Meta-analysis: the diagnostic value of alarm symptoms for upper gastrointestinal malignancy
Dr G. A. J. Fransen, Department of Gastroenterology and Hepatology, University Medical Center St Radboud Nijmegen, Internal code: 547, PO box 9101, 6500HB Nijmegen, the Netherlands.
Background : With the advent of empirical treatment strategies for patients with dyspeptic symptoms, it becomes increasingly important to select patients with a high risk of having cancer for immediate endoscopy. Usually alarming symptoms are used for this matter, but their diagnostic value is by no means clear.
Aim : To investigate the diagnostic value of alarm symptoms for upper gastrointestinal malignancy.
Methods : Meta-analysis of studies describing prevalence of alarm symptoms in patients with and without endoscopically verified upper gastrointestinal malignancy were identified through a Medline search. The prevalence, pooled sensitivity, specificity, positive and negative predictive values were calculated.
Results : About 17 case studies and nine cohort studies were selected. The mean prevalence of gastrointestinal malignancies in the cohort studies was 2.8% of 16 161 patients. Five cohort studies indicated that 25% of the patients diagnosed with upper gastrointestinal malignancy had no alarm symptoms. The pooled sensitivities of individual alarm symptoms varied from 9 to 41%, the pooled positive predictive value ranged from 4.6 to 7.9%, and was 5.9% for ‘having any alarm symptom’. The pooled negative predictive value was 99.4% for ‘having any alarm symptom’.
Conclusion : The risk of upper gastrointestinal malignancy in any individual without alarm symptoms is very low, but approximately one in four patients with upper gastrointestinal cancer have no alarm symptoms at the time of diagnosis.
With the advent of empirical treatment strategies (like Helicobacter pylori test-and-treat or acid suppressive therapy) for patients with dyspeptic symptoms, fewer patients have upper gastrointestinal (GI) endoscopy.1–3 However, it is important not to delay diagnosis in patients with underlying malignant disease. Therefore, it becomes increasingly important to select patients with a high risk of having cancer for immediate endoscopy in order to safely treat the remaining patients empirically. On the contrary, this selection should be specific in order to prevent large number of people having unnecessary endoscopy, which is costly and troublesome to the patients. Usually alarm symptoms such as weight loss, dysphagia, nausea, vomiting and anaemia or bleeding are used for this matter.4–6 However, although generally accepted, the diagnostic value of alarm symptoms is by no means clear, in spite of the amount of research conducted in this area.
Recently Boldys et al.7 concluded that weight loss and melaena are certainly indices of more advanced cancer, and in order to diagnose gastric cancer at an early stage the occurrence of these symptoms should not be awaited. On the contrary, Meineche-Schmidt and Jørgensen8 did not find a higher risk of cancer in patients with alarm symptoms in a large cohort comprising more than 600 patients.
A difficulty in the identification of factors related to diagnosis of upper GI malignancies is the low incidence of these cancers. As a result, large cohorts need to be studied, which often is not feasible. This problem may be overcome by performing meta-analysis. The aim of this study was to evaluate the diagnostic value of alarm symptoms for upper GI malignancy by means of a meta-analysis.
Identification and selection of publications
A literature search was performed in August 2003. Relevant publications were identified in Medline using key words such as ‘alarm’, ‘sinister’, ‘dyspepsia’ and ‘gastrointestinal malignancy’. Furthermore, additional publications were retrieved by reviewing references of selected studies. In order to be selected, publications had to fulfil the following criteria: (i) the presence or absence of upper GI malignancy was established endoscopically, and (ii) the number of patients and prevalence of alarm symptoms in patients with and without upper GI malignancy were described or could be calculated. To minimize selection bias all abstracts were assessed by two independent reviewers; in case of a difference of opinion a third independent reviewer was consulted.
Data analysis and statistical methods
Literature search showed two types of studies eligible for inclusion: cohort studies and case studies. Cohort studies included patients with and without upper GI malignancy and measured the alarm symptoms prospectively (i.e. before endoscopic examination), while case studies included only patients with confirmed gastric or oesophageal malignancy.
