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Evidence‐based approaches

As there are over 200 cancer types with each having different but sometimes overlapping features, there is a variation in referral and testing for possible cancers. The National Institute for Health and Care Excellence (NICE [112]) has produced evidence‐based guidance (NG12) for suspected cancers and their recognition and referral in children, young people and adults. Recommendations are presented by the site of the cancer. Further NICE ([108]) guidance (CG104) has been produced for malignancy of undefined primary origin (MUO) and metastatic malignant disease of unknown primary origin in adults.

In 2013, the ACB made the following recommendations as a result of the ACB national audit on tumour marker service provision.

Laboratories should:

adopt local guidelines for non‐specialist laboratories informing them of the most appropriate use of tumour markers that are based on nationally or internationally developed evidence‐based guidelines
provide guidance on frequency of tumour marker measurement
regularly audit their tumour marker service to review the requesting patterns and use
review their tumour marker requests, in particular those sent to another laboratory assay
state on reports for tumour markers measured on fluids that these results have not been validated
state the relevant reference range on the report and that the results are not well defined and are to be only used for guidance
state that a result out of the reference range does not imply tumour presence or exclude tumour presence
state that benign conditions may cause elevated serum results that can lead to misinterpretation
state that medication, medical intervention and lifestyle can influence results
advise users that factors such as urinary tract infection (UTI), catheterization prior to serum PSA and correct time of serum PSA after digital rectal examination may affect the result (ACB [5]).

Rationale

Tumour markers are used in cancer detection and management. The tests are potentially useful in cancer screening, aiding diagnosis, determining prognosis, surveillance post curative surgery, predicting drug response or resistance and monitoring therapy in advanced disease (ACB [5], Duffy [39]). Tumour markers should only be requested where the results can influence clinical practice and have a favourable outcome for patients (ACB [5]).

Indications

The main indication for serum tumour marker testing is the monitoring of patients diagnosed with cancer.

Primary care – the only tests that should be performed are PSA in males, CA 125 in females, and where the GP is following up a patient being cared for by a secondary physician.
Asymptomatic patients – potentially used for screening in early malignancy.
Symptomatic patients – to assist in differential diagnosis of benign and malignant disease, following diagnosis and surgical removal of a cancer to assess prognosis, post‐operative surveillance, therapy prediction, and monitoring the systemic therapy response (ACB [5], Duffy [39]; EGTM [46]).
Metastatic malignant disease of unknown primary origin in adults: second diagnostic phase – only in the following:
- alpha‐fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in patients with germ cell tumours, particularly in young men with mediastinal and/or retroperitoneal masses
- AFP in patients with hepatocellular cancer
- PSA in men with prostate cancer
- CA 125 in women with ovarian cancer including inguinal node, chest, pleural, peritoneal or retroperitoneal presentations (NICE [108]).

Contraindications

There are certain circumstances where tumour markers should not be used. These include:

metastatic malignant disease of unknown primary origin in adults: second diagnostic phase (NICE [108])
patients with vague symptoms when likelihood of cancer is low (ACB [5])
multiple tumour marker requests in the attempt to identify a primary cancer or the presence of secondary cancers; this is rarely valuable (ACB [5]).

Pre‐procedural considerations

There are various pre‐procedural considerations such as timing of specimen collection, other current treatment or medications, the patient's renal function, possible contamination of samples, type of specimen and the stability of the specimen during storage (Table 20.2).

Table 20.2 Pre‐analytical/pre‐procedural considerations

Consideration	Potential tumour markers affected
Timing of specimen collection	Pre‐treatment: specimen desirable for all markers Time of day variation: specimens can be taken any time for most markers Post‐operatively: CA 125 may be increased in peritoneal trauma Menses: avoid sampling during menses, especially CA 125 for high‐risk patients Urology: prostate biopsy/transurethral resection of the prostate (TURP), catheterization and acute painful urinary retention may increase serum PSA Prostatitis/UTI: may increase serum PSA. Sampling should occur several weeks after resolution of symptoms/infection Digital rectal examination (DRE): transient elevation of serum PSA Ejaculation: potential increase post ejaculation, note time post ejaculation Chemotherapy: hCG specimen: post chemotherapy timings need to be checked to avoid misleading elevated results
Effects of other treatment/medication	Immunometric methods: vulnerable to human anti‐mouse antibodies (HAMA) Monoclonal antibodies: previous treatment to be noted on request form Radioisotopes: invalid CA 19‐9 results if patient received radioisotopes within past 30 days Radioactive dyes: invalidates B₂M results if taken within one week of the test
Effect of renal failure/impairment	Potential elevation: in PSA, tissue polypeptide specific antigen (TPS) and other cytokeratins
Effect of cholestasis	Potential marked increase: carbohydrate antigen 19‐9 (CA 19‐9)
Contamination with saliva	Potential marked increase: CA 19‐9, squamous cell carcinoma antigen (SCCA), carcinoembryonic antigen (CEA) and TPS
Type of specimen	Serum or plasma: generally most appropriate and suited to most commercial assays Serum and EDTA plasma: difference in results may be due to complement effects, however little evidence available on effect of gel tubes
Stability of specimen on storage	Serum: stable. Separation of serum from clot and storage + 4°C (short term) or −30°C (long term) preferably within 3 hours or as soon as possible Heating: usually undesirable, e.g. PSA, human chorionic gonadotrophin (hCG) PSA: separation of serum from clot and storage + 4°C (short term) or −30°C (long term) preferably within 3 hours or as soon as possible. Refrigerate specimens up to 24 hours; beyond 24 hours specimens should be frozen at at least − 20°C. Longer term storage − 70°C

Source: Adapted from Chernecky and Berger ([26]), EGTM ([46]).

B₂M, beta‐2 microglobulin; PSA, prostate‐specific antigen; UTI, urinary tract infection.

Equipment

The equipment required will vary depending on the type of specimen to be collected such as serum, urine or cerebrospinal fluid (CSF). Please refer to Chapter c13: Diagnostic tests for the various types of equipment and method required, for example blood test, urine collection, CSF collection. The collection vessels or containers may vary according to each organization or laboratory. It is therefore essential to identify the required collection vessels or containers.

Post‐procedural considerations

Ongoing care

It is important to ensure that the patient is informed in regards to the significance of the tumour marker results in the context of other clinical examinations and investigations. Refer to Chapter c05: Communication, psychological wellbeing and safeguarding.