Impact of endoscopy on mortality from occult cancer in radiographically benign gastric ulcers

GASTROENTEROLOGY 1987;93:83545

Impact of Endoscopy on Mortality From Occult Cancer in Radiographically Benign Gastric Ulcers A Probability

Analysis

Model

RICHARD A. ERICKSON Deuartment of Medicine, Veterans Administration University of California, Irvine, California

Endoscopy is commonly used in the management of patients with radiographically benign gastric ulcers to detect occult malignancy. Clinical studies examining the cost-effectiveness of using endoscopy in such patients, however, have not been done. To address this issue using probability analysis, a probability tree was designed incorporating the possible clinical courses of patients with radiographically benign gastric ulcers managed with and without endoscopy, and probability estimates for each course were derived by compiling data from the literature. Probability and sensitivity analysis was used to compare the impact on overall mortality rate and cost-effectiveness of six commonly practiced methods of using endoscopy to manage patients with radiographically benign gastric ulcers: (1)all follow-up by upper gastrointestinal x-ray only; [2) endoscopy for nonhealing ulcers only; (3) endoscopy for all ulcers before medical therapy with all follow-up by upper gastrointestinal x-ray; [4) endoscopy for all ulcers after an initial trial of medical therapy; [5) endoscopy for all ulcers before therapy and for nonhealers; (6)endoscopy before therapy, and all follow-up by endoscopy. This analysis predicts that the greatest decrease in mortality rate occurs when endoscopy is used before medical therapy and for all follow-up, reducing the estimated number of deaths per 1000 patients with radiographicaJJy benign gastric ulcers from 36.7 with follow-up by upper gastrointestinal x-ray only to 27.2. Wowever, initial endoscopy with all subsequent follow-

Received October 28, 1986. Accepted April 22, 1987. Address requests for reprints to: Richard A. Erickson, M. D., Gastroenterology Section, Medical Service (lllG), Veterans Administration Medical Center, 5901 East Seventh Street, Long Beach, California 90822. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50

Medical Center, Long Beach, California and

up by upper gastrointestinal x-ray increased the overall death rate by only a small amount, to 28.0, and was consistently the most cost-effective method, and -60,000 diagnostic requiring 116 endoscopies dollars per additional 5-yr survivor.

Up to 7% of gastric ulcers that appear benign by upper gastrointestinal (UGI) x-ray are actually malignant (l-17). Because of the fear of missing an occult malignancy in a radiographically benign gastric ulcer (RBGU), many authors recommend that endoscopic examination with a biopsy of the ulcer be used at some point in the management of such patients (18-29). However, there are no clinical studies examining the degree to which, if any, the use of endoscopy actually affects the mortality rate from occult gastric cancer in patients with RBGUs. As there are -70,000 patients diagnosed per year with gastric ulcers in the United States (301, the impact and cost-effectiveness of using endoscopy in the management of these patients is of considerable therapeutic and economic importance. In 1977, the members of the gastric ulcer subcommittee of the American Society of Gastrointestinal Endoscopy concluded that a clinical trial specifically evaluating the impact of endoscopy in the management of RBGUs was not feasible because it would have to enroll thousands of patients to answer even a single question on this issue (31). Because a clinical study examining the cost-effectiveness of using endoscopy to reduce mortality rate from occult gastric cancer in patients with RBGUs is not likely to be done, it was the purpose of this study to use probability analysis (32-37) to address this problem. Abbreviations used in this paper: RBGU, radiographically nign gastric ulcer; UGI, upper gastrointestinal.

