“All screening programmes do harm; some do good as well, and, of these, some do more good than harm at reasonable cost. The first task of any public health service is to identify beneficial programmes by appraising the evidence” - Muir Gray et al(1).
Checking for cancer (or for conditions that may become cancer) in people who have no symptoms is called screening. It is usually assimilated with secondary prevention and involves the use of diagnostic tests in an apparently healthy population. Many people wrongly mistake screening for prevention(2).
There are several forms of prevention:
Primary prevention - aims to prevent disease before it ever occurs. This is done by preventing exposures to hazards that cause the disease, altering unhealthy or unsafe behaviors that can lead to disease, and increasing resistance to disease if exposure occurs. One example is vaccination(3).
Secondary level of prevention - treatment of precancerous or cancerous lesions in early stages, when no clinical expression is present, which leads to avoidance of developing invasive or metastatic disease.
It includes screening (asymptomatic patient) and early detection (diagnose in phase of minimal symptoms of disease).
Tertiary prevention - prevention of local relapse or/and metastatic disease after initial treatment. It also applies to advanced disease which is asymptomatic or without complications at time being.
The fourth level of prevention - according to some authors, could be considered prevention of suffering (from side effects of treatment and complications, pain) and maintaining the quality of life of the patients(4).
Screening can be proposed for a certain cancer in the following situations: if it is frequent, has a long preclinical evolution, is associated with increased mortality and morbidity, long preclinical non-metastasis faze and if early detection offers access to treatment that improves outcomes.
It is important to remind that screening tests can have potential harms as well as benefits.
Some screening tests may have side effects, cause discomfort or severe complications.
Screening tests can have false-positive results.
Screening tests can have false-negative results.
Overdiagnosis is possible. This happens when a screening test correctly shows that a person has cancer, but the cancer is slow growing and would not have harmed that person in his or her lifetime. This can lead to overtreatment(5).
Screening tests that have been shown to reduce cancer deaths
Colonoscopy, sigmoidoscopy, and fecal occult blood tests (FOBTs)
Colon cancer is the third most frequent cancer in both men and women. Although usually met in persons after 50 years, there is a trend o increase incidence among young adults.
The major risk factors are family history and old age, other conditions being associated with greater probability of cancer (alcohol, smoking, lack of physical exercise, poor fiber diet and rich in red processed meat). Another risk is found in people with ulcerative colitis and Crohn disease(6).
Hereditary cancers account for 5% of colorectal cancers (CCR).
Genetic consult, thorough history (till second degree relatives) and IHC (imunohistochemical) and genetic testing should be considered in those with HNPCC (hereditary nonpolyposis colorectal cancer) - like in Lynch syndrome with its variant - Turcot (patients with MMR - mismatch repair gene mutations and brain tumours), and Muir-Torre syndrome (MTS - cutaneous gland tumours like keratoacanthomas and sebaceous tumors associated with colon, breast, and genitourinary tract neoplasia).
Other hereditary cancers are “polyposis associated”: FAP (familial adenomatous polyposis), aFAP (attenuated form of FAP), MAP (MUTYH - associated polyposis – a gene which provides instructions for making an enzyme called MYH glycosylase, which is involved in the repair of DNA), and Peutz-Jeghers syndroms (hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa - melanosis).
The genetic testing refers to identifying MLH1 and PMS2 mutations (for Lynch syndrome), APC (for FAP and aFAP) and MUTYH (for MAP)(7).
The recommendation for screening is made for people at average or high risk of CCR, and usually includes regular testing with gFOBT (fecal occult blood test/guaiac test) or FIT (fecal immunochemical test), sigmoidoscopy or colonoscopy beginning at the age of 50 (earlier or more frequent for known hereditary terrain or inflammatory bowel disease).
Guaiac FOBT: is used to detect a part of the blood protein hemoglobin. It requires avoidance of certain food before testing (red meat).
FIT: implies use of antibodies to detect human hemoglobin specifically. No dietary restrictions are needed.
