Cancer is one of the leading causes of death, next only to heart disease in the United States. Cancer screening is the modality for prevention and early recognition of cancer. As per the CDC (Center for Disease Control and Prevention), new cancer cases that are expected in 2020 will be more than 1.8 million, with 606,520 cancer deaths. Fortunately, some of the cancers, for instance, colon, lung, cervical, breast cancer, can be detected with screening, which helps in delaying or even halting the progression of cancer.
Screening for cancer is a form of secondary prevention wherein the mortality from cancer is reduced with no change in incidence. Due to significant lag time in the malignant transformation; Screening provides an opportunity to detect premalignant lesions, early intervention in the carcinogenic process, and delay the course of cancer. Most of the risk factors for cancer are preventable. Eliminating the use of tobacco products and secondhand smoke exposure, getting vaccinated (HPV-Human Papilloma Virus), avoiding tanning beds, maintaining a healthy weight, staying physically active, avoiding processed or red meat, consuming a healthy diet with a high intake of fruits and vegetable are some of the measures that can substantially decrease a person's lifetime risk of developing or dying from cancer.
Healthy People Initiative (HPI) is a US program that develops and tracks health objectives for the nation. The National Health Interview Survey (NHIS) is a chosen data source for setting and assessing several HPI targets in cancer. The 2015 NHIS findings show that the utilization of cancer screening tests for cervical, colorectal, and breast cancer was below Healthy People 2020 target. In 2015, rates for Pap tests, mammography, colorectal cancer screening were 80%, 70%, and just above 60 %, respectively, whereas the HP 2020 targets are 93% for Pap tests, 81% for mammography, and 70.5 % for colorectal cancer screening.
In this article, we reviewed the four common cancers and the screening guidelines that are followed in the United States.
Breast Cancer Screening Guidelines
In the United States, breast cancer is the most common cancer among women and the second most common cause of cancer death. Female breast cancer incidence was on a declining trend before 2004 but has since increased at an average of 0.4% per year. After an initial decline in the incidence in the early 2000s following cessation of hormone-replacement therapy, the period from 2004 to 2014 showed an increase, which may partially be attributed to the obesity epidemic. Since mammography rates remained unchanged during the same period, the recent rise in incidence cannot be attributed to mammography's increased detection. However, due to breast cancer screening, most of the cases are diagnosed at stage I disease, which has a 5-year survival rate of 100 %. In terms of breast cancer mortality, there was a 39% drop from 1989 to 2015. From 2007, the mortality rate amongst women over 50 continued to decline, and it has stayed steady for those under 50 years of age.
Mammography, MRI breast, DBT (Digital breast tomosynthesis), Ultrasound of breast, and breast self-exam are modalities for breast cancer screening.
As per the USPSTF (the United States Preventive Services Task Force) guidelines, women aged 50 to 74 years are recommended to have biennial screening mammography, whereas, for women aged 40 to 49 years, the decision to screen should be an individual one as the reduction in breast cancer death is smaller than the rate of false-positive results and needless biopsy.This also increases the risk of overdiagnosis and treatment. This is in contrast to the ACS (American Cancer Society) guidelines, which strongly recommend annual mammography beginning at the age of 45. Between the age of 40-44 years, mammography should be offered. ACS also recommends a transition to biennial screening or have the opportunity to continue screening annually in women who are over 55 years. Women should not discontinue screening mammography after the age of 75 as long as their general health is good, and their life expectancy is ten years or longer.
Based on the USPSTF guidelines, mammogram in women aged 75 years or older, there is insufficient evidence to assess the balance of benefit and harm, which is the same in women with negative mammograms due to dense breasts, the use of DBT (Digital breast tomosynthesis), Ultrasound of the breast, MRI breast, and other modalities.
Women with High Risk: As per ACS guidelines published in 2007, annual mammography with MRI for women with increased risk. This group includes women with a known BRCA mutation, women who have not tested but have a first degree relative with a BRCA mutation, or women with a 20% to 25% or higher lifetime risk of breast cancer as predicted by breast cancer risk-estimation models, which include pedigree analysis of first and second-degree relatives on both the paternal and maternal side, those who were treated for Hodgkin disease with chest irradiation under age 30 years, women with Cowden, Li-Fraumeni, and Bannayan-Riley-Ruvalcaba syndromes and their first-degree relatives. Presently, the above ACS guideline for women at increased risk is in the process of updating.
Cervical Cancer Screening Guidelines
In women aged 20 to 39 years, cervical cancer is the second leading cause of cancer death. Cervical cancer was diagnosed in 569,847 women globally, with a mortality of 311,365 women in 2018. Persistent HPV infection is the cause of cervical cancer. As per NHIS 2013 (National Health Interview Survey), approximately 80 % of women in the age group of 21-65 received pap tests in the last three years. HPV vaccine also offers protection against nine types of HPV and hence prevents about 90% of cervical, anal, vulvar, and vaginal cancers. But the rates for vaccination are still low among adolescent girls and boys (37.6% and 13.9% respectively).
The tests for cervical cancer screening are- Pap test, pap test with HPV co-testing, high-risk HPV testing only.