be-

836

ERICKSON

GASTROENTEROLOGY Vol. 93, No. 4

PROBABILITY TREE SHOWING POSSIBLE OUTCOMES FOR RADIOGRAPHICALLY BENIGN GASTRIC ULCERS

ALL RADIOGRAPHICALLY BENIQN QASTRIC ULCERS

28 CA NDT DETECTED --ITRI~

-CA DETECTEd AFTER ,NlTlAL TRIAL DF MEDICAL RX

Figure

I. Probability tree used to analyze the impact of using endoscopy gastric ulcers.

Materials and Methods Design of the Probability

Tree

Almost all authorities on the management of gastric ulcers recommend that a radiographically benign gastric ulcer should be observed to complete healing to both rule out the possibility of an occult malignancy and to prevent a rapid recurrence (18-29,38-44).The initial follow-up diagnostic study is usually recommended after about 6 wk of medical therapy to assess the healing status of the ulcer. If the ulcer is completely healed at this point, therapy is usually stopped and the patient is observed clinically for symptoms or signs of a recurrence. If the ulcer is inadequately healed (~50% reduction in size), unchanged in size, or larger after the initial course of medical therapy and the patient has no other reasons for being clinically refractory (e.g., noncompliance, taking nonsteroidal antiinflammatory drugs, gastric outlet obstruction, penetration, Zollinger-Ellison syndrome), then an operation is usually indicated to definitively treat the medically refractory ulcer. If the ulcer has undergone satisfactory partial healing of ?50%, medical therapy is usually continued for another 46 wk and ulcer healing is again reassessed. If the ulcer is not completely healed by this point (i.e., after about 3 mo of effective medical therapy or a little longer for larger ulcers), an operation is again usually recommended to definitively treat the medically refractory ulcer. This general management scheme was translated into a probability tree that incorporates the major clinical

in the management

of patients with radiographically

benign

courses of patients with RBGUs, including those patients with RBGUs that are associated with an occult malignancy (Figure 1). The impact of adding endoscopic assessment of RBGUs was determined by adding appropriate branches at two points: [a) before initiation of medical therapy (branches 2A and 2B) and (b) after an initial course of medical therapy (branches 6A and 6B). To greatly simplify the tree and subsequent calculations, two assumptions were made, neither of which significantly changed the results or conclusions of this analysis. First, it was assumed that there are no false-positive histologic diagnoses of malignancy in patients with truly benign gastric ulcers. Although this must certainly occur, it is probably a very rare occurrence inasmuch as of the thousands of patients included in endoscopic series of gastric ulcers reviewed for this analysis, there were clearly documented only 4 patients from two studies where a false-positive diagnosis of malignancy was made in what was believed to be truly benign gastric ulcers (45,46). Second, it was assumed that there would be no mortality from endoscopy itself. This assumption is based on the fact that the mortality rate of elective endoscopy is very small, probably cl-2 per 20,000 (47-49), especially when compared with the estimated overall mortality rate from malignant IU3GUs in this analysis (500-700 per 26,000). The design of the probability tree in Figure 1 allowed for examining the cost-effectiveness of six basic management schemes for utilizing endoscopy in patients with RBGUs that have been recommended by various authorities: (1)

IMPACT OF ENDOSCOPY

October 1987

Table

ON GASTRIC ULCERS

1. Literature-Based Probability Estimates Used in Calculating the Impact of Various Endoscopic Schemes on the Mortality Rate of Patients With Radiographically Benign Gastric Ulcersa Endoscopic BraFch of probability

1B 2A 3A 4A 4c 5A 5c 8A 7B,13B 8A,9A 10A 11A 12A 14A,15A

tree in Figure

lb

-

Fraction of RBGU malignant Fraction of malignant RBGU detected by endoscopy and biopsy before initial therapy Five-year survival for malignant RBGU treated immediately Six-week complete healing rate of benign RBGU Six-week unsatisfactory healing rate of benign RBGU Six-week complete healing rate of malignant RBGU Six-week unsatisfactory healing rate of malignant RBGU Fraction of partially healed malignant RBGU detected by endoscopy and biopsy after 6 wk of therapy Operative mortality rate for elective gastric ulcer operation Five-year survival for malignant RBGU treated after 6 wk of therapy Fraction of benign RBGU, partially healed at 6 wk, healing after 12 wk of therapy Fraction of malignant RBGU, partially healed at 6 wk, healing after 12 wk of therapy Five-year survival for malignant RBGU treated after 12 wk of therapy Five-year survival for malignant RBGU treated after >12 wk of therapy