Sensitivity was calculated for cohort studies and case studies separately, by pooling the results of the individual studies using an approximation to the inverse variance approach.9 The estimate of the overall sensitivity is the sum of all true positives divided by the sum of all patients with upper GI cancer in the pooled studies. Additionally, for the cohort studies, overall specificity, and overall positive/negative predictive values (PPV/NPV) were calculated similarly. Analyses were performed for individual alarm symptoms separately (dysphagia, weight loss, bleeding, anaemia, nausea/vomiting) and, whenever possible, for having ‘any alarm symptom’ (vs. no alarm symptoms at all). Missing values were excluded from analyses.
Literature search identified 305 papers. After initial review, 39 papers were retrieved to be studied in detail. Of these papers, 13 were excluded because either the prevalence of alarm symptoms or malignancy was not clearly described or because not all patients underwent upper GI endoscopy. The remaining 26 publications, 17 case studies and nine cohort studies, were included in analyses.
The case studies described 1552 patients with upper GI malignancy (Table 1a), mostly identified through retrospective review of hospital records. The pooled sensitivities for the individual alarm symptoms (dysphagia, anaemia/bleeding, nausea/vomiting and weight loss) were respectively 30%, 27%, 21%, and 41% (Table 2). When looking at having ‘any alarm symptom’ the pooled sensitivity was 95%. Overall 10 case studies described 63 (6%) patients diagnosed with upper GI malignancy without any alarm symptom.
Table 1. Characteristics of selected publications: (a) case studies; (b) cohort studies
|(a) Case studies|
|Canga and Vakil20||1990–2000||USA||In teaching hospital identified from electronic database, all ADV||341||68 (22–94)|
|Christie et al.21||1986–1992||UK||Open-access endoscopy unit in district hospital||25||? all < 55|
|Sue-Ling et al.22||1970–1990||UK||Patients operated for EGC in university hospital reviewed||46||69* (38–86)|
|Gillen and McColl23†||1989–1993||UK||Hospital patient records, patients identified by means of West of Scotland Cancer Registry||76||50* (31–54)|
|Gillen and McColl23†||73||51* (37–54)|
|Eckardt et al.24||1977–1986||Germany||Records of out-patients who had an endoscopy resulting in a histological diagnosis of gastric cancer||241||EGC 62*; ADV 59*|
|Houghton et al.25||Since 1965||UK||University hospital records of patients with EGC||35||67* (44–79)|
|Carter et al.26||1974–1982||USA||Patients operated for gastric cancer in university hospital reviewed||31||EGC 44 (26–61); ADV 67 (37–83)|
|Ballantyne et al.27||1978–1985||UK||Patients operated for EGC in university hospital reviewed||20||74* (51–87)|
|Oleagoita et al.28||1975–1985||Spain||Patients operated for EGC in university hospital reviewed||142||55 (19–82)|
|Moreaux and Bougaran29||1965–1995||France||Hospital patients operated for EGC||101||61 (28–82)|
|Gozzetti et al.30||1974–1985||Italy||Patients operated for EGC in university hospital reviewed||49||59 (29–90)|
|Pinto et al.31||1977–1989||Italy||Patients admitted for EGC in university hospital reviewed||142||64 (34–84)|
|Thong-Ngam et al.32||1994–1998||Thailand||Hospital patient records||119||60 (22–91)|
|Ribichini et al.33||1971–1983||Italy||Patients operated for EGC reviewed||60||63 (34–84)|
|Saubier et al.34||1970–1980||France||Hospital patient records||30||60 (31–84)|
|Traynor et al.35|| ? 10-year period||Ireland||Patients operated for EGC reviewed||11||57 (35–70)|