Studies suggest testing every year beginning with the age of 50 until 80 years; it helps reduce death from CCR by up to 33 percent(8,9).
Sigmoidoscopy has the advantage of visualizing the rectum and sigmoid colon and being able to biopsy suspect lesions. Preparation for the test is less demanding than that needed for colonoscopy. Most patients don’t receive sedation during the test. Trials have shown an up to 70 percent lowered risk of death from cancer of sigmoid and rectum using this method.
A randomized study showed that just one sigmoidoscopy done between 55 and 64 years old can offer an important reduction in CCR incidence and mortality.
The usual recommendation is for the test to be done every 5 years in conjunction with FOBT every 3 years(10).
Colonoscopy examines the whole colon and rectum. A form of sedation is recommended for patient comfort. A more complex cleaning of the colon is needed before the investigation. It has the advantage of biopsy, too. Death from CCR is reduced by about 70 percent. The usual recommendation of testing is at 10 years, as long as other tests are negative(11).
Double-contrast barium enema: less sensitive than colonoscopy for detecting small polyps and cancers; has an utility for those who cannot undergo colonoscopy.
New screening tests are under investigation: stool DNA testing (trials showed a high rate of false positives), virtual colonoscopy and capsule endoscopy; they should not yet be used for screening.
Lung cancer screening - low-dose helical computed tomography
The NLST (National Lung Cancer Screening Trial) was a trial which enrolled 53.000 high risk patients (defined as at least 30 packs-years history of smoking) aged 55-74 years. It had two arms: one used low dose helical CT and the other, standard chest X ray.
On average over the three rounds of screening exams, 24.2 percent of the low-dose helical CT screens were positive and 6.9 percent of the chest X-rays were positive.
The results showed that using the CT screening there is a 15 to 20 percent lower risk of dying from lung cancer when compared with chest X ray.
The adenocarcinomas and squamous types were the most frequently detected, while small cell lung cancer, known for its agresivity, was infrequently found on either CT or chest X ray(12).
This screening test for breast cancer has been shown to reduce mortality from the disease in women aged 40 to 74, especially in those aged 50 or older.
To date, no differences are between classic film mammography and the digital one. Women with breast implants should continue to have mammograms. A special technique called implant displacement views may be used.
Modern mammograms require a very small amount of radiation. Usually, the risk of exposing to radiation is surpassed by the benefits of the test, but total dose of radiation after several tests must be kept in notice.
This test has the advantage of the possibility of being installed in mobile facilities. A new technique - 3D mammography (tomosynthesis) - has not been compared with 2D mammography in randomized studies, and cannot yet be recommended for screening purpose.
The results are given taking in account the BI-RADS system (Breast Imaging Reporting and Database System(13,14).
Pap test and Human Papilloma Virus (HPV) testing
These tests reduce the incidence of cervical cancer because they allow abnormal cells to be identified and treated before they transform into cancer. They also help reduce death from the disease. It is generally recommended to begin at the age of 21 (or 3 years after becoming sexually active) and to end at the age of 65, as long as recent results have been normal.
Almost all cases of cervical cancer are caused by infection with oncogenic/high risk types of HPV (Human Papilloma Virus). There are 12 high-risk HPV types, most cancers being linked to subtypes 16 and 18. Although the infection is very common, in most cases the immune system will suppress it in 1 to 2 years; but if the infections persists, the cellular changes can evolve to precancerous lesions, which finally turn into cancer. The process can take from 10 to 20 years.
The tests available are cytology-based screening, known as the Pap test or Pap smear, and HPV testing (by identifying DNA or RNA of HPV strains).
Results from Pap tests are reported using the Bethesda System. If results show severe abnormalities, further tests are needed (like colposcopy).
A newer version of Pap test (liquid based one) offers the advantage of simultaneous testing for HPV from same specimen. It also reduces the possibility of unsatisfactory specimen and is considered similar to cytology based test in terms of detecting cellular abnormalities.
