Earlier diagnosis is hailed as the key to improving cancer outcomes for the UK, through the identification of cancers at an earlier and therefore more treatable disease stage. Earlier diagnosis is sometimes used interchangeably to mean either diagnosing cancer at an earlier stage in the progression of the disease, or to mean a shorter diagnostic interval (shorter time from first symptomatic presentation of the patient to diagnosis). The evidence for whether earlier diagnosis is better within each of these two contexts is summarised below.
2.4.3.1 Earlier diagnosis: earlier disease stage
Previous research has examined the causes of delays in diagnosis and developed strate- gies to promote earlier diagnosis. It is generally assumed that diagnosis at an earlier stage will improve cancer outcomes. However, the evidence supporting this assump- tion is mixed, and there are potential harms from earlier diagnosis which should be considered. It can be difficult to separate the true effects of earlier diagnosis from con- founding and bias; particularly symptom lead time bias (whereby patients diagnosed with symptoms at an earlier stage appear to have greater survival time because of the earlier diagnosis date; they may not actually survive longer than they would have if they had been diagnosed later).
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Figure 2.1: Factors influencing cancer survival and premature mortality (Hiom, 2015).
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Studies that have investigated the causes of poorer cancer outcomes in the UK com- pared to the rest of Europe (described above) have concluded that late stage diagnosis is one important contributing factor. Certainly, late stage diagnosis is associated with poorer outcomes, and there is evidence to suggest that lower rates of investigation for cancer result in poorer survival: Møller et al. (2015) found low use of urgent referral pathways in GP practices to be associated with increased risk of death in cancer pa- tients (hazard ratio 1.07; 95% CI 1.05-1.08). A survey of GPs in countries involved in the ICPB found increased diagnostics to be associated with better outcomes; there was strong correlation between readiness to investigate for cancer and cancer survival rates (Rose et al., 2015). Although there could be other explanations for this association, such as greater cancer awareness in GPs who investigate more often, or the influence of ascertainment bias (as the population under study is not representative of the gen- eral population, being at greater risk of disease), overall there is strong evidence that greater investigation for suspected cancer is associated with better survival. Localised, smaller, earlier stage cancers are easier (and less expensive) (Insicive Health, 2014) to treat than more advanced disease. Patients want earlier diagnosis (and want investi- gation for cancer at lower risk thresholds when faced with hypothetical situations), as do other stakeholders including the government and the media (Banks et al., 2014). There are harms associated with later diagnosis; poorer survival and prognosis, greater morbidity from the disease and from treatment, and greater psychological trauma for patients and their families.
However, there are other considerations which mean that earlier diagnosis may not always be better. Earlier diagnosis could result in the identification of small, slow- developing cancers that may not have caused any additional morbidity or mortality over the patient’s life course (this is known as over-diagnosis) (Marcus et al., 2015). This will however result in the patient being subjected to otherwise unnecessary treatment. It is not always clear whether survival actually improves with earlier diagnosis or whether improved survival time is an artefact of symptom lead time bias. The issue is further confused by the fact that more aggressive, late stage cancers presenting with clearly identifiable symptoms will often have a very short diagnostic interval, and have poor outcomes and short survival time; this is known as the waiting time paradox, defined by Crawford et al. (2002).
2.4.3.2 Earlier diagnosis: shorter diagnostic interval
The previous section described earlier diagnosis in terms of aiming to diagnose patients at an earlier disease stage. Earlier diagnosis can also refer to a diagnosis happening more quickly after symptomatic presentation, reducing the time known as the diagnostic
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interval. The diagnostic interval is closely related to stage at diagnosis and also has an impact on cancer outcomes. It could be assumed that a shorter diagnostic interval, and therefore shorter time to treatment, would mean better survival but the evidence surrounding this issue is mixed.
In a cohort study in 2002, the relationship between treatment delay and survival was explored for 703 women with endometrial cancer (Crawford et al., 2002). The study found delayed time to treatment to be inversely related to survival; patients with the longest wait for surgical treatment survived significantly longer than those with a shorter time to wait. This may be the result of more serious, advanced disease cases being prioritised for treatment over less serious cases. Although this study focusses on the time from GP referral to surgical treatment, the concept of the waiting time paradox has been applied in other studies. Rupassara et al. (2006) studied this effect further in 154 patients with colorectal cancer. In this study, the interval of interest was the time from GP referral to a diagnosis of cancer being made. In a stratified analysis, 44 patients with a longer diagnostic interval (more than or equal to 50 days from referral to diagnosis) had a 93.7% 5-year survival rate; 110 patients with a shorter diagnostic interval (less than 50 days from referral to diagnosis) had a 5-year survival rate of 65.3%. The longer diagnostic interval group also had smaller tumours, more low-risk symptoms, and more early stage disease than patients with a shorter diagnostic interval.