|Heughan et al.36||1972–1980||Canada||Hospital patient records||10||? (43–76)|
|(b) Cohort studies|
|Melleney and Willoughby10||1999–2000||UK||GP referral and selection by specialist (one-stop-dyspepsia clinic)||7.1 (6/84)||59* (15–84)|
|Manes et al.37||1998||Italy||All patients referred for endoscopy||0.8 (6/706)||47 (15–86)|
|Sung et al.38||1998–1999||Hong Kong||GP referral for dyspepsia, endoscopy in regional hospital||0.8 (23/2627)||48|
|Numans et al.39||1986–1988||The Nether- lands||GP referral for recurrent and/or long-lasting episodes and/or alarming symptoms||2.4 (21/861)||?|
|Boldys et al.7||1983–1993||Poland||Patients with symptoms suggesting cancer were referred to secondary referral unit||9.7 (83/860)||44* (IQR: 35–54)|
|Adang et al.40||1989–1990||The Nether- lands||All patients referred for endoscopy by GP and hospital specialist||2.4 (70/2900)||56 (3–96)|
|Wallace et al.19||? (average of 5 years)||USA||Patients referred to open-access endoscopy unit: four units were academic and primary care referral centres, two were military centres||2.1 (81/3815)||47 (s.d.: 18)|
|Johannessen et al.41||1985–1987||Norway||Out-patients referred to open-access endoscopy unit, mostly by GP||1.0 (?/930)||50 (s.d.: 14)|
|Voutilainen et al.42||1996||Finland||GP referral for upper GI endoscopy||0.5 (17/3378)||58 (IQR: 25)|
Table 2. Sensitivity of alarm symptoms in case studies
| Canga and Vakil20||341||155||186||45|
| Christie et al.21||25||8||17||32|
| Gillen and McColl23*||76||18||58||24|
| Gillen and McColl23*||73||62||11||85|
| Thong-Ngam et al.32||119||8||111||7|
|634||Pooled sensitivity (95% CI)||40 (36–43)|
| Canga and Vakil20||341||145||196||43|
| Christie et al.21||25||14||11||56|
| Gillen and McColl23*||76||47||29||62|
| Gillen and McColl23*||73||46||27||63|
| Sue-Ling et al.22||46||10||36||22|
| Eckardt et al.24||241||86||155||36|
| Houghton et al.25||35||22||13||63|
| Carter et al.26||31||18||31||37|
| Moreaux and Bougaran29||101||4||97||4|
| Gozzetti et al.30||49||13||36||27|
| Pinto et al.31||142||58||84||41|
| Ribichini et al.33||60||27||33||45|
| Thong-Ngam et al.32||119||64||55||54|
| Traynor et al.35||11||4||7||36|
| Heughan et al.36||10||1||9||10|
|1350||Pooled sensitivity (95% CI)||41 (37–44)|
|Bleeding and/or anaemia|
| Canga and Vakil20||341||87||254||26|
| Christie et al.21||25||7||18||28|
| Houghton et al.25||35||15||20||43|
| Heughan et al.36||10||4||6||40|
|401||Pooled sensitivity (95% CI)||27 (24–31)|
| Gillen and McColl23*||76||6||14||30|
| Gillen and McColl23*||73||3||28||10|
| Sue-Ling et al.22||46||13||228||5|
| Eckardt et al.24||241||14||62||18|
| Carter et al.26||31||2||71||3|
| Ballantyne et al.27||20||5||44||10|
| Oleagoita et al.28||142||5||96||5|
| Moreaux and Bougaran29||101||7||135||5|
| Gozzetti et al.30||49||5||41||11|
| Pinto et al.31||60||7||53||12|
| Saubier et al.34||30||4||26||13|
| Thong-Ngam et al.32||119||34||85||29|
|988||Pooled sensitivity (95% CI)||11 (8–13)|
| Gillen and McColl23*||76||3||17||15|
| Gillen and McColl23*||73||17||59||22|
| Ballantyne et al.27||20||4||69||5|
| Moreaux and Bougaran29||101||1||100||1|
| Saubier et al.34||30||1||29||3|
|300||Pooled sensitivity (95% CI)||9 (6–11)|
| Canga and Vakil20||341||53||288||16|
| Gillen and McColl23*||76||21||25||46|
| Gillen and McColl23*||73||38||203||16|
| Sue-Ling et al.22||46||9||26||26|
| Eckardt et al.24||241||27||49||36|
| Houghton et al.25||35||26||47||36|
| Carter et al.26||31||5||15||25|
| Ballantyne et al.27||20||9||133||6|
| Oleagoita et al.28||142||37||105||26|
| Gozzetti et al.30||49||11||20||35|
