Suspected cancer: recognition and referral

Why the committee made the recommendations

For the utility of serum CA125 measurement and age thresholds, the committee agreed that using age-based serum CA125 thresholds in women, and trans men and non-binary people with female reproductive organs aged 40 and over can support referral decisions for ultrasound.

Moderate-certainty evidence showed that in women over 50, serum CA125 levels meet the predictive value needed to justify a strong recommendation to arrange an ultrasound scan. Based on the clinical and health economic evidence, the committee agreed age-specific thresholds in 10-year age bands for this age group.

For people aged 40 to 49 years, although the evidence was less certain and did not meet the required predictive value needed to justify a strong recommendation to arrange an ultrasound scan, the CA125 threshold of 35 U/ml or over still shows moderate‑to-high sensitivity. The committee agreed that for this age group, the measurement of CA125 remains useful in guiding decisions about further investigations.

The committee acknowledged that the low prevalence of ovarian cancer in younger age groups affects serum CA125 performance, which increases the risk of false reassurance and late diagnosis, particularly in those aged 39 and under. For this age group, the committee agreed that serum CA125 is not sufficiently accurate to support decision making. Therefore, the committee recommended that serum CA125 should not be used in isolation to guide suspected ovarian cancer decisions. The committee recommended considering an ultrasound scan for those with persistent symptoms. The committee also agreed the importance of safety netting for those aged 39 and under, and recommended that if an ultrasound scan is normal, other potential causes of symptoms should be investigated and people advised about when to return to their GP.

The committee agreed that the referral thresholds for serum CA125 should be reflected in the recommendations; they agreed not to label CA125 <35 U/ml as a 'normal' level and emphasised preserving clinical discretion in investigating vague or non-specific symptoms when appropriate.

The committee discussed the possible impact of the recommendations on numbers of ultrasound scans, and acknowledged that in practice, healthcare professionals frequently request a CA125 measurement and an ultrasound simultaneously. No evidence was identified comparing dual testing with the currently recommended sequential use. As a result, the committee did not make any new recommendations about simultaneous testing with serum CA125 and an ultrasound scan, did not change the existing recommendations, and made a recommendation for research on dual use.

How the recommendations might affect practice

Implementing age-based CA125 thresholds may increase the use of ultrasound in people aged 50 and over. The economic analysis suggested that additional annual funding would be needed, mainly because of increased ultrasound and follow-up care. However, as many GPs currently request ultrasound alongside CA125 testing, the recommendations could reduce unnecessary concurrent testing. Introducing age-based CA125 thresholds may also require updates to laboratory reporting systems and clinical pathways.

In the 40 to 49 age group, the current CA125 threshold remains unchanged, so no significant change in practice is expected. For those aged 39 years and under, the recommendations promote clinical judgement and an approach, which may reduce unnecessary CA125 testing but could increase targeted ultrasound use. Given the low prevalence of ovarian cancer in these younger age groups and the high current use of ultrasound in practice, these changes are not expected to have a significant resource impact.

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Why the committee made the recommendations

The guideline recommends referral via a suspected cancer pathway for endometrial cancer for people aged 55 and over with post-menopausal bleeding, and consideration of referral for those under 55. These recommendations do not address unscheduled bleeding that may be associated with HRT.

We undertook a systematic review to assess the diagnostic accuracy of unscheduled vaginal bleeding for detecting endometrial cancer in adults taking HRT, to inform referral decisions via a suspected cancer pathway. No relevant studies were identified.

In 2024, the British Menopause Society (BMS), in partnership with other specialist organisations and Royal Colleges, published guidance on the 'Management of unscheduled bleeding on hormone replacement therapy (HRT)'. The authors acknowledge a significant lack of evidence in many areas, with recommendations based on expert opinion. The committee noted this and the absence of studies in the NICE systematic review.

The committee discussed the increasing use of HRT (data from the NHS Business Services Authority showed a 47% increase in prescriptions in England in 2022/23) and agreed that recommendations are needed despite the evidence gap.

The committee acknowledged that the BMS recommendations are widely used in practice and agreed to signpost to them, while highlighting the lack of evidence and evolving clinical practice.

Given the lack of evidence, the committee made a recommendation for research to establish when unscheduled bleeding in those taking HRT should prompt referral via a suspected cancer pathway.