management

837

Management

scheme

1

2

3

4

5

6

0.05 0

0.05 0

0.05 0.67

0.05 0

0.05 0.67

0.05 0.67

0.54

0.54

0.54

0.54

0.54

0.54

0.72 0.03 0.15 0.50

0.72 0.03

0.72 0.03

0.72 0.03

0.72 0.03

0.15 0.50

0.15 0.50

0.10

0.50

0.15 0.50

0.72 0.03 0.10 0.50

0

0.67

0

0.67

0.67

0.67

0.01

0.01

0.01

0.01

0.01

0.01

0.38

0.38

0.38

0.38

0.38

0.38

0.80

0.80

0.80

0.80

0.80

0.80

0.15

0.10

0.15

0.10

0.10

0.10

0.24

0.24

0.24

0.24

0.24

0.24

0.10

0.10

0.10

0.10

0.10

0.10

RBGU, radiographically benign gastric ulcer. ‘See text for description of endoscopic management schemes and details of the derivation of these estimates. bOnly the A or B value of each branch number is shown, the probability value for the remaining branch is simply 1 minus the value in the above table.

radiographic follow-up alone (18,20,39-42,50), (2) endoscopy for nonhealing ulcers only (381, (3) endoscopy for all ulcers before initial medical trial (24,25,29), (4) initial endoscopy of all ulcers and endoscopic follow-up of nonhealing ulcers, (5) endoscopy of all ulcers after initial trial of medical therapy (24,25,29), and (6) endoscopy for all ulcers initially and all follow-up by endoscopy (19,2123,28). Probability

Estimates

From

the Medical

Literature Once the above probability tree was designed, estimates for the specific probability values for each branch of the tree in each of the above six management schemes were derived by compiling data from a comprehensive review of English-language articles containing information on the course of patients with RBGUs in the West, preferably the United States (summarized in Table 1). Where minimal data existed as to the probability of a specific branch, a “best-estimate” was made based on the information available. The impact of the uncertainty of such estimates was then evaluated by sensitivity analysis. Additional details for the derivation of these probability estimates are as follows. Branch 1: percentage of radiographically benign gastric ulcers eventually found to be malignant. Of 6934 patients with RBGUs from 17 series (l-17), a weighted

average of 5.1% were malignant. Thus, for this analysis it was assumed that an average of 5% of RBGUs are malignant. Branches 2 and 6:’ accuracy of endoscopy plus biopsy in detecting malignant radiographically benign gastric ulcers. Endoscopy with biopsy is often quoted as being 96%-99% accurate at determining the benignity or malignancy of UGI lesions (51-54). A literature review of the 120 malignant RBGUs, endoscopically examined, however, reveals that an underlying malignancy was diagnosed on the initial endoscopy in only two-thirds of cases (16,45,52,55-62). Therefore, the sensitivity of single endoscopy with biopsy for detecting a malignant RBGU was estimated to be 67% for this analysis. Branches 3, 8, 9, 12, 14, and 15: five-year survival rates for patients with malignant radiographically benign gastric ulcers. The 5-yr survival of patients with gastric cancer is very poor, about 10% overall and 24% for the -43% that are resectable (63-69). Of the 144 patients with malignant RBGUs for which survival data are reported (5,12,15,70-72), however, the 5-yr survival is 54% when they are recognized immediately and operatively managed without the delay of a trial of medical therapy. This remarkably good survival is also supported by a study by Desmond et al. (73) who found a 56% 5-yr survival in their review of patients with gastric cancer operated on for what was thought to be a benign gastric ulcer. Whether a patient’s prognosis from gastric cancer in a