| Pinto et al.31||142||21||28||43|
|1196||Pooled sensitivity (95% CI)||21 (18–25)|
|Any alarm symptom|
| Canga and Vakil20||341||324||17||95|
| Christie et al.21||25||24||1||96|
| Gillen and McColl23*||76||71||5||93|
| Gillen and McColl23*||73||73||0||100|
| Sue-Ling et al.22||46||42||4||91|
| Oleagoita et al.28||142||136||6||96|
| Moreaux and Bougaran29||101||95||6||94|
| Pinto et al.31||142||137||5||96|
| Saubier et al.34||30||26||4||87|
| Ribichini et al.33||60||49||11||82|
| Traynor et al.35||11||7||4||64|
|1047||Pooled sensitivity (95% CI)||94 (92–96)|
In the cohort studies, a total of 16 161 patients were described with a mean prevalence of upper GI malignancy of 2.8% (Table 1b). Most of the studies described patients referred for endoscopy by the general practitioner, the reasons for referral and way of patient selection varied between the studies. For example, the studies by Melleney and Willoughby10 and Boldys et al.7 included patients with a high suspicion of upper GI malignancy, which may explain the relatively high prevalence of upper GI malignancy. The pooled sensitivities for dysphagia, anaemia/bleeding, nausea/vomiting, weight loss, and ‘any alarm symptom’ were respectively 25%, 17%, 27%, 24% and 75% (Table 3). The pooled PPVs were respectively 6.6%, 4.6%, 7.5%, 7.9% and 5.9%.
Table 3. Sensitivity, specificity and predictive value of alarm symptoms in cohort studies
|Dysphagia||Sung et al.38||2627||1||28||22||2576||4||99||3||99.2|
|Numans et al.39||861||13||199||8||615||62||76||6||98.7|
|Adang et al.40||2900||14||169||56||2611||20||94||8||97.9|
| ||7058||Pooled estimate||25||94||6.6||98.8|
| || ||95% Confidence interval||17–23||93–94||4.2–9.0||98.5–99.1|
|Weight loss||Sung et al.38||2627||3||16||20||2588||13||99||16||99.2|
|Numans et al.39||861||14||195||7||645||67||77||7||98.9|
|Adang et al.40||2900||17||126||53||2654||24||95||12||98.0|
|Johannessen et al.41||930||7||244||2||683||78||26||3||99.7|
|Boldys et al.7||860||9||1||74||776||11||99.9||90||91.3|
| ||8178||Pooled estimate||24||93||7.9||97.9|
| || ||95% Confidence interval||18–30||92–93||5.8–10.0||97.6–98.2|
|Bleeding and/or anaemia||Sung et al.38||2627||1||79||22||2525||4||97||1||99.1|
|Numans et al.39||861||3||62||16||732||16||92||5||97.9|
|Boldys et al.7||860||15||60||68||717||18||92||20||91.3|
|Adang et al.40||2900||15||511||55||2269||21||82||3||97.6|
| ||7248||Pooled estimate||17||90||4.6||97.5|
| || ||95% Confidence interval||12–23||89–90||3.0–6.0||97.1–97.5|
|Nausea/vomiting||Boldys et al.7||860||20||145||63||632||24||81||12||90.9|
|Numans et al.39||861||8||199||13||614||38||76||4||97.9|
| ||1721||Pooled estimate||27||78||7.5||94.3|
| || ||95% Confidence interval||18–35||76–80||4.9–10.2||93.0–95.5|
|Any alarm symptom||Melleney and Willoughby10||84||5||37||1||41||83||53||12||97.6|
|Manes et al.37||706||4||34||2||666||67||95||11||99.7|
|Boldys et al.7||860||61||334||22||443||73||57||15||95.3|
|Voutilainen et al.42||3378||12||1092||5||2269||71||68||1||99.8|
|Sung et al.38||2627||19||109||4||2495||83||96||15||99.8|
| ||7655||Pooled estimate||75||79||5.9||99.4|
| || ||95% Confidence interval||67–82||78–80||4.8–7.0||99.2–99.6|
|Age > 45, male, anaemia or bleeding||Wallace et al.19||3815||74||2866||7||868||91||77||3||99.2|
The pooled NPV for the individual alarm symptoms (dysphagia, anaemia/bleeding, nausea/vomiting and weight loss) were 98.8%, 97.9%, 97.5%, and 94.3 respectively, for ‘having any alarm symptom’ it was 99.4%. This means that there is approximately a 1:175 chance of missing malignancy in patients without alarm symptoms.
