#91993: Cancer Screening

Patient-related factors have included race/ethnicity, attitude toward screening, obesity, education level, income level, level of trust, access to health care, and availability of health insurance [7,12,14,20,21,22,23,24]. Lack of healthcare professional recommendation has also been a barrier noted by patients, with one meta-analysis showing that it was the most often cited barrier [25,26]. This finding highlights the importance of clinicians enhancing their adherence to guidelines and recommending appropriate screening to their patients.

Among healthcare professional-related factors, age and gender, practice type, specialty area, attitude about screening guidelines or the recommending organization, patient concerns or preferences for screening, perception of patient risk, concern about medical-legal risk, and reimbursement and payment issues have been associated with adherence to appropriate screening [11,15,16,19,21,27,28,29,30,31,32,33,34]. As noted, many clinicians do not understand the accurate definition of effective cancer screening, which can also influence recommendations.

Adherence to guideline recommendations is also lacking in terms of patient-clinician discussion about options for screening modalities and the benefits and harms of screening. For example, many primary care providers do not discuss all colorectal screening options with their patients [35]. Also, although guidelines for prostate cancer screening emphasize informed decision making, most men have reported that they had no shared decision making [28,36].

Determining Patient Risk

An issue further complicating decision making about cancer screening is the difference in recommendations for the general (average-risk) population and for people at high risk because of a variety of factors (e.g., age, comorbidities, genetic testing, previous cancer). Many healthcare professionals are not only unfamiliar with the recommendations for high-risk patients but also have difficulty identifying patients who are at high risk. Some surveys have found that physicians recommended cancer screening because they estimated their patient's risk as being high [15,28]. In contrast, other studies have shown that healthcare providers did not offer appropriate screening to their patients who are at high risk because of a comorbidity or family history [31,33]. Both healthcare professionals and patients have been reported to be unfamiliar with screening guidelines for survivors of childhood cancer, who may be at high risk for certain cancers in adulthood [29,30].

Changing or Conflicting Guidelines

Cancer screening guidelines are updated frequently as compelling evidence emerges. Although updated guidelines are heavily promoted to clinicians, especially primary care providers, remaining up to date on specific screening criteria is difficult. In addition, most types of cancer have multiple guidelines, and although these guidelines are in general agreement, areas of disagreement may exist. Areas of discrepancy add to the challenge of decision making for clinicians as well as patients [19]. Together, changing and conflicting guidelines, as well as lack of knowledge about definitions of high risk, contribute substantially to suboptimal rates of adherence to screening guidelines [13,14,15,17,27,37,38,39,40].

As noted, financial issues that affect access to care are a primary system-related barrier to cancer screening [23,41,42,43]. A source of usual care is an important factor in cancer screening rates, with lower screening rates for people who lack a usual source of care. In the case of colorectal cancer screening, the screening rate is approximately 21% for people who do not have a usual source of care compared with 62% for people who do. The corresponding rates are approximately 36% and 75% for breast cancer screening and 65% and 86% for cervical cancer screening [20]. Cancer screening rates are also much lower for people with no health insurance than for people with insurance [44]. In fact, screening rates for individuals who have insurance or a usual source of care are higher than the overall screening rates, highlighting the role of these two factors in improving cancer screening rates (Table 5).

The impact of screening on mortality rates is the issue that generates the most controversy about appropriate cancer screening. Since the 1990s, the number of cancers diagnosed at later stages has decreased substantially [45]. Although regular cancer screening is likely to have contributed to this decline, the effect is not always clear. One exception is colorectal cancer screening, which has been shown to be associated with reduced colorectal cancer-specific mortality [46,47]. Another is lung cancer screening, which resulted in declines for advanced-stage diagnoses after the USPSTF first recommended lung cancer screening in 2013 [45]. Data are conflicting for other cancers. Guidelines for prostate cancer screening with prostate-specific antigen (PSA) were updated in 2012 when evidence showed little benefit in reduction of mortality among the general male population [48]. The guidelines were updated again in 2018 based on additional evidence that continues to demonstrate potential harms of PSA-based screening, including false-positives, biopsy complications, overdiagnosis, psychological harms, and harms of treatment [49]. Most recently, low-dose spiral computed tomography (LDCT) was recommended for lung cancer screening based on the findings of the National Lung Screening Trial (NLST), in which LDCT decreased the relative risk of lung cancer-specific death compared with chest x-ray alone [50]. Evidence in support of LDCT for high-risk individuals has strengthened in recent years, including a reported 39% reduction in lung cancer mortality compared with no intervention among current or former smokers with a more than 20 pack-year smoking history [45]. As a result, in 2021 the USPSTF issued an updated recommendation that expanded eligibility for adults with a 30 pack-year smoking history to include those with a 20 pack-year history [45,51]. Conflicting results of mortality reduction have led researchers to scrutinize the benefits and harms of cancer screening and to consider the populations who would benefit the most from screening.

Overdiagnosis is perhaps the most important harm associated with cancer screening, as it can have long-term effects on physical and emotional health [52]. Cancer overdiagnosis is defined as the diagnosis of a cancer that would otherwise not subsequently cause symptoms or death because of either lack of progression, slow growth, or even regression[52]. Overdiagnosis is distinct from a high rate of false-positive results, as overdiagnosis refers to a tumor that meets the pathologic criteria for cancer, whereas false-positive results do not[52].

Overdiagnosis is determined by analyzing long-term data from screening trials and population-based rates of cancer incidence and cancer-related mortality. In screening trials, the number of cancers in a screened group is initially higher than in an unscreened group because of the early detection that screening offers. However, over time, the number of cancers in an unscreened group is expected to increase and become similar to that in a screened group, as more cancers become clinically evident as they progress[52]. Thus, overdiagnosis is represented by an excess of cancers in a screened group years after a screening trial has been completed[52]. With population-based data, overdiagnosis is determined by comparing the rate of new diagnoses with the rate of mortality; if the mortality rate does not increase over time as the incidence increases, overdiagnosis is the most likely reason. For example, a review of 30-year data on incidence and mortality from the Surveillance, Epidemiology, and End Results (SEER) database showed that the rates of diagnosis for five cancers increased, but the mortality rates did not (Figure 1) [52]. The increase in the rates of new diagnoses was associated with an increased uptake of screening or greater use of imaging to detect cancers. Decreasing mortality rates for breast and prostate cancer may be the result of improvements in treatment, as well as increased screening, but evidence from randomized controlled trials support an effect of overdiagnosis. Few improved treatments have been put into practice for thyroid or kidney cancer or melanoma (during the time of the data), which means the gap in new diagnoses and mortality is most likely related to overdiagnosis[52].

