Otis W. Brawley and Howard L. Parnes
INTRODUCTION
Cancer screening refers to a test or examination performed on an asymptomatic individual. The goal is not simply to find cancer at an early stage, nor is it to diagnose as many patients with cancer as possible. The goal of cancer screening is to prevent death and suffering from the disease in question through early therapeutic intervention.
The assumption that early detection improves outcomes can be traced back to the concept that cancer inexorably progresses from a small, localized, primary tumor to local–regional spread, to distant metastases and death. This linear model of disease progression predicts that early intervention would reduce cancer mortality.
Cancer screening was an element of the “periodic physical examination,” as espoused by the American Medical Association in the 1920s.1 It consisted of palpation to find a mass or enlarged lymph nodes and auscultation to find a rub or abnormal sound. Today, screening has grown to include radiologic testing, the measurement of serum markers of disease, and even molecular testing. A positive screening test leads to further diagnostic testing, which might lead to a cancer diagnosis.
The intuitive appeal of early detection accounts for the emphasis that has long been placed on screening. However, it is not widely understood that screening tests are always associated with some harm (e.g., anxiety, financial costs) and may actually cause substantial harm (e.g., invasive follow-up diagnostic or therapeutic procedures). Because screening is, by definition, done in healthy people, all early detection tests should be carefully studied and their risk–benefit ratio determined before they are adopted for widespread usage.
Screening is a public health intervention. However, some draw a distinction between screening an individual within the doctor–patient relationship and mass screening, a program aimed at screening a large population. The latter may involve advertising campaigns to encourage people to be screened for a particular cancer at a shopping mall or at a community event, such as state fair.
Screening may be either opportunistic (i.e., a patient sees a health-care provider who chooses to screen or not to screen) or programmatic. Programmatic refers to a standardized approach with algorithms for screening and follow-up as well as recall of patients for regular routine screening with quality control measures. Programmatic screening is usually more effective.
PERFORMANCE CHARACTERISTICS
The degree to which a screening test can discriminate between individuals with and without a particular disease is described by its performance characteristics. These include the a test’s sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) (Table 34.1). It should be noted that these measures relate to the accuracy of a screening test; they do not provide any information regarding a test’s efficacy or effectiveness.
Sensitivity is the proportion of persons designated positive by the screening test among all individuals who have the disease: true positive (TP)/(TP + false negative [FN]).
Specificity is the proportion of persons designated negative by the screening test among all individuals who do not have the disease: true negative TN/(TN + false positive [FP]).
Positive predictive value is the proportion of individuals with a positive screening test who have the disease: (TP)/(TP + FP).
Negative predictive value is the proportion of individuals with a negative screening test who do not have the disease: (TN)/(TN + false negative [FN]).2
For a given screening test, sensitivity and specificity are inversely related. For example, as one lowers the threshold for considering a serum prostate-specific antigen (PSA) level to represent a positive screen, the sensitivity of the test increases and more cancers will be detected. This increased sensitivity comes at the cost of decreased specificity (i.e., more men without cancer will have positive screenings tests and, therefore, will be subjected to unnecessary diagnostic procedures).
Some screening tests, such as mammograms, are more subjective and operator dependent than others. For this reason, the sensitivity and specificity of screening mammography varies among radiologists. For a given radiologist, the lower his or her threshold for considering a mammogram to be suspicious, the higher the sensitivity and lower the specificity will be for them. However, mammography can have both a higher sensitivity and higher specificity in the hands of a more experienced versus a less experienced radiologist.
As opposed to sensitivity and specificity, the PPV and NPV of a screening test are dependent on disease prevalence. PPV is also highly responsive to small increases in specificity. As shown in Table 34.2, given a disease prevalence of 5 cases per 1,000 (0.005), the PPV of a hypothetical screening test increases dramatically as specificity goes from 95% to 99.9%, but only marginally as sensitivity goes from 80% to 95%. Given a disease prevalence of only 1 per 10,000 (0.0001), the PPV of the same test is poor even at high sensitivity and specificity. The positive association between breast cancer prevalence and age is the major reason why screening mammography is a better test (higher PPV) for women aged 50 to 59 than for women 40 to 49 years of age.