Overall, 16 studies (2238 patients) differentiated between early and advanced stages of upper GI malignancy: 710 patients had early stage cancer and 743 had advanced stage cancer.
Alarm symptoms are generally accepted as an indication for direct endoscopy. This is reflected in several guidelines for treatment of patients with dyspeptic symptoms1–4 and in the exclusion criteria for patient selection of most trials.11, 12 As a result, the usefulness of alarm symptoms for selection of patients with a higher risk of having upper GI malignancy is rarely questioned. However, the existing evidence does not consistently support the usefulness of alarm symptoms for this matter.
Therefore, we performed a meta-analysis to study the diagnostic value of alarm symptoms. Our results show that the sensitivity of symptoms indicating malignancy is rather disappointing, both for individual alarm symptoms and for having ‘any alarm symptom’. In addition to this, the pooled PPV is relatively low, indicating that only a small proportion of the patients with alarm symptoms does have cancer. On the contrary, the high NPV for having ‘any alarm symptom’ shows that there is little chance of missing a malignancy in patients without alarm symptoms, although this partially caused by the low prevalence of upper GI malignancy.
Moreover, it should be pointed out that the patients studied in the papers included show some selection. This is obvious for the case studies, but the cohort studies also show a degree of selection. This is reflected by the relatively high prevalence of upper GI cancer, with a mean of almost 3%, ranging from 0.5 to 9.7%. However, in most western countries the prevalence of upper GI malignancy is below 0.5%. Therefore, in the general population, both the sensitivity and the PPV of alarm symptoms will be worse, although the NPV will remain high.
In addition to this, the prevalence of alarm symptoms is high in patients consulting their general doctors for dyspeptic symptoms. This is illustrated by Meineche-Schmidt and Jørgensen,13 who showed that 10% of primary care patients with dyspeptic symptoms had one or more alarm symptoms, whereas only 3% of investigated patients with alarm symptoms were found to have cancer.
Combining the high prevalence of alarm symptoms with their relatively poor sensitivity and PPV leads to the following conclusion: if guidelines are strictly followed, a large number of patients will have endoscopy, whereas a relatively low number of cancers will be identified, and, although the absolute chance of missing malignancy because of the absence of alarm symptoms is small, relatively many malignancies (up to 25%) will be missed. This is supported by two studies in the United Kingdom that compared short-term endoscopies for high-risk patients with open-access endoscopies.14, 15 The results from both studies showed that relatively few patients with cancer were identified in the ‘high-risk’ group while most patients with cancer were found in the open-access group.14, 15
Furthermore, several studies showed that in patients with upper GI cancer the occurrence of alarm symptoms usually indicates more advanced cancer with worse prognosis.7, 14–17 Therefore, it is questionable whether prompt endoscopy improves prognosis for patients with alarm symptoms. This is confirmed by Martin et al.18 who did not find a relationship between delay in diagnosis and prognosis for patients with gastric cancer. Unfortunately, most studies included in this meta-analysis did not provide sufficient information about the stage of the cancers detected in relation to the presence of alarm symptoms. Therefore, it was not possible to perform a proper subgroup analysis.
Possibly, a better diagnostic tool might be created by combining a selection of alarm symptoms with patient characteristics. One of the cohort studies showed a sensitivity of 91% and a specificity of 77% when using a combination of age over 45 years, male gender and anaemia or bleeding.19 This result indicates that the combined presence of alarm symptoms, especially in combination with other factors-like age, gender or smoking might be a better tool for selection of high-risk patients. More research is necessary to define such a tool.
In conclusion, although alarm symptoms are generally accepted as an indication for prompt endoscopy, our results show that the diagnostic value of alarm symptoms is not optimal. Other factors such as age and family history should be taken into account when estimating a patient's risk of having upper GI cancer.