RATE OF NEW DIAGNOSES AND DEATH IN FIVE CANCERS IN THE SURVEILLANCE, EPIDEMIOLOGY AND END RESULTS DATA FROM 1975 TO 2005

Figure 1

Source :Reprinted, with permission, from Welch H, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010;102(9):605-613.

Overdiagnosis has been associated most often with breast, prostate, and lung cancer. There is little evidence of overdiagnosis with screening for either cervical or colorectal cancer (with conventional methods), because the rate of diagnosis of both cancers is decreasing [52].

The age at which cancer screening may be stopped has been debated for many cancers, and a lack of clear guidance on an ending age in some guidelines has an impact on clinicians' decision making [53]. In addition, multiple screening guidelines for the same type of cancer may recommend different age cutoffs [53,54]. For example, at one time, three organizations recommended three different ending ages for mammography, and a fourth organization specified no age limit [54]. An important reason for the lack of clarity about ending ages is that people older than 75 years of age have been excluded from most trials of cancer screening tests, and extrapolating data on a younger population to an older one is difficult [54].

Some expert panels have noted that the presence of comorbidities and life expectancy are better determinants of an ending age than a chronologic age. Consideration of comorbidities addresses the diversity in health status within the older population [53]. Determining life expectancy is important because the weight of benefit versus harm is distinct in the older population. Older adults are unlikely to benefit from cancer screening if they have a life expectancy of less than five years. In a meta-analysis of survival data from nine randomized controlled trials around the world, survival curves for people screened for breast and colorectal screening did not separate significantly until more than 5 to 10 years after the start of screening [55]. The authors concluded that screening for these two types of cancer is most appropriate for people with a life expectancy of more than 10 years.

In contrast, the potential harms associated with screening are immediate, and the risk for harm is greater among older people. Among the greatest harms is the detection and treatment of a cancer that would not have become clinically significant within an older person's remaining lifetime [54]. Other potential harms include complications related to diagnostic tests and psychologic distress related to false-positive results or anxiety related to the screening test itself or to a cancer diagnosis [54]. These harms may be greater in the older population, as tests and follow-up procedures may be more difficult, painful, or frightening in people with cognitive or sensory problems [54].

The National Comprehensive Cancer Network (NCCN) and the Society of Breast Imaging/American College of Radiology (SBI/ACR) recommend screening mammography beginning at 40 years of age for women with average risk for the disease and no symptoms [56,58]. The American College of Physicians (ACP) and the American College of Obstetrics and Gynecology (ACOG) determined that clinicians should discuss the potential benefits and harms of screening mammography with women 40 to 49 years of age and base decisions about screening on these benefits and harms, as well as on a woman's preferences and breast cancer risk profile [57,60]. Physicians should order biennial mammography screening if an informed woman requests it.

The USPSTF had also recommended a starting age of 40 years, but in 2009 (and reaffirmed in 2016), the Task Force changed the recommended starting age to 50 years, stating that the absolute reduction in breast cancer-related mortality is greater for women 50 to 74 years of age than for women 30 to 49 years of age [59]. The USPSTF noted that, according to pooled breast cancer mortality data, 1,904 women 39 to 49 years of age must be screened in order to prevent one breast cancer death; that number decreased to 1,339 for women 50 to 59 years of age, and 377 to women 60 to 69 years of age [59]. The Task Force also reported age-specific screening results from the Breast Cancer Surveillance Consortium (BCSC). These data show that the following number of women in each age-group would need to have mammography to diagnose one case of breast cancer [59]:

For women younger than 50 years of age, the USPSTF guideline echoes the ACP statement, noting that the decision is an individual one and should be based on a woman's values regarding the benefits and risks [59].

Despite the USPSTF recommendation of 50 years as a starting age, some experts continue to advocate the younger starting age of 40 years [56,58]. In its guideline, the ACOG notes that, although the incidence of breast cancer is lower among women in their 40s, the sojourn time (i.e., time between mammographic detection of a small breast cancer and the time the cancer is large enough to be symptomatic) is short in this age-group (about two years) [57]. As such, the window of opportunity to detect early-stage cancer is smaller, and more frequent screening for this age-group should be considered.

To evaluate the impact of the higher starting age recommended by the USPSTF, researchers reviewed screening mammographies at a single institution between 2014 and 2016 and found that women 40 to 49 years of age accounted for approximately 33% of all screened women and for about 18.8% of the screen-detected cancers, half of which were invasive [62]. The authors suggested that these findings support the American College of Radiology recommendation for annual screening mammography beginning at 40 years of age [62].

In a review of invasive breast cancers diagnosed between 1990 and 1999 and followed up through 2007, investigators found that 29% of 609 confirmed breast cancer-related deaths were among women who had been screened, and 71% were among women who had never been screened or who had been screened more than two years previously [63]. The median age at the time of diagnosis of the fatal cancers was 49 years. The authors encouraged initiation of regular screening before 50 years of age.

A modeling study found that biennial screening for women 50 to 69 years of age would reduce mortality by 15%, averting approximately five breast cancer-related deaths per 1,000 women [64]. Lowering the starting age to 40 years would change the mortality decrease to 16% and avert one more breast cancer-related death per 1,000 women. With regard to annual screening, mortality would be reduced 20% for women 50 to 69 years of age (averting approximately eight deaths per 1,000 women) and 22% for women 40 to 69 years of age (averting approximately seven deaths per 1,000 women) [64].

The U.S. Preventive Services Task Force concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women 75 years of age or older.

(https://www.uspreventiveservicestaskforce.org/uspstf/document/RecommendationStatementFinal/breast-cancer-screening Last Accessed: January 13, 2023)

Strength of Recommendation: I (Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.)

The USPSTF recommends screening mammography until 74 years of age and concluded that there was insufficient evidence to assess the benefits and harms of screening mammography for women 75 years of age and older [59]. The SBI/ACR expert panel notes that screening should be stopped when the life expectancy is less than five to seven years (on the basis of age or comorbidities) or when abnormal results would not prompt action because of age or comorbidities [58]. Similarly, the ACS recommends that screening continue for patients "as long as their overall health is good and they have a life expectancy of 10 years or longer" [42]. The ACOG guideline states that there is no consensus on the age limit for screening mammography but notes that the benefits of screening decrease with increasing age compared with the harms associated with overtreatment [57]. The guideline recommends that physicians discuss the continuation of screening with their female patients older than 75 years of age. The NCCN guideline does not specify an ending age, noting that the high incidence of breast cancer in older women merits continued screening. The guideline also notes that screening recommendations be tailored according to an individual woman's health status, with screening not recommended for women who have severe comorbidities and limited life expectancy [56].