ASSESSING SCREENING TESTS AND OUTCOMES
Screening Test Results
Lead time bias occurs whenever screening results in an earlier diagnosis than would have occurred in the absence of screening. Because survival is measured from the time of diagnosis, an earlier diagnosis, by definition, increases survival. Unless an effective intervention is available, lead time bias has no impact on the natural history of a disease and death will occur at the same time it would have in the absence of early detection (Fig. 34.1).
Length bias is a function of the biologic behavior of a cancer. Slower growing, less aggressive cancers are more likely to be detected by a screening test than faster growing cancers, which are more likely to be diagnosed due to the onset of symptoms between scheduled screenings (interval cancers). Length bias has an even greater effect on survival statistics than lead time bias (Fig. 34.2).
Overdiagnosis is an extreme form of length bias and represents pure harm. It refers to the detection of tumors, often through highly sensitive modern imaging modalities and other diagnostic tests, that fulfill the histologic criteria for malignancy but are not biologically destined to harm the patient (see Fig. 34.2).
There are two categories of overdiagnosis: the detection of histologically defined cancers not destined to metastasize or harm the patient, and the detection of cancers not destined to metastasize or cause harm in the life span of the specific patient. The importance of this second category is illustrated by the widespread practice in the United States of screening elderly patients with limited life expectancies, who are thus unlikely to benefit from early cancer diagnosis.
Overdiagnosis occurs with many malignancies, including lung, breast, prostate, renal cell, melanoma, and thyroid cancers.3 Neuroblastoma provides one of the most striking examples of overdiagnosis.4 Urine vanillylmandelic acid (VMA) testing is a highly sensitive screening test for the detection of this pediatric disease. After screening programs in Germany, Japan, and Canada showed marked increases in the incidence of this disease without a concomitant decline in mortality, it was noticed that nearby areas that did not screen had similar death rates with lower incidence.4,5 It is now appreciated that screen-detected neuroblastomas have a very good prognosis with minimal or no treatment. Many actually regress spontaneously.
Stage shift—i.e., a cancer diagnosis at an earlier stage than would have occurred in the absence of screening—is necessary, but not sufficient, for a screening test to be effective in terms of reducing mortality. Both lead time bias and length bias contribute to this phenomenon. Although it is tempting to speculate that diagnosis at an earlier stage must confer benefit, this is not necessarily the case. For example, a substantial proportion of men treated with radical prostatectomy for what appears to be a localized prostate cancer relapse after undergoing surgery. Conversely, some men who are treated with definitive therapy would never have gone on to develop metastatic disease in the absence of treatment.
Selection bias occurs when enrollees in a clinical study differ from the general population. In fact, people who voluntarily participate in clinical trials tend to be healthier than the general population, perhaps due to a greater interest in health and health-care research. Screening studies tend to enroll individuals healthier than the general population. This so-called healthy volunteer effect6,7 can introduce a powerful bias if not adequately controlled for by randomization procedures.
Assessing Screening Outcomes
The usual primary goal of cancer screening is to reduce mortality from the disease in question (a reduction in disease-specific mortality). Screening studies generally do not have sufficient statistical power to assess the impact of screening for a specific malignancy on overall mortality. (Lung cancer screening provides an exception to this rule; see the following.) As discussed previously, the fact that a screening test increases the percentage of people diagnosed with early stage cancer and decreases that of late stage cancer (stage shift) is not equivalent to proof of mortality reduction. Further, due to the healthy volunteer effect, case control and cohort studies cannot provide definitive evidence of mortality benefit. Prospective, randomized clinical trials are required to address this issue. In such trials, volunteers are randomized to be screened or not and are then followed longitudinally to determine if there is a difference in disease-specific or overall mortality.
