Indication - Cancer
First added in 2019
Changed in 2020
Screening, Staging, Aid to diagnosis
To screen for hepatocellular carcinoma (HCC) in high-risk individuals with liver cirrhosis or with a family history, in conjunction with ultrasound; For staging and monitoring of germ cell tumours; To aid in the diagnosis and staging of hepatoblastoma
WHO prequalified or recommended products
WHO supporting documents
Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection (2018). https://apps.who.int/iris/handle/10665/273174 Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection https://apps.who.int/iris/handle/10665/154590 WHO classification of tumours of the urinary system and male genital organs. WHO classification of tumours, 4th edition, volume 8. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-The-Urinary-System-And-Male-Genital-Organs-2016; WHO classification of tumours of female reproductive organs. WHO classification of tumours, 4th edition, volume 6. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Female-Reproductive-Organs-2014
ICD11 code: 2C12.02
Summary of evidence evaluation
Monitoring patients at high risk of HCC with AFP combined with ultrasound is effective in detecting HCC (WHO guidelines). AFP testing is recommended by WHO for screening for HCC in patients with cirrhosis in the guidelines for the management of viral hepatitis B and C, including monitoring high- risk patients. Use of AFP increased the sensitivity of detection of early HCC in patients with cirrhosis in a metanalysis (RR 0.81; 95% CI 0.71 ; 0.93), with a sensitivity of 63% (95% CI: 48 ; 75), demonstrating its effectiveness for detecting more diseases at an earlier stage, when it is eligible for curative treatment (4). AFP has also been suggested as a prognostic marker for HCC, with an HR for survival of 4.35 when AFP is > 1000 ng/mL (11). AFP testing is recognized as an aid in diagnosis, prognosis, staging and disease monitoring for germ-cell tumours in international guidelines (6–8). AFP testing plays a critical role in prognostication of germ-cell tumours, in risk classification of advanced tumours and in risk- adapted intensity of treatments for patients, according to the International Germ Cell Cancer Collaborative Group (8), as well as in early monitoring of the response of non-seminomatous germ-cell tumours, to anticipate platinum resistance and intensify treatment in a personalized approach (10). The submission did not provide evidence for the use of AFP testing in other cancers, such as testicular cancer.
Summary of SAGE IVD deliberations
The test is recommended for screening people at high risk for HCC (with chronic hepatitis B or C, a family history or cirrhosis), in conjunction with ultrasound, consistent with WHO guidelines, although testing by ultrasound should have precedence over AFP testing. The test is also used for staging and disease monitoring of germ-cell tumours for deciding the intensity of treatment, although there are few data on this use. Consensus documents on staging and management of adolescent tumours include AFP, as ultrasound is not sufficient for paediatric tumours, and testing for AFP and hCG are necessary. The advantage of AFP testing is that it is done on blood samples, which can be sent elsewhere, whereas ultrasound requires the person to be present. Expert opinion and systematic reviews on AFP thresholds should be provided. SAGE IVD recommendation, with rationale The SAGE IVD recommended conditional inclusion on the EDL of AFP testing, pending submission of further evidence to support recommendations in international guidelines on its use in the staging, determining the intensity of treatment and monitoring of germ-cell tumours, especially in adolescents. The Group called for a systematic review of thresholds for AFP that indicate the presence of malignancy.
SAGE IVD recommendation
The SAGE IVD recommended conditional inclusion on the EDL of AFP testing, pending submission of further evidence to support recommendations in international guidelines on its use in the staging, determining the intensity of treatment and monitoring of germ-cell tumours, especially in adolescents. The Group called for a systematic review of thresholds for AFP that indicate the presence of malignancy.
Details of submission from 2020
Disease condition and impact on patients: Monitoring of patients at high risk of hepatocellular carcinoma (HCC) (with chronic hepatitis B or cirrhosis) with AFP combined with ultrasound is effective in detecting these tumours. Some guidelines recommend AFP testing as one of several tests for staging and treatment decisions for germ-cell cancer. Does this test meet a medical need? The AFP immunoassay is used to screen for HCC in patients with cirrhosis, as noted in the WHO guidelines for the management of viral hepatitis, including monitoring high-risk patients (1). How this test is used: The AFP immunoassay is used for diagnosis, prognosis and monitoring of liver and germ-cell cancers.
Public health relevance
Prevalence: Testicular cancer is diagnosed in approximately 9600 men each year in the USA, but only approximately 400 men die of their disease (4.2%). According to data from the International Agency for Research on Cancer (IARC) for 2018, 11 290 new cases of testicular cancer were reported in LMICs, with 3984 related deaths, accounting for 35.3% of the cases. Testicular cancer is the most frequently diagnosed tumour in young men. Globally, the prevalence is 284 073. According to IARC, liver cancer was predicted to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death in 2018, with 841 000 new cases and more than 780 000 related deaths. Socioeconomic impact: Germ-cell tumours arise mainly in young men; timely access to treatment, surgery, chemotherapy and radiotherapy with curative intention can increase their survival substantially at all stages of disease. According to IARC, testicular cancer is most frequently diagnosed between the ages of 20 and 34 years. Disparities in survival from testicular cancer have been described, with a large gap between high-income (mortality to incidence ratio: 0.03) and LMICs (0.17). For liver cancer, the highest rates are observed mainly in lower-income settings: liver cancer is the most common cancer diagnosed in 13 countries in northern and western Africa and east and south‐east Asia. This is related to suboptimal control of the risk factors, including vaccination coverage against hepatitis B virus. For instance, liver cancer incidence rates in Mongolia exceeded those of any other country in the same region as a result of a high prevalence of uncontrolled hepatitis B and C, affecting more than 20% of the population.