The NCCN and the SBI/ACR recommend that screening be done every year for women 40 years of age and older; the USPSTF recommends screening every two years for women 50 years of age and older; and ACS recommends screening every year for women 45 to 54 years of age, and every other year beginning at 55 years of age [56,57,58,59,61]. The ACP and the ACOG recommend individualized risk assessment and discussion of screening harms and benefits as well as the woman's preferences; biennial screening is recommended beginning at 50 years of age [57,60].

Using modeling, Mandelblatt et al. evaluated the effects of different schedules of mammography screening and found that screening every two years achieves most of the benefit of annual screening but with less harm [64]. Specifically, screening every two years retained an average of 81% of the benefit of annual screening with about half the number of false-positive results.

Although the ACOG recommends a range (one to two years) for the screening interval, the guideline notes that annual mammography offers the best chance for early detection and treatment. The ACOG bases its recommendation for the screening interval primarily on the sojourn time. The greatest predictor of sojourn time is age, with the shortest average sojourn time (2 to 2.4 years) associated with an age of 40 to 49 years; the longest average sojourn time (4 to 4.1 years) is associated with an age of 70 to 74 years [57].

Preliminary findings from a retrospective review of data on 300 women with screen-detected breast cancers provide further support for more frequent screening. The investigators divided the women according to screening interval (less than 1.5 years, 1.5 to 3 years, and more than 3 years) [65]. After controlling for age, breast density, high-risk status, and family history of breast cancer, the authors found that the rate of positive lymph nodes was significantly higher in the groups with the longer intervals (8.7%, 20.5%, and 15.4%, respectively).

Digital mammography has nearly entirely replaced film mammography in the United States and is the screening method recommended in all guidelines [56,57,58,59,60,61]. Meta-analyses of large randomized trials have shown that the detection rate is slightly higher for digital mammography compared with film mammography. However, data on the benefit of digital mammography have been conflicting. In one meta-analysis, the higher detection rate was found primarily among women 60 years of age and older, whereas in another, the detection rate was higher among women younger than 50 years of age [66,67]. The NCCN notes that digital mammography appears to most benefit young women and women with dense breasts [56].

The USPSTF concluded that the current evidence is insufficient to assess the additional benefits and harms of either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as the recommended screening method [59]. Similarly, the ACP recommends additional research on the benefits and harms of other screening modalities [60].

Some studies have supported the use of ultrasound as an adjunct to mammography for women with dense breast tissue. However, no organization recommends ultrasound in this context. The SBI/ACR guideline states that ultrasound may be considered as an adjunct to mammography for women with dense breast tissue, whereas the ACR Appropriateness Criteria notes that, although ultrasound may enhance cancer detection in women with dense breast tissue, such screening is associated with a high rate of false-positive results and is time-consuming [58,68]. The NCCN notes that there is insufficient evidence to support the routine use of ultrasound as adjunct screening for women with dense breast tissue and no other risk factors [56]. A systematic review found no sound evidence to support the routine use of breast ultrasound as an adjunct to mammography for screening women at average risk [69].

Clinical Breast Examination

Clinical breast examination has been shown to add incremental value to screening mammography, which can miss 10% to 15% of palpable masses [70]. However, the effectiveness of clinical breast examination is limited; in a large study of women 40 years of age or older, the sensitivity of clinical breast examination for detection of cancer was 58.8% and the specificity was 93.4% [71]. In addition, the rate of false-positive screening results is higher with the combination of mammography and clinical breast examination than with mammography alone.

The NCCN recommends that women 40 years of age and older should have an annual clinical breast examination [56]. The USPSTF notes that there is insufficient evidence to assess the additional benefits and harms of clinical breast examination beyond screening mammography for women in this age-group [59].

With regard to younger women, the ACOG recommends clinical breast examination every one to three years for women 20 to 39 years of age, and the NCCN recommends this examination every one to three years for women 25 to 39 years of age [56,57]. The USPSTF concluded that the evidence is insufficient to assess the additional benefits and harms of clinical breast examination (in addition to screening mammography) for women 40 years of age or older [59].

Breast Self-Examination

The term "breast self-examination" has been replaced by the concept of "breast self-awareness," which describes a woman's understanding of the normal appearance and feel of her breasts. No time interval is associated with breast self-awareness, as it had been with self-examination, but the goal is for women to pay attention to any change and report it to her clinician. The USPSTF, the ACOG, and the NCCN have embraced the use of this newer concept [56,57,59]. The ACOG endorses educating women about breast self-awareness beginning at 20 years of age. These organizations all note that women may continue with traditional monthly self-examinations if they wish, but the USPSTF has recommended against clinicians teaching breast self-examination [59]. The ACS specifically recommends against breast self-examination [61].

The age at which screening should start varies according to the high-risk feature (Table 7) [56,58,61,79]. In general, the NCCN and the ACS recommend a starting age of 30 years, with the SBI/ACR guideline stating that screening for high-risk women should begin by 30 years of age but not before 25 years of age[58,61,79].

As with screening for average-risk women, mammography is the primary method for breast cancer screening. Other imaging modalities, such as ultrasound and contrast-enhanced MRI, have been evaluated as adjuncts to mammography for women at intermediate or high risk. Ultrasound plus mammography in this setting has improved the detection rate compared with mammography alone; however, it is also associated with a low positive predictive value, an increased biopsy rate, and substantial physician time [86,87]. Similarly, the combination of mammography with either ultrasound or MRI has resulted in a higher cancer detection yield among high-risk women but also an increase in false-positive findings [88]. The findings of a systematic review (11 nonrandomized studies) suggested that screening with both MRI and mammography may rule out breast cancer lesions better than mammography alone among women who are known or likely to have an inherited predisposition for breast cancer [89]. The NCCN recommends the combination of mammography and MRI for this population, and the SBI/ACR guideline adds that ultrasound of the breast can be used for women who cannot have MRI [56,58,79].

The intervals for imaging and clinical breast examination also vary according to the high-risk feature [56,58,79]. In general, imaging is recommended annually, and clinical breast examination is recommended every 6 to 12 months.

Among the benefits of breast cancer screening is a greater likelihood of detecting cancer at an early stage. An analysis of 30-year data on screening mammography in the United States demonstrated that screening was associated with an absolute increase of 122 cases of early-stage breast cancer per 100,000 women [90]. Some experts have proposed that early detection is not as important as it once was because of advances in breast cancer treatment, especially adjuvant therapy; however, analysis of this issue has shown that overall survival is considerably better for node-negative disease compared with later stages, supporting the value of early detection [91]. Early detection also means a greater range of treatment options, many of which are less aggressive than those needed for later stage cancers [42].

Breast cancer screening has been widely encouraged as essential for the early detection of cancer and promoted as "saving lives." But the issue of decreased mortality as a result of early detection with screening has been debated.