A reduction in mortality rates or in the risk of death is often stated in terms of relative risk. However, this method of reporting may be misleading. It is preferable to report both the relative and absolute reduction in mortality. For example, the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed that screening reduced the risk of prostate cancer death by 20%. However, this translates into only 1 prostate cancer death averted per 1,000 men screened (5 prostate cancer deaths per 1,000 men not screened versus 4 prostate cancer deaths per 1,000 men screened) and a relatively modest lifetime reduction in the absolute risk of prostate cancer death of only 0.6%, from 3.0% to 2.4%.8
PROBLEMS WITH RANDOMIZED TRIALS
It is important to acknowledge that even prospective, randomized trials can have serious methodologic shortcomings. For example, imbalances caused by flaws in the randomization scheme can prejudice the outcome of a trial. Other flaws include so-called drop-in or contamination, in which some participants on the control arm get the intervention. Patients on the intervention arm may also drop out of the study. Both drop-ins and drop-outs reduce the statistical power of a clinical trial.
In the United States, it is now considered standard to obtain informed consent before randomization takes place. However, there have been several published studies that randomized participants from rosters of eligible subjects such as census lists. In these trials, informed consent was obtained after randomization and only among those randomized to the screening arm of the study. Those randomized to the control arm were not contacted, and indeed, did not know they were in a clinical trial. They were followed through national death registries. Although the study was analyzed on an intent-to-screen basis, this method can still introduce biases. For example, only patients on the intervention arm had access to the screening facility and staff for counseling and treatment if diagnosed; those in the control group were more likely to be treated in the community as opposed to high-volume centers of excellence and were less likely to be treated with surgery and more likely to be treated with hormones alone than those on the screened arm. The study arms would also tend to differ in their knowledge of the disease, which may contribute to an overestimate of the benefits of a screening test.9
Virtually every screening test is a balance between known harms and potential benefits. The most important risk of screening is the detection and subsequent treatment of a cancer that would never have come to clinical detection or harmed the patient in the absence of screening (i.e., overdiagnosis and overtreatment). Treatment can cause emotional and physical morbidity and even death.10 Even when screening has a net mortality benefit, there can be considerable harm. For example, in the recent randomized trial of spiral lung computed tomography (CT) scan, approximately 27,000 current smokers and former smokers were given three annual low-dose CT scans. More than 20% had a positive screening CT scan, necessitating further testing. About 1,000 subsequently underwent invasive diagnostic procedures and 16 deaths were reported within 60 days of the procedure.11 It is not known how many of these deaths were directly related to the screening.
It can be dangerous to extrapolate estimates of benefit from one population to another. In particular, studies showing that a radiographic test is beneficial to average risk individuals may not mean that it is beneficial to a population at high risk, and vice versa. For example, women at high risk for breast cancer due to an inherited mutation of a DNA repair gene may be at higher risk for radiation-induced cancer from mammographies compared to the general population; a screening test (e.g., spiral lung CT scan), shown to be efficacious in a high-risk population of heavy smokers may result in net harm if applied to a low or average risk population.
SCREENING GUIDELINES AND RECOMMENDATIONS
A number of organizations develop cancer screening recommendations or guidelines. These organizations use varying methods. The Institute of Medicine (IOM) has released two reports to establish standards for developing trustworthy clinical practice guidelines and conducting systematic evidence reviews that serve as their basis.12,13 The U.S. Preventive Services Task Force (USPSTF) and the American Cancer Society (ACS) are two organizations that issue respected and widely used cancer guidelines (Table 34.3). Both have changed their methods to comply with the IOM standards.
The USPSTF is a panel of experts in prevention and evidence-based medicine.14 They are primary care providers specializing in internal medicine, pediatrics, family practice, gynecology and obstetrics, nursing, and health behavior. The task force process begins by conducting an extensive structured scientific evidence review. The task force then develops recommendations for primary care clinicians and health-care systems. They adhere to some of the highest standards for recommending a screening test. They are very much concerned with the question, “Does the evidence supporting a screening test demonstrate that the benefits outweigh its harms?”
The ACS guidelines date back to the 1970s. The current process for making guidelines involves commissioning academics to do an independent systematic evidence review. A single generalist group digests the evidence review, listens to public input, and writes the guidelines. The ACS panel tries to clearly articulate the benefits, limitations, and harms associated with a screening test.15
BREAST CANCER
Mammographies, clinical breast examinations (CBE) by a health-care provider, and breast self-examinations (BSE) have long been advocated16 for the early detection of breast cancer. In recent years, ultrasound, magnetic resonance imaging (MRI), and other technologies have been added to the list of proposed screening modalities.