838 ERICKSON

GASTROENTEROLOGYVol.93,No.4

malignant RBGU is significantly worsened if diagnosis and 93). There are essentially no data on the rate of complete definitive treatment is delayed for a few weeks by a trial of endoscopic healing of malignant RBGUs. Clearly this ocmedical therapy is unclear from the scant literature availcurs, as evidenced by many reports in the literature of able on this subject. A 2-4-wk delay in diagnosis is said to complete endoscopic healing of gastric ulcers that ultimately proved to be malignant (58, 94-99). It seems make little difference in prognosis (2,74). It seems logical reasonable to assume that, because of the ability of endosto assume, however, that some patients might progress to a less curable stage of cancer during more prolonged periods copy to detect subtle mucosal abnormalities, some of the of medical therapy. The only literature addressing this 15% of malignant RBGUs that appear completely healed specifically for malignant RBGUs is the series by Brown et radiographically would still not be healed endoscopically. al. (5), where the 5-yr survival of those patients operated Therefore, the probability of malignant RBGUs completely healing endoscopically was assumed to be 10% (branch on immediately was 75% (12 of 16),whereas that of 5A). patients operated on after a <3-mo delay by medical The partial healing of malignant RBGUs is probably a therapy was 56% (19 of 34) and the survival of those delayed for >3 mo was 42% (30 of 72).Additionally, relatively common event (12,13,15,99). Sakita et al. (99). in a describing the life cycle of the malignant gastric ulcer in number of series report that in those patients where diagnosis of malignancy is very delayed (i.e., >6 mo) the Japan, reported that 71% of these ulcers showed partial endoscopic healing. In fact, after an initial 2-6-wk course prognosis is more like the 10% 5-yr survival of gastric Based on this limited data, for of medical therapy with only weak antacids and cancer in general (2,12,75). probanthine, 10% of these malignant ulcers showed >50% this analysis it was estimated that if the diagnosis and decrease in size and almost 50% showed at least a 25% operative treatment of a patient’s malignant RBGU was reduction in endoscopic size. This rate of healing was missed because the ulcer healed completely only to rereported to be similar to that of benign gastric ulcers. It present many months later, his or her chance of surviving seems reasonable to assume therefore that satisfactory 5 yrs would be that of the gastric cancer patient in general, partial healing (>50% reduction in size after 6 wk) might i.e., 10% (branches 14A and 15A).As discussed above, the be even more frequent on the more potent medical therasurvival of patients with malignant RBGUs treated immepies available today. For this analysis it was assumed that diately was assumed to be 54% (branch 3A). As found in the study by Brown et al. (5), if the malignancy was after an initial trial of medical therapy, one-half of maligdiagnosed and operatively treated after a 3-mo delay by nant RBGUs will heal partially or completely by endosmedical therapy, then the prognosis was assumed to be copy or UGI x-ray. The satisfactory partial healing rate for radiographic follow-up was assumed to be this 50% minus about 30% less than the survival of immediate diagnosis the complete radiographic healing rate of 15%, i.e., 350, and operation, i.e., 54% - 30% = 24%, (branch 12A), which is the same as the survival of patients with resect(branch 5B). The corresponding rate for satisfactory partial able gastric cancers. The impact of delaying diagnosis and healing by endoscopic follow-up was 50% minus the complete endoscopic healing rate of lOoh,i.e., 40% (branch treatment of a malignant gastric ulcer by 6 wk was as5B). The remaining 50% (branch 5C) of malignant RBGUs sumed to be halfway between 54% and 24%, i.e., 38% (branches 8A and 9A). was assumed to fail an initial trial of medical therapy by Branches 4 and 10: healing rates of benign gastric either enlarging or showing minimal or no healing either ulcers. For this analysis, it was estimated that 72% endoscopically or radiographically. Patients with these (branch 4A) of truly benign RBGUs would heal after 6 wk ulcers would be operated on as a medical therapy failure. of therapy with the currently recommended therapy for The fraction of malignant RBGUs that will partially heal gastric ulcers (cimetidine or ranitidine) (58,76-83) and enough to warrant a second trial of medical therapy and that 3% (branch 4C) of truly benign RBGUs will fail an then ultimately go on to heal is completely unknown. It is initial trial of medical therapy to the point of needing probably a relatively infrequent occurrence (99), and thus operative intervention (58,76,77,84,85). Of the remaining was estimated to be similar to the complete healing rate 25% (branch 4B) that would be therefore partially healed after an initial course of medical therapy, i.e., 15% radiographically (branch 11A) and 10% endoscopically (branch after 6 wk of medical therapy, 80% (branch 10A) would heal after another 6 wk of therapy to yield the overall 11A). 12-wk healing rate of 92% (58,83,86,87). Branches 7 and 13: operative mortality rate for Calculation of Cost-Effectiveness of benign gastric ulcers. The operative mortality rate for an Endoscopy for Radiographically Benign elective vagotomy and pyloroplasty should be -0.5%Gastric Ulcers 1.5% and for a partial gastrectomy l%-2% (28,37,88-90). For this analysis the operative mortality rate of an elective The total mortality rate of an experimental populaulcer operation was assumed to be 1%. In addition, it was tion of 1000 patients with RBGUs managed by each of the assumed that intraoperative biopsy would detect all those above six endoscopic management schemes was estimated malignant RBGUs that came to operation for nonhealing. by first calculating the fractional mortality rates of each Branches 5 and 11: radiographic and endoscopic clinical course in the probability tree in Figure 1 that healing rate of malignant radiographically benign ulcers. ended in death (branches 13B, 7B, 3B, 14B, 8B, 15B, 12B, Of the 243 evaluable malignant RBGUs reported, the and 9B). Using the appropriate probability estimates from probability of complete radiographic healing on medical Table 1 for each management scheme, the fractional mortherapy (branch 5A) was about 15% (2,4,5,8,12,13,15,91tality rate of a specific clinical course was calculated by