Some studies of population-based mammography screening in England have shown no significant effect of screening on mortality [92,93]. A review of the effectiveness of the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) on mortality rates from 1990 to 2004 found that the screening rate was significantly associated with a decrease in mortality within the same year; however, changes in the screening rate were not related to breast cancer-related mortality in subsequent years [94].

A meta-analysis done as part of the USPSTF literature review showed that reductions in mortality differ among age-groups. Screening with mammography reduced breast cancer-related mortality by 15% for women 39 to 49 years of age, by 14% for women 50 to 59 years of age, and by 32% for women 60 to 69 years of age [95]. Investigators conducting a Cochrane review also found that screening was associated with a significant reduction in mortality but that screening had no effect on mortality when only trials with adequate randomization were considered [96]. These authors estimated that screening reduced mortality by approximately 15%, but with an absolute reduction of about 0.05% per year for a woman of average risk [96]. The Cochrane review excluded observational studies, which have shown a positive effect of mammography [70].

In a review on the issue of the effect of screening on mortality, investigators noted that in the four most recent high-profile reviews (USPSTF analysis, Cochrane review, UK Independent Review, and EUROSCREEN), the reduction in mortality ranged from 14% to 48% [91]. These reductions translated to a range in the number needed to screen (or invite to screen) of 111 to 2,000 to prevent one breast cancer-related death. In an effort to explain the wide range, the authors analyzed the data from the perspective of only one scenario (as defined in the UK Independent Review) and found a narrower range, from 64 to 257, in the number needed to screen (or invite to screen) to prevent one breast cancer-related death [91].

The review of 30-year data on mammography screening in the United States demonstrated that since screening began, breast-cancer related mortality among women 40 years of age and older has decreased 28% (from 71 to 51 deaths per 100,000 women) [90]. The degree of this decrease that can be attributed to screening is unclear. As noted, screening reduces mortality by increasing the number of breast cancers detected at an early stage, with a concomitant decrease in the number of breast cancers detected at a late stage. The 30-year data, however, demonstrated that the absolute increase in early-stage breast cancer (122 cases per 100,000 women) was accompanied by an absolute decrease of eight late-stage cancers per 100,000 women [90].

These findings reflect an important issue in determining the effect of screening on mortality: the role of improved treatments in decreasing mortality. Modeling studies have found a wide range for the effect that can be attributed to screening—ranging from 28% to 65% [97]. However, the 30-year data suggest that the effect of screening is at the low end of that range [90]. These data also showed a greater decrease in mortality among women younger than 40 years of age (who were not routinely screened) than among women 40 years of age and older (42% compared with 28%). This difference further supports a greater effect of improved treatment rather than screening. In a Norwegian study, the effect of screening was calculated to be approximately 33% [98]. The WHO notes that breast cancer screening reduces mortality 20% to 30%, but only in women 50 years of age or older who live in high-income countries where screening coverage is more than 70% [99].

The harms associated with screening mammography include false-positive and false-negative results, the potential need for additional procedures, and overdiagnosis. The safety of mammography in terms of exposure to radiation has been evaluated, and the risk is considered to be moderate and not enough to deter women older than 40 years of age from being screened [100]. The risk associated with radiation exposure is also offset by the benefits of screening [70].

False-Positive and False-Negative Results

Studies have shown that the cumulative risk for a false-positive result after 10 mammograms is 21% to 50% [95,101]. Analysis of data from the BCSC demonstrates that the rate of false-positive results varies according to age, with the highest rate (within one screening round) found among women 40 to 49 years of age (97.8 per 1,000 screened) and the lowest rate found among women 80 to 89 years of age (59.4 per 1,000 screened) [95]. False-positive results are associated with medical, psychologic, and financial effects related to follow-up tests. Among women screened annually between 40 and 69 years of age, two or more abnormal test results will occur and an unnecessary biopsy will be done in approximately 16% of women [95,101]. Complications may occur as a result of these procedures, especially in older women or women in poor health [101]. The anxiety associated with false-positive results is also an important consideration. In a meta-analysis of European studies, a false-positive result caused breast cancer-specific psychologic distress that lasted for as long as three years and was associated with a likelihood of not returning for the next appropriate screening mammography [102].

The BCSC data demonstrate that the rate of false-negative results is low and also varies according to age, with the lowest rate found among women 40 to 49 years of age (1.0 per 1,000 screened) and the highest rate found among women 70 to 79 years of age (1.5 per 1,000 screened) [95]. False-negative results may provide false reassurance to women (and their healthcare providers) about the lack of breast cancer as well as delay necessary treatment.

Potential Need for Additional Procedures

Mammographic findings also commonly lead to additional procedures. Additional imaging is done in 56.3 to 84.3 women per 1,000 screened, with the highest rate among women 40 to 49 years of age [95]. The rate of biopsy is lower, ranging from 12.2 per 1,000 screened for women 70 to 79 years of age to 9.3 per 1,000 screened for women 40 to 49 years of age. An estimated 47 women per 1,000 screened 40 to 49 years of age will have additional imaging to diagnose one case of invasive breast cancer, and an estimated five women per 1,000 screened of the same age will have a biopsy to diagnose one case of invasive breast cancer [95]. These numbers are lower for other age-groups, ranging from eight to 22 per 1,000 screened for additional imaging and 1.5 to three per 1,000 screened for biopsy [95].

Overdiagnosis

According to data from randomized trials, the magnitude of overdiagnosis in breast cancer (detected by mammography) is estimated to be 10% to 25%, although the USPSTF notes that no data are specific for U.S. trial samples and reports a much lower rate of overdiagnosis of less than 1% to 10% [95,101]. Many of these overdiagnosed cancers are ductal carcinoma in situ [42,101]. The 30-year data on breast cancer screening in the United States indicate that breast cancer was overdiagnosed in 1.3 million women; in 2008 alone, breast cancer was overdiagnosed in more than 70,000 women, which represents about 31% of all breast cancers diagnosed [90]. Similarly, the rate of overdiagnosis and overtreatment was estimated to be 30% in the Cochrane meta-analysis [96]. Those authors found higher rates of lumpectomy, mastectomy, and radiation therapy among screened women than among unscreened women and estimated that for every 2,000 women invited for screening throughout 10 years, 10 healthy women will receive unnecessary treatment for an overdiagnosed breast cancer.

The USPSTF and the ACS/ASCCP/ASCP recommend that cervical screening should begin at 21 years of age [105,106]. This age was established because studies showed that screening of women in their teens was associated with few detected cases of cancer and a high number of false-positive test results [107]. Screening is not recommended for women younger than 21 years of age regardless of the age at which sexual activity began or of other risk factors [105].

Both guidelines also note that women who have received the human papillomavirus (HPV) vaccine should continue to have screening [105,106]. Screening is not recommended for women who have had a hysterectomy with removal of the cervix who do not have a history of a high-grade precancerous lesion or of cervical cancer [105,106].