Mammographic screening was first advocated in the 1950s. The Health Insurance Plan (HIP) Study was the first prospective, randomized clinical trial to formally assess its value in reducing death from breast cancer. In this study, started in 1963, about 61,000 women were randomized to three annual mammograms with clinical breast examination versus no screening, which was the standard practice at that time. HIP first reported that mammography reduced breast cancer mortality by 30% at about 10 years after study entry. With 18 years of follow-up, those in the screening arm had a 25% lower breast cancer mortality rate.16
Nine additional prospective randomized studies have been published. These studies provide the basis for the current consensus that screening women 40 to 75 years of age does reduce the relative risk of breast cancer death by 10% to 25%. The 10 studies demonstrate that the risk–benefit ratio is more favorable for women over 50 years of age. Mammography has also been shown to be operator dependent, with better performance characteristics (higher sensitivity and specificity and lower FP rates) reported by high-volume centers (Table 34.4).
It is important to note that every one of these studies has some flaws and limitations. They vary in the questions asked and their findings. The Canadian screening trial suggests mammographies and clinical breast examinations do not decrease risk of death for woman aged 40 to 49 and that mammographies add nothing to CBEs for women age 50 to 59 years.17 On the other extreme, the Kopparberg Sweden study suggests that mammographies are associated with a 32% reduction in the risk of death for women aged 40 to 74 years.18
To date, no study has shown that BSEs decrease mortality. BSEs have been studied in two large randomized trials. In one, approximately 266,000 Chinese women were randomized to receive intensive BSE instruction with reinforcements and reminders compared to a control group receiving no instruction on BSE. At 10 years of follow-up, there was no difference in mortality, but the intervention arm had a significantly higher incidence of benign breast lesions diagnosed and breast biopsies preformed. In the second study, 124,000 Russian women were randomized to monthly BSEs versus no BSEs. There was no difference in mortality rates, despite the BSE group having a higher proportion of early stage tumors and a significant increase in the proportion of cancer patients surviving 15 years after diagnosis.
Ultrasonography is primarily used in the diagnostic evaluation of a breast mass identified by palpation or mammography. There is little evidence to support the use of ultrasound as an initial screening test. This modality is highly operator dependent and time consuming, with a high rate of FP findings.19 An MRI is used for screening women at elevated breast cancer risk due to BRCA1 and BRCA2 mutations, Li-Fraumeni syndrome, Cowden disease, or a very strong family history. MRI is more sensitive but less specific than mammography, leading to a high FP rate and more unnecessary biopsies, especially among young women.20 The impact of MRI breast screening on breast cancer mortality has not yet been determined.
Thermography, an infrared imaging technology, has some advocates as a breast cancer screening modality despite a lack of evidence from several small cohort studies.21 Nipple aspirate cytology and ductal lavage have also been suggested as possible screening methods. Both should be considered experimental at this time.22
Effectiveness of Breast Cancer Screening
Breast cancer screening has been associated with a dramatic rise in breast cancer incidence. At the same time, there has been a dramatic decrease in breast cancer mortality rates. However, in the United States and Europe, incidence-by-stage data show a dramatic increase in the proportion of early stage cancers without a concomitant decrease in the incidence of regional and metastatic cancers.23 These findings are at odds with the clinical trials data and raise questions regarding the extent to which early diagnosis is responsible for declining breast cancer mortality rates.