Women with certain risk factors may need to have more frequent screening or to continue screening beyond the age of 65. These risk factors include being infected with the human immunodeficiency virus (HIV), being immunosuppressed, having been exposed to diethylstilbestrol before birth, and having been treated for a precancerous cervical lesion or cervical cancer.
Women who have had a hysterectomy (surgery to remove the uterus and cervix) do not need to have cervical screening, unless the hysterectomy was done to treat a precancerous cervical lesion or cervical cancer.
For women aged 30 and older, Pap and HPV co-testing is less likely to miss an abnormality than Pap testing alone. A good option in this case, sustained by clinical trials, is to lengthen the screening interval to 5 years, still allowing the detection and treatment in time.
The ATHENA trial, which included 47,000 women, showed that HPV testing performed better than Pap testing at identifying women at risk of developing high risk cervical cell abnormalities.
Other studies also confirm this hypothesis. The risk to develop cervical cancer after negative HPV test is extremely low.
The testing alone is regarded as a future direction in screening for cervical cancer, and is expected to be implemented soon in practice guidelines(15,16,17).
Also, vaccines for HPV are giving good results and should be encouraged before becoming sexually active(18).
Other screening tests - can be used in certain high risk situations, in selected patients
The test is often done in association with a digital rectal exam, and it was thought to be able to detect cancer at an early stage. Expert groups no longer recommend routine testing for most men because trials have shown little to no effect on prostate cancer death and the screening can lead to overdiagnosis and overtreatment(19)
Clinical breast exams and regular breast self-exams
Routine examination done by women themselves or by doctors wasn’t proven to reduce death from breast cancer. If a woman or her doctor notices a lump, unusual discharge or other modification in the breast, it is important to have additional tests. The best moment for breast exam is 5 days after the end of the period.
This test is used in women who carry a mutation in the BRCA (1 and 2) genes, who are at high risk of developing breast cancer (40-80% chance of developing it), ovarian cancer and other types of cancer(20).
Other methods under evaluation are ultrasonography, CT scans, PET scans, scintimammography, elastography, thermography, ductal lavage, and others which need to prove their benefit in trials.
The use of mammography is limited to advanced age, as there are evidence suggesting that BRCA carriers are more susceptible to breast cancer induction by X-ray damage(21).
This test is sometimes used to explore a woman`s ovaries and uterus, especially in those with high risk (BRCA 1 and 2 carriers for ovarian cancer and Lynch syndrome for endometrial cancer). It has not been shown to reduce deaths from cancer.
Regular examination of skin done by doctor or high risk skin cancer patient patients has not been proven to reduce the risk of dying by skin cancer and may lead to overtreatment. However, people should be aware of changes in their skin, such as the apparition of a new lesion or change in a existing one, and report it to their doctor.
Alpha-fetoprotein blood test
The test is used in selected, high-risk cases (mostly patients with hepatitis B and C, heavy alcohol consumption, cirrhosis, exposure to aflatoxins), along with liver ultrasound to try to find liver cancer in early stage.
The test is often done in association with transvaginal ultrasound, and has been tested to be included in screening especially for women with high risk of the disease.
It has not been shown to be an effective screening test. Its best use remains evaluating the recurrence in women previously diagnosed with the cancerous disease(22).
Although many methods of screening have been tested and several are still under evaluation, the ideal test for certain cancer sites is still waited for. A great enthusiasm was seen initially with the apparition of tumor markers (like PSA, CEA, CA 125, CA199) regarding their use in screening - unfortunately not confirmed by clinical trials. The desiderate for an ideal tumor marker for every site, available for testing on blood samples of healthy persons, still remains an idea not yet feasible. Also, more precise, with low-radiation dose and accessible imagistic studies, that allow detection of cancer or its precursors in early stage, are urgently needed.
That is why, using medically proven forms of primary prevention (like education and vaccines) and secondary prevention (screening), in well organized national health strategies, along with investigating new accessible methods for testing, should be our major interest and concern. n