The USPSTF recommends the discontinuation of screening at 65 years of age for women who have had adequate prior screenings and are not otherwise at high risk for cervical cancer, as screening offers little to no benefit for women in this age-group [106]. Adequate prior screening is defined as three consecutive negative cytology results (or two consecutive negative co-testing results) within the past 10 years, with the most recent test occurring within the past 5 years. The recommendation in the ACS/ASCCP/ASCP guideline is similar, with the added note that screening can be discontinued after 65 years of age for women who have no history of cervical intraepithelial neoplasia grade 2 or higher within the past 20 years [105]. In addition, screening should not begin again in older women for any reason, including a new sexual partner.

The U.S. Preventive Services Task Force recommends screening for cervical cancer every three years with cervical cytology alone in women 21 to 29 years of age. For women 30 to 65 years of age, the USPSTF recommends screening every three years with cervical cytology alone, every five years with high-risk human papillomavirus (hrHPV) testing alone, or every five years with hrHPV testing in combination with cytology (cotesting).

(https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/cervical-cancer-screening Last Accessed: January 13, 2023)

Strength of Recommendation: A (Recommends the service based on high certainty that the net benefit is substantial)

Cytology (Papanicolaou [Pap] testing) remains the primary method for cervical cancer screening. Pap test alone is recommended for women 21 to 29 years of age and is acceptable for women 30 to 65 years of age [105]. No clinically important differences have been found between liquid-based cytology and conventional cytology [106]. Since the discovery that persistent HPV infection is integral to the development of cervical cancer, combination testing (co-testing) with cytology and HPV testing has been proposed, and the ACS/ASCCP/ASCP guidelines states a preference of co-testing for women 30 to 65 years of age [105]. The USPSTF notes a comparable ratio of benefits to harms in both methods and does not indicate a preference [106]. The USPSTF recommends HPV testing alone every five years as an alternative to cytology testing [106].

Screening for cervical cancer was long recommended at an interval of every year. However, studies showed that annual testing (by any method) led to few cancers prevented, with an excess of unnecessary procedures and treatments [105]. A modeling study showed that among women 30 to 64 years of age who had negative results on three or more consecutive Pap tests, screening every three years was associated with an average excess risk of cervical cancer of approximately three per 100,000 women compared with annual screening for three years [108].

Both updated guidelines now recommend screening with cytology alone every three years for women 21 to 29 years of age [105,106]. For women 30 to 65 years of age, the screening interval can be lengthened to five years if screening includes HPV testing or the combination of cytology and HPV testing; cytology alone every three years is an acceptable alternative. The ACS emphasizes the new screening interval with the statement, "Women at any age should NOT be screened annually by any screening method" [42].

A positive HPV result with a negative cytology result occurs in approximately 11% of women 30 to 34 years of age and in 2.6% of women 60 to 65 years of age [109]. Direct referral for colposcopy should not be done for women who have a negative cytology result with a positive HPV result [105]. Instead, the ACS/ASCCP/ASCP guideline recommends that repeat co-testing be done in 12 months for women with these results. If either repeat test is positive, colposcopy is recommended; if both tests are negative, routine screening may be resumed [105]. Alternatively, women who have a negative cytology result and a positive HPV result may have HPV genotype-specific testing for HPV16 alone or for HPV16/18. Colposcopy is recommended if either test is positive; if testing results are negative, co-testing should be repeated in 12 months.

The ASCCP also developed consensus guidelines for the management of abnormal results of cervical cancer screening [110]. The recommendations address screening intervals for cytology results of unsatisfactory findings, atypical squamous cells of undetermined significance, and negative findings with an absent or insufficient endocervial/transformation zone (Table 9).

According to the U.S. Multi-Society Task Force of Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy, colorectal cancer screening should begin at 50 years of age in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years.

(https://www.asge.org/docs/default-source/education/practice_guidelines/piis0016510717318059.pdf Last Accessed: January 13, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

Most guidelines recommend beginning colorectal cancer screening at 50 years of age for people at average risk for the disease [115,116,117,118,122]. The 2009 update of the American College of Gastroenterology (ACG) guideline recommends that screening begin at 45 years of age for Black individuals because of the higher incidence of colorectal cancer and related mortality in that population, as well as an earlier average age at the time of diagnosis [116].

Most guidelines do not specify an ending age. The USPSTF recommends that clinicians selectively offer screening for colorectal cancer in adults 76 to 85 years of age, based on individualized assessment, but notes evidence of net benefit of screening all persons in this age group is small [118]. The ACP recommends against screening for people who are older than 75 years of age or who have a life expectancy of fewer than 10 years [117]. The risks associated with colonoscopy increase with age, and decision making on screening for older men and women should be individualized according to the specific benefits and harms for a person [117]. Lee et al. estimated that it took 10.3 years before one colorectal cancer-related death was prevented among 1,000 people screened [55]. The authors suggest that the findings indicate that colorectal cancer screening should be done only for people who have a life expectancy of at least 10 years.

Seven methods for colorectal screening—used alone or in combination—are currently available and recommended (Table 10):

The guideline developed jointly by the ACS, the U.S. Multi-Society Task Force on Colorectal Cancer, and the ACR (ACS/USMSTF/ACR) categorizes these screening options either as methods that detect adenomatous polyps and cancer or that primarily detect cancer [115]. The goals of colorectal cancer screening should be prevention and early detection; thus, screening methods designed to detect adenomatous polyps and cancer should be encouraged [115,122]. The ACS/USMSTF/ACR guideline states that it is the "strong opinion" of each of the three organizations that prevention of colorectal cancer should be the primary goal of screening.

The wide range of screening methods is unique to colorectal cancer, and in general, patients can choose the option that is best for them in terms of access, comfort, and convenience. The risks and benefits of the methods vary, and patient preference should be a factor [115]. The ACG recommends that clinicians establish a "preferred strategy" for colorectal cancer screening, as this approach provides advantages (clinician-patient discussions are easier, and the likelihood that a patient is offered screening is greater) compared with offering several options [116].

Colonoscopy

Colonoscopy is often considered to be the preferred screening method in evidence-based guidelines as well as in clinical practice [116,122,124,125,126]. According to the National Health Interview Survey (NHIS), 61% of adults 50 years of age and older reported having a colonoscopy in the past 10 years (as recommended) [127]. Physician surveys have shown that the number of colonoscopies ordered had increased somewhat or substantially for 73% of respondents [126]. Colonoscopy requires an extensive bowel cleansing preparation and dietary restrictions before the procedure and sedation during the procedure.