From 1976 to 2008, the incidence of early-stage breast cancer for American women aged 40 and older increased from 112 to 234 per 100,000. This is a rise of 122 cases per 100,000, whereas the absolute decrease in late-stage cancers was only 8 cases per 100,000 (from 102 to 94 cases per 100,000). These data raise questions regarding the magnitude of benefit, as well as the potential risks, of breast cancer screening. The discrepancy between the magnitude of the increase of early disease and the decrease of late-stage cancer and cancer mortality suggests that a proportion of invasive breast cancers diagnosed by screening represents overdiagnosis. These data suggest that overdiagnosis accounts for up to 31% of all breast cancers diagnosed by screening.24 Others have estimated that up to 50% of breast cancers detected by screening mammography are overdiagnosed cancers. In an exhaustive review of the screening literature, a panel of experts concluded that overdiagnosis does exist and estimated it to be 11% to 19% of breast cancers diagnosed by screening.25
A confounding factor with regard to the mortality benefits of breast cancer screening is the improvement that has occurred in breast cancer treatment over this period of time. The effects of the advances in therapy are supported by cancer modeling studies. Indeed, the Cancer Intervention and Surveillance Modeling Network (CISNET), supported by the U.S. National Cancer Institute (NCI), has estimated that two-thirds of the observed breast cancer mortality reduction is attributable to modern therapy, rather than to screening.26
Questions have also been raised regarding the quality of the randomized screening trials that demonstrated the mortality benefits of mammography and clinical breast examination because these trials suffered from a variety of design flaws. In some, randomization methods were suboptimal, others reported varying numbers of participants over the years, and still others had substantial contamination (drop-ins). Perhaps more importantly, most trials were started and concluded before the widespread use of more advanced mammographic technology, before the modern era of adjuvant therapy, and before the advent of targeted therapy.
Although randomized control trials (RCT) remain the gold standard for assessing the benefits of a clinical intervention, they cannot take into account improvements in both treatment and patient awareness that occurred over time. For this reason, observational and modeling studies can provide important, complementary information.
One systematic review of 17 published population-based and cohort studies compared breast cancer mortality in groups of women aged 50 to 69 years who started breast cancer screening at different times. Although these studies are subject to methodologic limitations, only four suggested that breast cancer screening reduced the relative risk of breast cancer mortality by 33% or more and five suggested no benefit from screening. The review concluded that breast cancer screening likely reduces the risk of breast cancer death by no more than 10%.27
Even with these limitations, a systematic review of the data sponsored by the USPSTF concluded that regular mammography reduces breast cancer mortality in women aged 40 to 74 years.28 The task force also concluded that the benefits of mammography are most significant in women aged 50 to 74 years.
Screening Women Age 40 to 49
Experts disagree about the utility of screening women in their forties. In the HIP Randomized Control Trial, women who entered at age 40 to 49 years had a mortality benefit at 18 years of follow-up. However, to a large extent, the mortality benefit among those aged 45 to 49 years at entry was driven by breast cancers diagnosed after they reached age 50 years.16
Mammography, like all screening tests, is more efficient (higher PPV) for the detection of disease in populations with higher disease prevalence (see Table 34.2). Mammography is, therefore, a better test in women age 50 to 59 years than it is among women age 40 to 49 years because the risk of breast cancer increases with age. Mammography is also less optimal in women age 40 to 49 years compared to women 50 to 59 years of age for the following reasons:
A larger proportion have increased breast density, which can obscure lesions (lower sensitivity).
Younger women are more likely to develop aggressive, fast-growing breast cancers that are diagnosed between regular screening visits. By definition, these interval cancers are not screen detected.29
The USPSTF meta-analysis of eight large randomized trials suggested a 15% relative reduction in mortality (relative risk [RR], 0.85; 95% confidence interval [CI], 0.75 to 0.96) from mammography screening for women aged 40 to 49 years after 11 to 20 years of follow-up. This is equivalent to a needing to invite 1,904 women to screenings over 10 years to prevent one breast cancer death. Studies, however, show that more than half of women aged 40 to 49 years screened annually over a 10-year period will have an FP mammogram necessitating further evaluation, often including biopsy. In addition, estimates of overdiagnosis in this group range from 10% to 40% of diagnosed invasive cancers.30
In an effort to decrease FP rates, some have suggested screening every 2 years rather than yearly. Comparing biennial with annual screening, the CISNET Model consistently shows that biennial screening of women ages 40 to 70 only marginally decreases the number of lives saved while halving the false positive rate.29 Notably, the Swedish two-county trial, which had a planned 24-month screening interval (the actual interval was 33 months) reported one of the greatest reductions in breast cancer mortality among the RCTs conducted to date.