As per USPSTF Guidelines, women aged 21 to 29 years should get cervical cytology every three years (Grade A). In the age group of 30 to 65 years, screening can be continued with cervical cytology alone every three years or with high-risk HPV testing (hrHPV co-testing) every five years or only hrHPV test every five years (Grade A). USPSTF recommends against screening for women less than 21 years of age, in women who have had a hysterectomy with cervix removal and do not have a history of a high-grade precancerous lesion (i.e., cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer and in women older than 65 years if prior screening has been adequate and is not high risk for cervical cancer (Grade D).
As per the joint guideline of ACS, ASCP (American Society of Clinical Pathology ), ASCCP (American Society of Colposcopy and Clinical Pathology), screening recommendation is similar to USPSTF with no screening prior to the age of 21. The guideline recommends that women with Atypical squamous cells of undetermined significance (ASC-US) with negative HPV should get the repeat screening in 3 years. HPV vaccination status does not influence the screening practice. After age 65, screening can be discontinued if women have had 3 consecutive negative cytology tests or 2 consecutive negative co-test results in the last 10 years before discontinuing screening, with the latest test done within the last 5 years. Women with ASC-US and HPV negative results should be considered as negative to discontinue screening. Once screening is ceased, it should not be restarted for any reason, including a woman with a new sexual partner. After spontaneous resolution or pertinent management of cervical intraepithelial neoplasia 2 (CIN2), CIN3, or adenocarcinoma in situ, routine screening should not be discontinued for at least 20 years (even if this extends beyond age 65 years).
Lung cancer is one of the leading causes of death from cancer. In the year 2020, new cases and deaths due to lung cancer in the US are estimated at 228,820 and135,720, respectively.
The National Lung Screening Trial (NLST), published in 2011, is one of the largest multicenter randomized lung cancer screening studies worldwide assessing LDCT (Low Dose lung Computed Tomography) in lung cancer screening. Mortality from lung cancer was the primary endpoint. The conclusion was that lung cancer screening by LDCT reduced mortality by 20 %. NLST was the basis of the USPSTF recommendation. However, there is a concern that NLST included only 4 % of the African American population and did not consider differences in smoking patterns among racial groups.
As per the USPSTF guidelines, adults aged 55 to 80 years who are currently smoking or have a 30 pack-year history of smoking and have quit in the last 15 years are recommended to get annual low dose lung computed tomography (LDCT). Screening discontinued once the person has not smoked for 15 years or has a limited life expectancy or inability to perform curative lung surgery due to health problems.
The recommendation from ACS is similar to the USPSTF recommendation except for the age range of 55 to 74 yr. Like USPSTF recommendation, the patient should have received evidence-based smoking cessation counseling if they are current smokers and have undergone an informed/ shared decision-making process which included information about the potential benefits, harms, and limitations of screening with LDCT and have access to a superior-quality lung carcinoma screening and treatment center.
There have been studies in the past that have shown that if the screening is implemented in the target population as described in the NLST trial, then 12,250 deaths due to lung cancer can be averted.
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. As per the NIH (National Institute of Health) data, it is estimated that new cases of colorectal cancer will be at 147,950, and CRC related death is estimated at 53,200.
The options for CRC screening are annual fecal immunochemical test high-sensitivity, annual guaiac-based fecal occult blood test, multitarget stool DNA test once every three years; colonoscopy every ten years; flexible sigmoidoscopy every five years, and computed tomography colonography every five years.
Guidelines from ACS for colon cancer screening were updated in 2018. In the past 2 decades, colon cancer incidence and mortality have decreased, mainly due to screening practices. Adults with an average risk of CRC aged 45 years and older undergo screening with either a high-sensitivity stool-based test or a structural (visual) examination, based on patient preference and test availability. As part of the screening process, positive screening test results on non-colonoscopy should be followed up with a prompt colonoscopy. ACS strongly recommends that adults aged 50 years and older should begin screening with the method mentioned above. Adults with average risk and good health with a life expectancy of greater than ten years can continue screening for CRC through the age of 75. CRC screening decisions should be individualized in adults aged 76 through 85 years based on patient preferences, health status, life expectancy, and prior screening history. Individuals older than 85 years should be discouraged from continuing CRC screening.
A high-risk patient is a person with a CRC family history or a documented advanced adenoma at age <60 years in a first-degree relative or two first-degree relatives with above findings at any age are recommended to undergo colonoscopy every five years, beginning ten years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed with CRC at ≥60 years or an advanced adenoma can be considered for average-risk screening options at age 40.
Colonoscopy is the gold standard screening tool for CRC. It provides us with an opportunity to detect and resect precancerous and cancerous lesions with data showing adverse events like colonic perforation rate in screening/surveillance colonoscopy was 0.010-0.067% and in diagnostic colonoscopy was 0.022% to 0.268%.
Stool Based Tests
g-FOBT- Detects blood in stool-based on peroxidase activity of heme. It is non-invasive, inexpensive, and used as a screening tool endorsed by the highest quality evidence, randomized controlled trials. The method relies on simple oxidation. Hence, any dietary peroxidases, such as peroxidase in plants, heme from myoglobin in red meat, or any antioxidant, such as vitamin C, can confound the result. The g-FOBT has a very low PPV ( positive predictive value) of 3% to 10%.