IMPACT OF ENDOSCOPY ON GASTRIC ULCERS 839

October 1987

Table 2. Estimated Impact on Overall 5-yr Mortality Rate and Cost Efiectiveness of Six Methods of Using Upper Benign Endoscopy and Upper Gastrointestinal X-Ray in the Management of Patients With Radiographically Gastric Ulcers Using Probability Analysis

Endoscopic management scheme 1. Follow-up by UGI only 2. EGD for nonhealing REIGUs only 3. EGD initially for all RBGUs with follow-up by UGI only 4. EGD for all RBGUs after initial medical therapy with follow-up of nonhealers by EGD 5. EGD initially for all RBGUs with follow-up of nonhealers by EGD 6. EGD initially for all RBGUs with follow-up of all REJGUsbv EGD

No. of UGIs per 1000 patients

No. of EGDs per 1000 patients

5-yr mortality rate per 1000 patients

Additional 5-yr survivors per 1000a

No. of EGDs per survivor

Diagnostic dollars per survivor

34.79

1.89

191

95,000

1,255 1,243

0 361

1,210

1,000

28.02

8.65

116

57,000

0

1,244

34.18

2.50

497

173,000

967

1,519

27.39

9.29

164

77,000

2,206

27.20

9.48

233

97,000

0

36.68

-

EGD, upper endoscopy; RBGU, radiographically benign gastric ulcer; UGI, upper gastrointestinal. gastrointestinal x-ray only (endoscopic management scheme 1).

multiplying the probabilities of each branch on the path leading to the final outcome of the death of the patient (100). For example, the fractional mortality rate from branch 12B in a group of 1000 patients with RBGUs that are managed with endoscopy before and after the initial trial of medical therapy [management scheme 6) is the product of the probabilities on the branches leading to branch 12B, i.e., branches lBX2Bx5BXGBXllBXl2B Xl000 patients = 0.05 X 0.33 X 0.40 X 0.33 X 0.90 X 0.76 X 1000 = 1.49. The overall mortality rate for each management scheme was then calculated by summing the calculated fractional mortality rates for branches 13B, 7B, 3B, 14B, 8B, 15B, 12B, and 9B. For example, the respective fractional mortality rates for these branches with management scheme 6 were 0.29, 0.48, 15.41, 1.49, 2.74, 0.20, 1.49, and 5.12. The sum of these values, 27.2, is the total mortality rate per 1000 patients with RBGUs using endoscopy initially and for all follow-up. Similarly, the total number of endoscopies and UGI examinations that would be performed with each management scheme per 1000 patients with RBGUs was calculated using the probability estimates in Table 1. The total diagnostic cost could then be calculated by multiplying the number of each of the procedures per 1000 patients by the cost of endoscopy and UGI x-ray. In the United States, endoscopy usually costs 2-4 times as much as UGI x-ray (101). Therefore, for this analysis it was assumed that the total costs of UGI x-ray would be $150 and of an upper endoscopy $500 (including the costs of biopsy and hospital charges). The relative advantages of each endoscopic management scheme could then be compared by calculating the number of endoscopies performed per additional life. This value was derived by dividing the number of endoscopies that

