointestinal cancer. Hans Huber Publishers, Toronto, 1988, 17-24 16. Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two county trials of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health 1989, 43, 107-114 17. Winawer S , Schottenfeld D, Sherlock P. Screening for colorectal cancer: the issues. Gastroenterology 1985, 88, 841-844