Compared with stool-based testing, colonoscopy offers the advantage of visualization and examination of the entire colon as well as removal of polyps in the same procedure. As the standard for colorectal cancer screening, colonoscopy is the screening method that is used to evaluate the efficacy of other screening options. Although colonoscopy offers many benefits compared with the other screening options, it is not fail-safe. Studies have indicated that colonoscopy is associated with a miss rate for cancer of 5% and a miss rate for large adenomas of 6% to 12% [115].

Flexible Sigmoidoscopy

Flexible sigmoidoscopy also allows for visualization of the colon and removal of polyps in one procedure, but only the lower half of the colon can be visualized [122]. In the NCI's Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial, approximately 44% of undetected cancers were related to a limitation of sigmoidoscopy—37% were beyond the area that could be examined with the sigmoidoscope and 7% were attributed to inadequate depth of insertion of the sigmoidoscope [128]. The authors suggested that if colonoscopy had been used instead, an additional 15% to 19% of colorectal cancers may have been detected [128]. Sigmoidoscopy requires less bowel preparation than that for colonoscopy, and the procedure is usually done without sedation. Colonoscopy is required as follow-up if polyps larger than 1 cm are found [122].

Sigmoidoscopy may be done alone or in combination with stool-based testing [115,116,117,122,123]. The use of sigmoidoscopy for screening has been declining. More than half of primary care physicians reported that their sigmoidoscopy volume had decreased somewhat or substantially [126].

Stool-Based Testing

The ACS/USMSTF/ACR guideline notes that the FOBT or FIT used for screening should have at least 50% sensitivity [115]. This guideline also states that patients should perform stool testing at home, adhering to the manufacturer's recommendations on collecting the sample and the number of samples to collect. FOBT on a single specimen collected during a digital rectal examination (DRE) in a healthcare setting is not recommended. Immunochemical tests have been shown to have better sensitivity than guaiac-based tests and are more patient-friendly [115,129,130]. The ACG recommends FIT as a preference over FOBT [116]. FOBTs of lower sensitivity have been associated with reduced mortality related to colorectal cancer, but modeling studies suggest that tests with higher sensitivity are associated with a greater number of life-years gained [123]. FOBT is the second most commonly used screening method (11%) [127].

Another stool-based screening method, fecal DNA testing, has been shown to be accurate, but evidence on a screening interval is lacking. The USPSTF concluded that fecal DNA testing is estimated to provide a reasonable balance of benefit in life-years gained and harms compared with no screening [123]. The NCCN acknowledges that emerging evidence supports the accuracy of FDA-approved fecal DNA testing for screening but does not recommend an optimal interval; every three years is suggested [122]. The ACS/USMSTF/ACR guideline lists fecal DNA testing as an acceptable screening option, and the ACG lists the test as an "alternative" option [115,116].

Stool-based testing may be used alone or in combination with flexible sigmoidoscopy, but the combination was used in less than 1% of colorectal cancer screenings in 2012 [113,115,117,122,124]. Annual stool-based testing should not be done in combination with colonoscopy [122]. Positive results on any stool-based test require follow-up testing with colonoscopy.

CT Colonography

CT colonography is minimally invasive and does not require sedation, but if polyps are noted, a colonoscopy must be done as follow-up [115,122]. Guidelines note that CT colonography is an acceptable screening option [115,116,122,123]. As of 2022, the NCCN has added CT colonography as a primary screening modality for average-risk individuals [122].

Double-Contrast Barium Enema

Only the ACS/USMSTF/ACR guideline includes double-contrast barium enema as an option [115]. The ACG guideline notes that CT colonography replaces double-contrast barium enema as an option [116].

The colorectal cancer screening interval depends on the screening method used and the results of screening. Stool-based tests are recommended annually, with or without flexible sigmoidoscopy every five years (regardless of the findings) 115; 117; 122]. Colonoscopy should be done every 10 years; if polyps are found, the procedure should be done every 5 years [115,122]. The recommended interval for CT colonography is five years, and the ACS/USMSTF/ACR recommended interval for double-contrast barium enema is also five years [115,116,117,122].

The results of modeling have shown that colorectal cancer screening among the average-risk population would result in approximately equally effective life-years gained (assuming 100% adherence) with three screening options: colonoscopy every 10 years; high-sensitivity FOBT every year; and flexible sigmoidoscopy every 5 years, with high-sensitivity FOBT every 3 years [123].

In general, screening for high-risk men and women should begin at 40 years of age, or 10 years younger than the age of the youngest affected relative at the time of colorectal cancer diagnosis[116,122]. Screening should begin earlier for individuals with hereditary syndromes, as noted (Table 11) [85,115,116,122]. Colonoscopy is the recommended method for colorectal cancer screening for high-risk adults[116,122].

There is convincing evidence that colorectal screening, with any method, detects cancer at an early stage, detects precursor lesions, and is associated with better outcomes [123,131]. The incidence of colorectal cancer has been decreasing over the past several years, primarily because of increases in screening uptake, which allows for detection and removal of precancerous and early-stage cancerous polyps [45]. Follow-up data from the National Polyp Study showed that removal of polyps led to a 53% reduction in mortality; after a median of 15.8 years of follow-up, there were 12 colorectal cancer-related deaths in the screened group compared with an expected 25.4 deaths in the general population (based on incidence-based colorectal cancer-related mortality in the SEER database) [132].

A retrospective review of data on 354 patients with colorectal cancer in a Veterans Administration hospital showed that colorectal cancer was diagnosed by screening in 34% [133]. Compared with colorectal cancer diagnosed by symptom evaluation, screen-detected cancers were more often found at an earlier stage, were more likely to be treated with a curative-intent procedure, and were associated with better five-year survival rates [133].

In a meta-analysis (nine studies), flexible sigmoidoscopy was associated with a 28% reduction in mortality compared with no screening [131]. Similar reviews have shown that FOBT (either annually or biennially) led to a 14% to 15% reduction in colorectal cancer-related mortality [131,134]. The positive impact of FOBT was supported by the results of long-term follow-up of more than 46,000 people (50 to 80 years of age) in the Minnesota Colon Cancer Control Study [46]. The participants in this study were randomly assigned to usual care (control) or to annual or biennial FOBT. Through 30 years of follow-up, screening reduced colorectal cancer-related mortality by 32% (annual screening) and 22% (biennial screening) compared with no screening. There was no reduction in all-cause mortality. The findings in this population suggest that the effect of screening persists after screening has stopped [135].