’ Compared

to follow-up

by upper

would be done per 1000 patients by the net drop in overall mortality per 1000 patients of using that scheme compared with radiographic follow-up alone (management scheme 1). The cost-effectiveness of each management scheme was calculated by dividing the number of diagnostic dollars per 1000 patients (endoscopies plus UGI x-rays) by the net drop in overall mortality per 1000 patients compared with UGI x-ray follow-up alone. To simplify these and the sensitivity analysis calculations, all computations were performed by converting the above probability tree calculations into a spreadsheet program run on a 256 K personal computer. Sensitivity

Analysis

Inasmuch as some of the probabilities used in this analysis were subject to significant uncertainty, the total results of the probability analysis were recalculated while varying the uncertain probability estimates through a range of reasonable values. The impact of changing these probability estimates on the overall conclusions of this analysis was then assessed.

Results The results of this analysis are summarized in Table 2. Compared to radiographic follow-up alone (management scheme I), the greatest reduction in mortality rate in a population of patients with RBGUs occurred by using management scheme 6, endoscopy before the initial course of medical therapy and then following up all patient’s ulcers to healing with endoscopy (36.7 deaths per 1000 pa-

840

Table

GASTROENTEROLOGY Vol. 93. No. 4

ERICKSON

Impact of Performing This Analysis Using Different Probability Values per 1000 Patients (S/1000) and Number of Endoscopies per Additional Survivor (No. of EGDIS) With the Various Methods of Using Upper Endoscopy in the Management of

3. Sensitivity Analysis: The Estimated on the Additional 5-Yr Survivors Patients Alone

With Radiographically

Benign

Standard probabilities

2% RBGUs malignant

Endoscopic management scheme 2. EGD for nonhealing RBGUs only 3. EGD initially for all RBGUs with follow-up by UC1 only 4. EGD for all RBGUs after initial medical therapy with follow-up of nonhealers by EGD 5. EGD initially for all RBGUs with follow-up of nonhealers by EGD 6. EGD initially for all RBGUs with follow-up of all RBGUs by EGD

Gastric

Ulcers

Compared

to Upper

Survival for malignant BetteP

RBGUs

Gastrointestinal

X-Ray

30% of malignant RBGUs heal by UGI

EGD 95%

accurate

Worseb No. of EGD/S

Follow-up

No. of EGD/S

No. of EGDiS

S/1000

No. of EGDiS

S/l000

453

0.53

684

0.38

947

2.68

133

1.22

288

3.46

289

2.04

491

1.60

627

12.27

81

9.39

106

497

1.00

1247

1.34

929

0.56

2229

3.36

368

3.60

345

9.29

164

3.72

411

2.24

679

1.73

880

12.41

121

9.83

154

9.48

233

3.79

589

2.48

891

1.78

1240

176

10.58

208

S/1000

No. of EGDiS

S/l000

1.89

191

0.76

8.65

116

2.50

No. of EGDiS

Silo00

12.4

S/l000

EGD, upper endoscopy; RBGU, radiographically benign gastric ulcer; UGI, upper gastrointestinal. aAssuming the 5-yr survival of malignant radiographically benign gastric ulcers will be 54% as long as it is diagnosed and treated within 3 mo and the survival of a missed malignant radiographically benign gastric ulcer is that of resectable gastric cancer, i.e., 24%. bAssuming the 5-yr survival of malignant radiographically benign gastric ulcers will be that of gastric cancer in general, i.e., 10% as long as it is diagnosed and treated immediately, 7.5% if treated within 6 wk, 5% if treated within 3 mo, and 0% if the malignant radiographically benign gastric ulcer is diagnosed after > 3 mo.