WHO or other clinical guidelines relevant to the test
WHO has not issued treatment guidelines but has issued lists of priority medical devices for cancer management (2, 3). WHO guidelines for hepatitis B and C include a recommendation to monitor patients with AFP and ultrasound to detect HCC.
Evidence for clinical usefulness and impact
A meta-analysis showed that the test increased detection of early HCC in patients with cirrhosis, with a sensitivity of 63% (4). Use of AFP for tumour monitoring and prognosis is recommended on the basis of evidence-based national and regional guidelines for germ-cell tumours (testicular, ovarian, non-genital midline and unknown primary germ-cell tumours) (5–7). AFP has been used in indicating the prognosis of germ-cell tumours for classifying the risk of advanced tumours (8) and monitoring the response of non-seminomatous germ-cell tumours to anticipate platinum resistance and intensify treatment (9, 10). AFP can predict the prognosis of patients with HCC (11).
Evidence for economic impact and/or cost–effectiveness
AFP is a generally low-cost, feasible test. AFP with liver ultrasound as a screening strategy for patients at high risk for liver cancer has been used only in high- income countries, where cost–effectiveness has been assessed, with varying results. For example, a comparison of AFP and liver ultrasound with ultrasound only in the USA showed that the combination would yield an additional 27.8 life- years gained (US$ 13 000 per life-year gained), while ultrasound alone would result in 38.9 life-years gained (US$ 21 000 per life-year gained) (12). Use of AFP on blood samples does not require highly specialized laboratory personnel, and it is considered a standard laboratory biochemical test.
Ethical issues, equity and human rights issues
Consent is required to obtain a serum or plasma sample. When AFP is used in patients with cirrhosis to monitor the disease and screen for liver cancer, timely access to care must be ensured. Early recognition of HCC ensures successful treatment of small, localized tumours, including multi-nodular liver presentations amenable to local and locoregional approaches (13). Use of AFP to monitor germ-cell tumours, which are generally diagnosed in young patients, allows early detection of relapse of cancers that are amenable to curative treatment in a high percentage of cases. Furthermore, early, accurate diagnosis allows adaptation of treatment to reduce toxicity and avoid overtreatment. Moreover, the kinetics of AFP levels after initiation of treatment predict resistance to treatment, so that a timely change can be made to the cytotoxic regimen.
1. WHO guidelines on hepatitis B and C testing. Geneva: World Health Organization; 2017 (http:// apps.who.int/iris/bitstream/handle/10665/254621/9789241549981-eng.pdf;jsessionid=31 A015 94E5FB11FCA57D141A0FBEC796?sequence=1, accessed April 2019) 2. WHO list of priority medical devices for cancer management. Geneva: World Health Organization; 2017 (http://www.who.int/medical_devices/publications/priority_med_dev_cancer_management/ en/, accessed May 2019). 3. Hepatocellular carcinoma: hepatitis B and C guidelines (in preparation). 4. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta- analysis. Gastroenterology. 2018;154(6):1706–18. 5. Honecker F, Aparicio J, Berney D, Beyer J, Bokemeyer R, Cathomas R, et al. ESMO 2018 consensus conference guidelines on testicular germ-cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018;29:1658–86. 6. NCCN Clinical Practice Guidelines in Oncology. Fort Washington (PA): National Comprehensive Cancer Network; 2018 7. Clinical guidelines for the management of testicular cancer. Arnhem: European Association of Urology; 2018 (https://uroweb.org/guideline/testicular-cancer/, accessed August 2019). 8. International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ-cell cancers. J Clin Oncol. 1997;15(2):594–603. 9. Fizazi K, Pagliaro L, Laplanche A, Fléchon A, Mardiak J, Geoffrois L, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol. 2014;15(13): 1442–50. 10. Fizazi K, Flechon A, Le Teuff G, Mardiak J, Pagliaro LC, Geoffrois L, et al. Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors (GCT). J Clin Oncol. 2016;34 (Suppl):abstract 4504. 11. Tyson GL, Duan Z, Kramer JR, Davila JA, Richardson PA, El-Serag HB. Level of alpha-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9(11):989–94. 12. Gounder PP, Bulkow LR, Meltzer MI, Bruce MG, Hennessy TW, Snowball M, et al. Cost-effectiveness analysis of hepatocellular carcinoma screening by combinations of ultrasound and alpha- fetoprotein among Alaska Native people, 1983–2012. Int J Circumpolar Health. 2016;75:31115. 13. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 2016;334(11):693–9