Another large, long-term study provides evidence of the effect of endoscopic screening on mortality. In this study, nearly 89,000 participants in the Nurses' Health Study and the Health Professionals Follow-up Study were followed up for more than 22 years. Compared with no endoscopic screening, sigmoidoscopy and colonoscopy were associated with a lower incidence of distal colorectal cancer, and colonoscopy was associated with a modestly lower incidence of proximal colon cancer as well [47]. The total number of colorectal cancers diagnosed was 1,164 in the group that had no screening, 82 in the group that had endoscopic polypectomy, 348 in the group that had sigmoidoscopy, and 221 in the group that had colonoscopy. Multivariate analysis demonstrated that these data represent incidence reductions of 43%, 40%, and 56%, respectively. Both types of endoscopic screening were also associated with lower mortality. The number of deaths in the no-screening group was 349, compared with 73 and 52 in the sigmoidoscopy and colonoscopy groups, respectively. According to multivariate analysis, these data represent mortality reductions of 41% and 68%. An analysis of trends in the incidence of colorectal cancer and related mortality from 2015 to 2019 demonstrated an overall decrease in the incidence of colorectal cancer; however, rising rates of obesity, diabetes, and physical inactivity are believed to be contributing to upward trends of new colorectal cancer cases [136].

Harms are more likely with endoscopic screening than with stool-based testing, but the rates are low. The potential harms of stool-based testing are related primarily to follow-up colonoscopy for positive results [115,123]. Evidence of overdiagnosis with colorectal cancer screening is lacking, as the rate of diagnosis of colorectal cancer has decreased over time, in part because of the detection and treatment of precancerous polyps [52].

One analysis of data on flexible sigmoidoscopy indicates a rate of serious complications of 0.34 per 1,000 procedures, whereas other studies have shown that fewer than one colonic perforation occurs in 20,000 examinations [115,137]. A meta-analysis found that a major complication was reported for 0.08 cases among more than 60,000 flexible sigmoidoscopy screenings and nearly 6,000 follow-up colonoscopies [131]. Colonoscopy is associated with a higher rate of serious complications (e.g., perforations, hemorrhage, diverticulitis, cardiovascular events, severe abdominal pain, and death), with an estimated 2.0 serious complications per 1,000 procedures [137]. Complications related to the sedation required for the procedure may also occur.

The American Society of Clinical Oncology (ASCO), the NCCN, the ACS, and the ACCP, with input from the American Thoracic Society (ATS), collaborated on a literature review on lung cancer screening from which evidence-based guidelines were developed [144]. According to these guidelines, screening is recommended for individuals 55 to 74 years of age who are current or former smokers who have (or had) smoked for at least 30 pack-years and, if a former smoker, who has quit within the past 15 years [144]. Guidelines established individually by these organizations, as well as by the American Lung Association, define high risk similarly [146,147,151,152,153]. In 2020, the NCCN revised its screening recommendations to include individuals 50 years or older with a 20 or more pack-year smoking history [146]. The pack-year threshold was lowered from 30 based on trial data suggesting that lung cancer risk for individuals with a 20–29 pack-year smoking history is similar to that of individuals with a 30 or more pack-year history. The age range was lowered (from 55 to 50) for several reasons, including the observation that approximately 5.6% of lung cancer is diagnosed in patients 45 to 54 years of age. The NCCN felt that these changes would help reduce disparities in LDCT screening for Black patients and to a lesser degree in women [146]. Citing uncertainty about the appropriate duration of screening and the age at which screening is no longer appropriate, as well as reports that approximately 27% of lung cancer is diagnosed in patients 75 to 84 years of age, the NCCN removed an upper age cutoff for lung cancer screening [146]. The NCCN also has not placed a time limit for screening eligibility after smoking cessation, citing that the 15-year restriction is not based on or justified by evidence [146]. In its own guideline, the ATS notes that screening may begin at 50 years of age for individuals who have a 20 pack-year history of smoking and one additional comorbidity that results in a 5% cumulative risk of lung cancer developing over the next five years [154].

Guidelines note that it is crucial for the harms associated with lung cancer screening to be balanced with the benefits [144,146,147,148]. In its review of screening strategies to determine the best balance of benefits and harms, the USPSTF found that an age of 50 to 80 years (with the same defined smoking-related risk factors) was associated with a reasonable balance of benefits and harms [51,148]. In addition, the Task Force found that screening focused on persons with a smoking history of 20 pack-years or more resulted in the lowest number of screening examinations per death averted and thus the least harm in terms of radiation exposure, risk for overdiagnosis, and consequences of false-positive results [51].

Guidelines recommend that screening be offered only in settings that can provide the comprehensive care that was provided to participants in the NLST; such settings must offer multidisciplinary coordinated care along with a comprehensive process for screening, interpretation of screening images, management of the findings, and expert evaluation and treatment of potential cancers [144,145,147,152]. The ACCP also recommends that screening be accompanied by counseling, with a complete discussion of the potential benefits and harms [147]. In addition, it is recommended that healthcare professionals emphasize to their patients the importance of smoking cessation, noting that screening is not a substitute for quitting [144,146,147].

LDCT is the recommended method for lung cancer screening, as it has shown to be associated with higher sensitivity than chest radiography or sputum cytology, either alone or in combination, with LDCT leading to a high percentage (60% to 80%) of lung cancers being detected at stage 1 [148,155,156]. In the NLST, the sensitivity and specificity of LDCT, based on the initial screen, was 93.8% and 73.4%, respectively, compared with 73.5% and 91.3% for chest radiography [50]. In addition, neither chest radiography nor sputum cytology—once or at regular intervals—has been shown to decrease mortality, and thus, neither is recommended for screening [144,147,148,152,157,158]. In a meta-analysis of trials in which different frequencies of chest radiography were compared, frequent screening was associated with an 11% relative increase in lung cancer-related mortality compared with less frequent screening [158]. There was a trend toward lower lung cancer-related mortality with the combination of chest radiography and sputum cytology (compared with chest radiography alone), but the difference was not significant [158].

Although the ACCP noted that the effective frequency or duration of screening has not been determined, guidelines recommend annual screening [51,144,146,147,152]. According to estimates from modeling studies performed by the Cancer Intervention and Surveillance Modeling Network (CISNET), annual screening for the defined high-risk group provided greater benefit in decreasing lung cancer-related mortality than screening every two or three years [148].

The age to start a discussion about screening varies slightly among the guidelines. The earliest age is 45 years (40 years for African-American men), recommended in the NCCN guideline, which suggests measurement of the PSA level beginning at this age and that clinicians talk to patients about the risks and benefits of a baseline DRE [165]. The ACP recommends a discussion for men 50 to 69 years of age, and the American Urological Association strongly recommends shared decision making for men 55 to 69 years of age, as the benefit of screening appears to be greatest for men in this age-group [162,163]. The ACS recommends that the potential benefits and substantial harms of screening be discussed with men who are 50 years of age or older and have a life expectancy of at least 10 years. The USPSTF guideline recommends beginning a discussion that emphasizes shared decision making for men 55 to 69 years of age [49].

