Strengths and limitations of the review
The definition of symptom differed between studies. In some, only the computer codes allocated to the consultation in the medical records were used, while others used the whole medical record including free text. The latter method will detect a greater number of patients with symptoms, as the computer code generally represents a summation of the consultation into a diagnosis or term representing patient management. This approach is encouraged in research practices (personal communication, Royal College of General Practitioners' [RCGP] Weekly Returns Service, 2010), with a stated preference for GPs to record diagnostic computer codes rather than symptom codes. It is unusual for a GP to record multiple history or symptom codes for a single problem. The studies that calculate PPVs for computer codes thus give values for patients in whom a GP is unable to make a more specific diagnosis. These studies do not give PPVs for symptoms presented to GPs, unlike studies in which free text is also analysed. Both types of study overestimate the PPV as a consequence of under-recording by GPs, especially when the clinician has a low level of suspicion for cancer. The size of this effect is not known. The PPVs will only remain valid if GP recording and patient consultation behaviour do not change with time.
A significant source of bias in studies using clinicians to specifically register a patient is selection of those with more severe symptoms and those in whom the clinician has a greater suspicion of malignancy. Such studies are considered to have a low weight in the present review of unselected primary care populations due to this selection bias, and are likely to overestimate the PPV. In the meta-analysis of rectal bleeding, there is a large degree of heterogeneity and a trend for the PPV to be lower in more recent studies. This partially reflects this source of bias and a change in recruitment methods over time from the use of specifically registered patients to routinely recorded data. In studies using computer codes, the actual codes used were not reported and may differ significantly between studies even when the symptom appears to be a single entity (personal communications, W Hamilton and R Jones, 2009).
A recent systematic review and meta-analysis on studies that only involved the recruitment of cases of rectal bleeding by GPs commented on the difficulties of complete identification and follow-up of all incident cases of rectal bleeding in primary care and differences in age cut-off points between studies.38 The authors gave an estimated PPV of over 5% in those aged ≥60 years with rectal bleeding.
Several other methodological problems can overestimate the PPV in studies, including the use of cancer registries resulting in the inclusion of cancers not diagnosed through primary care (for example, screen detected, referral within hospital, and admission via accident units), cancers diagnosed as an association and not the cause of symptoms, and recall bias in case-control studies.
Underestimation of the PPV may occur with inadequate follow-up, and the length of follow-up varied between studies from no follow-up to 11 years. The study by Jones et al indicates that some cancers are diagnosed 3 years after initial presentation.12
Other potential sources of bias in this review were that it only included English language papers, and that some papers in more specialist journals could not be located. This potential bias is unlikely to affect the results of the review, as, on closer examination of the abstracts, they are unlikely to have matched the study eligibility criteria.
The studies identified that calculated PPVs for combinations of symptoms, signs, or non-diagnostic test results and risk of cancer, involved populations that were too small and/or methods of recruitment that were subject to too high a risk of bias to draw firm conclusions. Three recent systematic reviews on the diagnostic utility of combinations of symptoms, signs, and test results for colorectal cancer showed that evidence in primary care is lacking, and when present only shows modest diagnostic value.38–40
A potential criticism of this review is that it only included symptoms, signs, and tests with a point estimate PPV of 5% or more. It is likely that it excluded good-quality studies with a point estimate of less than 5%, but in which the 95% CIs included 5%. It is possible that future research may identify additional symptoms, signs, and tests with a point estimate of 5% or more.
The level of risk an individual is prepared to take is specific to that person at that moment, and is dependent on many factors. Twenty-six additional studies were identified with PPVs of other symptoms, signs, and non-diagnostic test results for cancer of less than 5%. A lower level of PPV than that used in this study will identify more symptoms, signs, and non-diagnostic test results for cancer, and additional age and sex groups in unselected primary care populations. Selecting a lower level of risk may diagnose cancer earlier in presenting populations but with the disadvantage that more individuals will undergo negative investigation with physical, psychological, and economic cost from the tests. A maximum level of risk for a population of 5% was chosen for this review, based on stated levels of risk in national guidelines concerning a comparable disease and treatment. The lower the level of risk, the greater the disagreement as to whether or not inaction can be justified.
When communicating with patients, it is preferable to use absolute measures of risk (number needed to investigate) rather than relative measures of risk.41 In assessing a patient's level of risk using predictive values, it is important to individualise the risk, as the PPV of the population will be modified by the individual's risk factors for the illness. There has been no debate with the public regarding what level of risk is acceptable.14
Implications for future research and clinical practice
This study found evidence for only nine symptoms, signs, and non-diagnostic test results that have a high predictive value for cancer in patients presenting to GPs during routine consultations. A number of studies were subject to methodological and sample size difficulties, and for one symptom (change in bowel habit and colorectal cancer), high-quality studies using different methodology produced contradictory results. On the basis of good quality studies (with one or more studies on the quality-assessment tool at a level of 6 stars or more and no similar quality contradictory studies), broad consistency with published guidelines,4 and the unlikelihood that further research will change the conclusion of studies performed on large databases, it can be concluded that robust evidence exists for a PPV of 5% or more in specific age/sex groups as detailed in Table 11.
Table 11 Symptoms, signs and non-diagnostic tests in unselected primary care populations with a PPV of ≥5% for cancer for which there is robust evidence.
The low number of symptoms, signs, and non-diagnostic test results with a PPV of 5% or more was not unexpected, as the difficulties in diagnosing cancer in primary care have been commented on before.5 While these symptoms, signs, and non-diagnostic test results occur in the minority of patients with cancer, when they do occur, exclusion of cancer is obligatory unless exceptional circumstances exist. There is some evidence that GPs do not always act upon them.28,42,43 A previous effort to trigger GP action concerning one of the tests was unsuccessful,44 but this may have been due to the form of trigger used. The identified symptoms, signs, and non-diagnostic test results are broadly consistent with NICE recommendations for referral for suspected cancer. However, NICE generally uses a lower threshold for referral for additional symptoms and tests, and in the case of haemoptysis, even when the computer code is associated with a PPV of 5% or more.
The authors recommend research and development of general practice computer systems to produce effective warning flags when the symptoms, signs, or test results with a PPV of 5% or more from unselected primary care populations are entered for patients within the specified sex and age groups. The management of these patients should be audited and appraised. There is a need to standardise terms and analyses, and for further research on combinations of symptoms, signs, and non-diagnostic test results. There should be more open debate on the level of PPV that triggers a recommendation for referral by a GP.