How the recommendations might affect practice

Raising the awareness of the BMS guideline among healthcare professionals could help reduce unnecessary referrals for cases of unscheduled bleeding attributable to HRT. This may reduce the stress and anxiety for people who are unnecessarily referred and ease the pressure on the healthcare system.

Return to recommendations

Why the committee made the recommendation

The evidence on the diagnostic accuracy of fixed and age-specific prostate-specific antigen (PSA) thresholds was very uncertain because all of the studies were based on a population that had already been referred to secondary care. The 2019 guideline recommended referral if PSA levels were above the age-specific reference range. The committee agreed that referral should be considered based on PSA thresholds, but did not make a stronger recommendation because of the uncertainty in the evidence and the likely low positive predictive value of the PSA test for prevalence estimates based on UK population data. The committee noted that many prostate cancers are slow growing and might never impact life expectancy. Some might choose not to be referred to secondary care to avoid invasive investigations and treatment that might not benefit them. Therefore, the committee agreed that a patient-centred approach to referral is important, and recommended that personal preferences and any comorbidities should be taken into account.

The committee agreed that more research is needed in this area to better understand the most appropriate thresholds that should prompt referral to secondary care for each age group. The committee noted that ethnicity and family history are important factors that affect the risk of prostate cancer. Therefore, they recommended that the data from research be stratified by these factors to determine whether different PSA levels should prompt referral in these groups. Research in this area may also help to address health inequalities in prostate cancer diagnosis and outcomes in the UK.

There was no strong evidence to differentiate between using age-specific or fixed PSA thresholds. The committee also noted that no cost-effectiveness evidence comparing age-specific thresholds with fixed thresholds was identified. However, because PSA levels increase naturally with age, the committee agreed a lower fixed PSA threshold would detect more cases of prostate cancer but also lead to unnecessary biopsies and overtreatment in some age groups. This would also be likely to result in more referrals to secondary care and have a significant impact on NHS resources. The committee therefore recommended the use of age-specific thresholds, which are already established in current practice and were recommended in the previous version of the guideline. Because of regional variations in practice (particularly in the 50 to 69 age range), the committee decided to define the age-specific PSA thresholds. The committee agreed that the thresholds used in the reviewed studies on people with symptoms of possible prostate cancer should be used in the absence of evidence to support alternative values, because these studies were most applicable to the population that the recommendation applies to. No evidence was available specifically for those under 40 or over 79, and so the committee recommended that clinical judgement is used when deciding whether to refer people in these groups to secondary care.

How the recommendation might affect practice

Referral based on age-specific PSA thresholds is already recommended, so practice should not change significantly. Also, clarifying the age-specific thresholds will help standardise care. Taking into account patient preferences and comorbidities should also lead to a more patient-centred approach to referral.

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Why the committee made the recommendation

The evidence showed that positive predictive values of 3% or above were seen in people aged 60 and over who presented in primary care with unexplained weight loss (a mean loss of more than 5% of body weight within a 6-month period). Based on this finding, the committee recommended adding age and unexplained weight loss thresholds to the existing recommendation on unexplained weight loss as a non-site-specific symptom of cancer. Although the certainty of the evidence was low – this was a single study without data on sensitivity or specificity to assess imprecision based on the GRADE framework – the study was well-conducted, directly applicable to the UK and based on a sufficiently large sample size. The committee agreed that a potential benefit of this recommendation would be to identify those people with cancer more rapidly highlighting that the use of urgent investigation or a suspected cancer pathway referral or a non-specific symptoms pathway referral should be made. The committee outlined that the choice of referral pathways is related to the person presenting to primary care and clinical judgement. Furthermore, the committee agreed that introducing age thresholds for unexplained weight loss may minimise the number of inappropriate referrals for people without cancer, while maximising the number of appropriate referrals for people with cancer. The committee also agreed to retain the list of potential cancers associated with unexplained weight loss.

The committee acknowledged that the updated recommendation does not apply to adults aged 18 to 59. However, they were reassured that the guideline's recommendations on safety netting allow for reviews of people with any symptom that may be associated with an increased risk of cancer.

How the recommendations might affect practice

The committee agreed that the potential benefit of introducing age thresholds for unexplained weight loss could be to save time and resources by reducing the number of unnecessary referrals, while improving the accuracy of referrals for people most at risk of cancer.

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