For men who elect prostate cancer screening, measurement of the PSA level is the preferred method, with repeat PSA testing based on elevated initial PSA level; DRE should be measured if warranted by elevated an PSA level in a second test [165]. PSA in combination with DRE provides better predictive value than either method alone, but stand-alone DRE should not be performed. The positive predictive value of DRE in men with normal PSA levels is only 4% to 21% [165]. The sensitivity of PSA testing is higher than that of DRE, especially for tumors that are more aggressive [167]. However, the PSA level can vary as a result of several factors (e.g., recent ejaculation, instrumentation, infection, trauma) [165]. For this reason, an elevated PSA level should prompt a repeat test.

The primary benefit of prostate cancer screening is a lower stage and grade of cancer at the time of diagnosis [42,49,167]. However, despite this benefit, an effect of screening on mortality has not been clearly demonstrated. After 13 years of follow-up in the PLCO trial, there was no benefit of annual screening on mortality [168]. A subsequent meta-analysis (five randomized controlled trials) similarly demonstrated no effect of screening on prostate cancer-specific or overall mortality [169]. However, data from the European Randomized Study of Screening for Prostate Cancer demonstrated that screening reduced the risk for prostate cancer death by 7% to 9% per year [170].

Many potential harms have been associated with prostate cancer screening, including a high rate of false-positive results and unnecessary biopsies; overdiagnosis and subsequent overtreatment; and complications [49,162,165,171]. The false-positive rate for the PSA test depends on the PSA threshold used. For example, in Sweden, where a low PSA threshold (3.0 ng/mL) was used to determine a positive test result and men were screened every 2 years, more than 45% of men who participated in all screening rounds had a false-positive result over 10 years of screening [49]. The false-positive rate has been reported to be 80% for a PSA cutoff of 2.5–4.0 ng/mL [163]. False-positive results may lead to psychologic effects as well as unnecessary biopsies or treatments. In addition, prostate biopsies have been associated with a high rate of complications, especially infection [165].

In an effort to enhance the specificity of PSA testing, variations of the PSA test have been developed, including free PSA, PSA density, PSA velocity, and complexed PSA [165]. Each has its benefits and limitations, and the AUA notes that none increases the benefit-harm ratio of screening [162]. Levels of free PSA have been shown to be significantly lower in men with prostate cancer than in men without the disease [165]. The U.S. Food and Drug Administration has approved percent-free PSA for the early detection of prostate cancer in men with PSA levels between 4 and 10 ng/mL [165]. A 25% fPSA cutoff is expected to detect 95% of prostate cancers while preventing 20% of unnecessary biopsies.

PSA density is the result of dividing the PSA level by the volume of the prostate, as measured by transrectal ultrasonography, and a higher result suggests a greater likelihood of prostate cancer [165]. Greater PSA density has correlated with the presence of prostate cancer, as well as with the pathologic stage of the tumor and its aggressiveness and progression after treatment [166]. The use of PSA density has been limited by the lack of precision of total PSA, of measurement of prostate volume, and of the need to carry out transrectal ultrasonography [165]. In addition, PSA density does not offer much benefit compared with other PSA derivatives (notably, percent-free PSA)[165].

PSA velocity is the rate at which a PSA level increases over a period of time, and it has been most helpful for longitudinal monitoring of men younger than 50 years of age who have normal PSA levels and no prostate enlargement [165]. The test is not useful for men with PSA values greater than 10 ng/mL [165]. A high PSA velocity alone should not prompt biopsy but instead aid in decision making [165]. The ratio of complexed PSA to total PSA provides information comparable to the ratio of free to total PSA, and the use of complexed PSA has been approved as a detection aid (in conjunction with DRE) for men 50 years of age or older; however, the test is not widely used in practice [165].

Rates of overdiagnosis with prostate cancer screening have been estimated at 17% to 60%, and 23% to 50% of all screen-detected prostate cancers are overtreated [49,52,171]. In addition, treatment of screening-detected prostate cancers has been associated with such adverse effects as incontinence and erectile dysfunction in 200 to 300 of 1,000 men treated with surgery or radiation therapy and death within one month after prostate cancer surgery in five of 1,000 men [42]. Treatment also has been associated with high rates of complication, ranging from 20% to 50% [48,162].

Researchers continue to investigate ways to make screening more effective. Using a higher PSA threshold for biopsy for older men and less frequent screening for men with low PSA levels are strategies that may reduce the risk of overdiagnosis as well as prostate cancer-related mortality [172].

As with other cancers, most cases of pancreatic cancer are sporadic, with about 10% being related to genetic factors [196]. Several hereditary syndromes are associated with an increased lifetime risk for pancreatic cancer; the highest estimated risk—nearly 40%—is associated with hereditary pancreatitis [194,197]. The lifetime risk of pancreatic cancer is 11% to 36% for individuals with Peutz-Jeghers and 1% to 6% for individuals with Lynch syndrome [196,201]. Familial breast-ovarian cancer syndrome also confers an increased risk for pancreatic cancer, with BRCA1 mutations associated with 2.3-fold to 3.6-fold increased risk and BRCA2 mutations associated with a 3-fold to 10-fold increased risk [194]. Familial atypical multiple mole melanoma, another hereditary syndrome, has been associated with an increased risk for nonmelanoma cancers, including pancreatic cancer. The risk is 13-fold to 22-fold higher in individuals with this syndrome compared with the general population [194].

Familial pancreatic cancer is the occurrence of pancreatic cancer in two or more first-degree relatives in a family that is not associated with a known cancer syndrome. The causative genetic mutation has not been identified [197]. The risk for pancreatic cancer increases with the number of family members affected [196,197].

Some recommendations for pancreatic cancer screening have been established on the basis of consensus. Participants of the Fourth International Symposium of Inherited Diseases of the Pancreas recommended screening for the following populations [195,196]:

The Symposium participants did not reach consensus on a specific screening modality but suggested that endoscopic ultrasound is the preferred modality at many institutions, as it has been found to be the most sensitive and specific screening technique for evaluating the pancreas [195,202]. Consensus also was not reached on the age at which to begin screening or on screening intervals [196]. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography are other options [195]. It is recommended that screening of high-risk individuals be done within research protocols with multidisciplinary teams with expertise in genetics, gastroenterology, radiology, surgery, and pathology [197].

The NCCN recommends screening only after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of pancreatic abnormalities, and uncertainties about the benefits of screening. Magnetic resonance cholangiopancreatography or endoscopic ultrasound is recommended every one to two years beginning at 30 to 35 years of age for individuals with Peutz-Jeghers syndrome [79]. The NCCN recommendations for pancreatic cancer screening for individuals with other hereditary syndromes vary, depending on the pathogenic/likely pathogenic germline variant [79].