FIT- is an antibody to human globin, and hence the cross-reaction to dietary meat is unlikely. It detects colonic blood as upper GI (gastrointestinal) globin is degraded by digestive proteolytic enzymes. Recent systematic review and meta-analysis showed an overall accuracy of FIT for detection of CRC of 95% with a sensitivity of 79% and specificity of 94%.
Stool DNA test- Cologuard® became the first multitarget stool DNA that was approved by the FDA (Food and Drug Administration) in August 2014 for CRC screening. It detects abnormal DNA present in stool in individuals with malignancy. In a study comparing FIT with the stool DNA test, the latter had higher sensitivity but lower specificity and high false-positive rates.
USPSTF recommends starting screening at the age of 50 with a stool-based test ( gFOBT, FIT, and FIT-DNA) or direct visualization test (colonoscopy every 10 years, sigmoidoscopy every 5 years, if done with the annual FIT then every 10 years and CT colonography every 5 years).
A serology test (SEPT 9 DNA) is recently FDA (Food and Drug Administration) approved for CRC screening. However, during a systematic evidence review, there was limited sensitivity to detect CRC of less than 50%. This test has not been included as one of the screening tests for colon cancer.
For patients above 75 years old, the recommendation chimes with the ACS recommendation with a strong recommendation against colonoscopy beyond age 85.
According to USPSTF, there are no head-to-head trials that prove one form of screening is superior to the other. Studies comparing colonoscopy with FIT in reducing mortality from CRC are still underway, like the CONFIRM trial.
USPSTF has not reviewed the evidence on screening high-risk populations.
SEPT 9- This a PCR serology test that detects hypermethylated Septin9 DNA, which is present in the tumor DNA that has been shed into the bloodstream from all intestinal anatomical sites. Epi proColon® (also known as the mSEPT9 assay) became FDA approved in April 2016 for CRC screening. It is the first blood test that has been approved for CRC screening. A prospective multicenter study, Sept9 testing compared with the FIT, showed similar sensitivity (73% vs. 68%) but markedly lower specificity (81% vs. 97 %). But studies have noted that offering a non-invasive test for CRC screening improved compliance with testing; for instance, one study showed 97 % of individuals who declined colonoscopy were willing to do a non-invasive test, of which 83 % was willing to do the SEPT 9 test.
Prostate cancer is the second most frequent cancer (after lung cancer) in men worldwide, with an incidence of 1,276,106 cases and causing 358,989 deaths in 2018. Of note, incidence and mortality rate is higher in African American when compared to white men. Incidence and mortality also increased with increasing age, with the mean age at diagnosis being 66 years.
The current ACS guideline was published in 2010 and states that men with at least a 10-year life expectancy should be provided with an opportunity to consider screening for prostate cancer with serum prostate-specific antigen (PSA), with or without DRE, after making an informed/shared decision with their health care provider provided they receive information about the uncertainties, benefits, and risks correlated with prostate cancer screening and therapy.
Men at higher risk, including those with a family history (father or brother) diagnosed with prostate cancer before age 65 and African American men, should receive information on prostate cancer screening beginning at age 45. Men at considerably higher risk (prostate cancer diagnosed before age 65 years in multiple family members) should receive screening information beginning at age 40. For men who are unable to make a decision, the decision to screen can be left to the discretion of the healthcare provider, who should consider the patient's general health preferences. Asymptomatic men with life expectancy based upon age and health status of less than a 10-years should not be offered to screen for prostate cancer.
For men who choose to be screened for prostate cancer after an informed decision making:
1) The recommendation is to screen using the PSA test along with or without the DRE (DRE is recommended in men with hypogonadism along with PSA due to reduced sensitivity of PSA); 2) interval between screening can be extended to every two years for men whose PSA is less than 2.5 ng/mL, and yearly screening for men whose PSA level is 2.5 ng/mL or higher; and 3) referral recommended for further evaluation or biopsy if PSA level is 4.0 ng/ml or higher in men who are at average risk for prostate cancer. If classes are between 2.5 and 4.0 ng/mL, then risk factors for developing high-grade prostate cancer should be assessed in the individual, and the decision to make a referral for further diagnostic evaluation should be made by the health care provider. Factors that enhance the risk of prostate cancer are African American race, advancing age, family history of prostate cancer, high age-specific PSA level, and abnormal DRE.
A prior negative biopsy lowers risk.
In 2018, updated USPSTF recommendations on screening for prostate cancer was published with the PSA blood test. Based on the review of the evidence of prostate cancer-related issues, the USPSTF deduced that there is a small net benefit of screening for prostate cancer with PSA-based test in men aged 55 to 69 years, and that "the decision should be individualized to undergo periodic PSA based screening after discussion with their clinician of the potential benefits and harms of PSA testing (C recommendation). The USPSTF continues to recommend against prostate cancer screening in men aged 70 years and older with PSA-based test (D recommendation) mainly because false-positive PSA results causes more harm, over-diagnosis, biopsies, and treatment in older men.