2.4.3.3 The association between diagnostic interval and cancer outcomes The relationship between longer diagnostic interval and poorer cancer outcomes has been investigated in a number of observational studies. It can be difficult to compare or combine results from studies of this type due to heterogeneity in measures of ‘diagnostic interval’; in a systematic review of diagnostic intervals discussed later in this section, 15 different definitions for diagnostic interval were used in 177 articles. Studies also use varying measures of outcomes.
Neal et al. (2015) carried out a systematic review to assess the evidence for whether a more timely diagnosis improves cancer outcomes. Of the 1,036 full text papers assessed for inclusion, 177 articles were included in their narrative synthesis, which reported on 209 studies. They found that only seven of these addressed the waiting time paradox (described by Crawford et al. (2002)). 28 different cancer sites were investigated by the included papers, and 15 different time intervals were described as the ‘diagnostic interval’. The methodology of the included papers was too heterogeneous for meta- analysis.
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methodological quality. Even within specific types of cancer the authors found contra- dictory evidence about whether a shorter diagnostic interval had no effect on survival, improved survival, or in some cases decreased survival. An extensive analysis of the findings is presented in the original publication; the results for the four most common cancers are summarised here. For lung cancer, studies supporting a positive association between diagnostic interval and outcomes (shorter interval meaning better outcomes), no association, and a negative association (shorter interval meaning poorer outcomes) were found. Only one of these accounted for the waiting time paradox in the analysis; in that study, a positive association was found. For colorectal cancer, more studies showing a positive association than a negative association were found. Three of the four colorectal cancer studies that accounted for the waiting time paradox had found a positive association. For breast cancer, all included studies reported either a positive association, or no association. For prostate cancer, two studies reported a positive association (one of which accounted for the waiting time paradox) and the remaining four found no association. There was also strong evidence for benefits of a shorter diagnostic interval for head and neck, testicular, and melanoma. To a lesser extent, the same was also true for pancreatic and bladder cancer. Of the seven studies that had taken the waiting time paradox into consideration, most reported poorer outcomes associated with shorter diagnostic intervals.
Overall, this systematic review concluded that it is ‘reasonable to assume’ that shorter diagnostic intervals are associated with better survival, reduced mortality, and improved outcomes. This takes into account the effects of late stage disease with symp- toms very strongly suggestive of cancer having short diagnostic intervals and poor out- comes. The methodological heterogeneity makes it difficult to sum or directly compare papers, but the recently published Aarhus statement which promotes greater precision and transparency in definitions and methods in early diagnosis research should mean that this improves with time (Weller et al., 2012). Aside from the effects on outcomes, shorter diagnostic intervals are also desirable as patients and other stakeholders want quicker diagnosis (Banks et al., 2014), and earlier stage cancers are easier and less expensive to treat (Insicive Health, 2014).
2.4.3.4 What factors contribute to delays in diagnosis?
The process of diagnosing cancer is complex and multi-factorial and there are many potential causes of delay throughout the process (see the NAEDI pathway discussed in Section 2.4.2); these fit in to three broad areas: the patient interval (delay in presenting to primary care); the primary care interval (delay in diagnosis); and the secondary care interval (delays to treatment). Delays at any of these stages can result in poorer
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outcomes, and delays in the patient and primary care intervals can contribute to delays in diagnosis.
Within primary care, missed opportunities to diagnose can result in longer diag- nostic intervals, longer time to treatment, and potentially later stage diagnosis (Lyrat- zopoulos et al., 2015). A missed opportunity occurs when an alternative course of action would have resulted in the diagnosis being made sooner (McGlynn et al., 2015). Missed opportunities for diagnosis often result in repeated primary care consultations all cause delay and increase the primary care interval; an increased number of consulta- tions in primary care is associated with a longer primary care interval (Lyratzopoulos et al., 2013), although not all of these consultations will reflect missed opportunities. Lyratzopoulos et al. (2013) found that one in five patients diagnosed with cancer con- sulted their GP ≥ 3 times before being referred; this varied by type of cancer from 7.4% of breast cancer patients to 50.6% of multiple myeloma patients. This study did not examine whether patients with more pre-referral consultations were diagnosed at a later disease stage, or had poorer survival.