tients was reduced to 27.2 deaths). The most cost-effective means of using endoscopy in patients with RBGUs, however, was to do an initial endoscopy with biopsy in all patients, and to follow the patients radiographically thereafter. Using this mode of endoscopic management for patients with RBGUs would entail performing 116 endoscopies for each additional patient surviving 5 yr at an additional diagnostic dollar cost of $57,000. The results of sensitivity analysis are shown in Table 3. The impact of varying any of the probability estimates in this study through a wide range of values did not change the conclusion that the most cost-effective method for using endoscopy was to do a single initial endoscopy in all patients with RBGUs. The overall cost-effectiveness of endoscopy was, however, dramatically affected by changes in the probability estimates, usually for the worse. The probability values that had the largest impact on the results of this analysis were the incidence of malignant RBGUs and the survival statistics for malignant RBGUs. As many of the radiographic studies on the incidence of malignancy in RBGUs are rather old, it

might be argued that the true frequency of malignancy in gastric ulcers in the United States should now be much less than this, inasmuch as the annual incidence of gastric cancer in general has dropped dramatically in the past few decades (102,103) while the incidence of gastric ulcer has remained relatively stable (50,104). If instead of 5% only 2% of RBGUs were malignant, then it would take almost 30~1 endoscopies and cost approximately 144,OOO diagnostic dollars per additional life. If the degree to which a delay in diagnosis of a malignant RBGU affected the 5-yr survival was overestimated, then endoscopy becomes much more cost-ineffective. Taking the extreme assumption that the 5-yr survival of patients with malignant RBGUs will be 54% as long as they are diagnosed and treated within 3 mo and that the survival of a missed malignant RBGU is still at least that of resectable gastric cancer, i.e., 24% then it would take almost 500 endoscopies and 250,000 diagnostic dollars per additional life. If, on the other hand, the survival of patients with malignant RBGUs is actually not any better than those with gastric cancer in general when immediately

October 1987

diagnosed and treated (i.e., lo%), then it requires more than 600 endoscopies and 300,000diagnostic dollars per additional life. The cost-effectiveness of endoscopy is improved if endoscopy with biopsy is assumed to be more accurate at diagnosing malignant RBGUs. For example, if the sensitivity of endoscopy with biopsy is increased to 95% instead of 67%, it only requires 81 endoscopies and 40,000 diagnostic dollars to save an additional life. Or if the complete radiographic healing rate of malignant RBGUs is 30% instead of 15%, it takes 106 endoscopies and 53,000 diagnostic dollars per additional life. Finally, as the cost of endoscopy decreases, the relative cost advantages of the various methods of using endoscopy also decrease. In fact, if taken to the extreme where endoscopy was the same cost as UGI x-ray, it would cost only an additional $17,000 per extra 5-yr survivor using a single endoscopy at the start of therapy.

Discussion Because there are no clinical studies on the subject, the only guidelines that the clinician currently has on how best to use endoscopy in the management of patients with RBGUs are the recommendations of experts in the field. Unfortunately, also in part secondary to the lack of clinical studies of the problem, the authorities in this area often have widely differing viewpoints. The purpose of this study was to use probability analysis to provide relatively quantitative estimates of the impact on mortality and cost-effectiveness of using a variety of endoscopic management schemes for patients with RBGUs. The data compilation necessary to make the probability estimates used in this study pointed out a number of important, yet previously poorly documented, observations. It would appear that the 5-yr survival of malignant RBGUs is clearly better than that of gastric cancer in general, 54% versus 10%. This improved survival is in part, but not completely, related to the increased frequency of early gastric cancers (105) in patients with malignant RBGUs. Patients with early gastric cancer in western countries have a 5-yr survival of about 70% (61-63, 66-68,106-111). Only about 6% of gastric cancers in the West are early gastric cancers (52,57,63,64,94, 106,107,112-117); however, of 158 malignant RBGUs for which such data were available, 25% could be classified as early gastric cancers (5,57,72, 103,118,119). Similarly, whereas an average of 5%-6% of gastric cancers in general present as RBGUs (5,7,64,70,75,76,120-122), almost one-third of early gastric cancers will be initially diagnosed as a RBGU (52,59,61,62,107,109,110,1~1,114,123-126).

IMPACT OF ENDOSCOPY ON GASTRIC ULCERS

841

Additionally, the frequency of gastric lymphoma in patients with malignant RBGUs is about 10% (5,12,15,55,58,127) versus <2% for gastric cancer in general (?28--133). Gastric lymphomas have a much better 5-yr survival of 20%60% (134-138) compared with gastric carcinoma. Another important observation was that the complete radiographic healing of a malignant RBGU is not an unusual event in that it probably occurs in ~15% of patients (2,4,5,8, 12,13,15,91-93). Inasmuch as these data are derived from studies before the advent of potent medical therapy for gastric ulcers, the healing rate for malignant RBGUs could conceivably be higher. Lastly, endoscopy with biopsy only detected two-thirds of malignant RBGUs (16,45,52,55-62) versus the generally quoted literature value of >95% detection (51-54). There are several important conclusions that can be drawn from this analysis. This analysis estimates that radiographic follow-up alone would result in 36.7 deaths after 5 yr per 1000 patients with RBGUs, with most of these deaths occurring because of missed gastric cancers. That this is a reasonable estimate is supported by similar results from a clinical study by Montgomery and Richardson (139) of 210 patients with RBGUs that were managed primarily by radiographic follow-up. He found a 5-yr mortality rate of 3.2% from missed cancers. This analysis estimates that using endoscopy before initiating a trial of medical therapy and following all RBGUs endoscopically thereafter (management scheme 6) would decrease the 5-yr mortality rate to 27.2 per 1000 patients. To statistically demonstrate the difference between a mortality rate of 36.7 (management scheme 1) and 27.2 (management scheme 6) using a one-tailed t-test with an (Yerror of 0.05 and p error of 0.50 would require almost 4000 patients (100,140). This supports the conclusions of the gastric ulcer subcommittee of the American Society for Gastrointestinal Endoscopy (31) that such a study would not be economically feasible. More importantly, this analysis indicates that the most cost-effective method for using endoscopy in the management of patients with RBGUs is to perform a single endoscopy for all patients before the initial course of medical therapy and then to do all follow-up by UGI x-ray thereafter (116 endoscopies per additional life). This conclusion remained despite varying the probability estimates used through a wide range of reasonable values. The main reason that this management scheme was consistently the most cost-effective was that it minimized the number of malignant RBGUs that were missed because they either radiographically or endoscopically completely healed on initial follow-up only to re-present as advanced cancer many months later. The estimated

842

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diagnostic cost per additional life of this management scheme was $60,000.This diagnostic cost per additional life must be weighed against the economic costs incurred by a patient dying of gastric cancer that would include the direct health care costs of about $10,000 to $20,000 (141-143),the indirect cost of the lost economic productivity of that patient, which was estimated in 1978 to be about $43,000 per cancer death (143), and the incalculable costs of human suffering. If the cost of endoscopy was much closer to that of UGI x-ray (as is the case in most of Europe), the diagnostic cost per additional life would be proportionately lower. The major problem with this type of probability analysis is that the conclusions made can only be as good as the design of the probability tree and the probability estimates used in the calculations. However, even when some of the probability estimates have little basic data to support them in the medical literature, the impact of this uncertainty on the overall conclusions of the analysis can be assessed by performing sensitivity analysis. An advantage of probability analysis over clinical studies is that it allows one to test the impact of variations in the questions being asked without having to do a totally new clinical study. This can be done by simply modifying the probability tree or changing the probability estimates of selected branches. Despite the problems with the methodology, I believe this and other probability analysis studies (32,100) demonstrate that it can be a useful tool for physicians to appy to clinical questions that cannot be addressed by the preferable randomized controlled trial.

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