Screening Women at High Risk
There is interest in creating risk profiles as a way of reducing the inconveniences and harms of screening. It might be possible to identify women who are at greater risk of breast cancer and refocus screening efforts on those most likely to benefit.
Risk factors for breast cancer include the following:
Extremely dense breasts on mammography or a first-degree relative with breast cancer are each associated with at least a twofold increase in breast cancer risk
Prior benign breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts each increase risk 1.5- to twofold
Current oral contraceptive use, nulliparity, and age at first birth 30 years and older increase risk 1- to 1.5-fold.31
Importantly, these are risk factors for breast cancer diagnosis, not breast cancer mortality. Few studies have assessed the association between these factors and death from breast cancer; however, reproductive factors and breast density have been shown to have limited influence on breast cancer mortality.32,33
Genetic testing for BRCA1 and BRCA2 mutations and other markers of breast cancer risk has identified a group of women at high risk for breast cancer. Unfortunately, when to begin and the optimal frequency of screening have not been defined. Mammography is less sensitive at detecting breast cancers in women carrying BRCA1 and BRCA2 mutations, possibly because such cancers occur in younger women in whom mammography is known to be less sensitive.
MRI screening may be more sensitive than mammography in women at high risk, but specificity is lower. MRIs are associated with both an increase in FP and an increase in the detection of smaller cancers, which are more likely to be biologically indolent. The impact of MRIs on breast cancer mortality with or without concomitant use of mammographies has not been evaluated in a randomized controlled trial.
Breast Density
It is well established that mammogram sensitivity is lower in women with heterogeneously dense or very dense breasts.29,32 However, at this time, there are no clear guidelines regarding whether or how screening algorithms should take breast density into account.
In the American College of Radiology’s Imaging Network (ACRIN)/NCI 666 Trial, breast ultrasound was offered to women with increased mammographic breast density and, if either test was positive, they were referred for a breast biopsy.34 The radiologists performing the ultrasounds were not aware of the mammographic findings. Mammography detected 7.6 cancers per 1,000 women screened; ultrasound increased the cancer detection rate to 11.8 per 1,000. However, the PPV for mammography alone was 22.6%, whereas the PPV for mammography with ultrasound was only 11.2%.
It has yet to be determined whether supplemental imaging reduces breast cancer mortality in women with increased breast density. Although it continues to be strongly advocated by some, systematic reviews have concluded that the evidence is currently insufficient to recommend for or against this approach.35 There are also a number of barriers to supplemental imaging, including inconsistent insurance coverage, lack of availability in many communities, concerns about cost-effectiveness (particularly with regard to MRI), and the increased FP rate associated with supplemental imaging leading to unnecessary biopsies.36
Newer technologies may improve screening accuracy for women with dense breasts. Compared to conventional mammography, full field digital mammography (FFDM) appears to have less FPs. This could reduce the number of women needing supplemental imaging and biopsies.37 Digital breast tomosynthesis (DBT) uses x-rays and a digital detector to generate cross-sectional images of the breasts. Data are limited, but compared to mammograms, DBT appears to offer increased sensitivity and a reduction in the recall rates.38 Another potential supplementary imaging modality currently under investigation is three-dimensional (3-D) automated breast ultrasound, and having screening ultrasounds performed by technologists rather than radiologists.
Ductal Carcinoma In Situ
The incidence of noninvasive ductal carcinoma in situ (DCIS) has increased more than fivefold since 1970 as a direct consequence of widespread screening mammographies.39 DCIS is a heterogeneous condition with low- and intermediate-grade lesions taking a decade or more to progress. Nevertheless, women with this diagnosis are uniformly subjected to treatment. A better understanding of this entity and an increased ability to predict its biologic behavior may enable more judicious, personalized treatment of DCIS.
There is little evidence that the early detection and aggressive treatment of low- and intermediate-grade DCIS reduces breast cancer mortality. The standard of care for all grades of DCIS is lumpectomy with radiation or mastectomy, followed by tamoxifen for 5 years. Interestingly, patterns of care studies indicate that mastectomy rates are increasing,40 and that women are more often choosing double mastectomies for the treatment of DCIS.41Genomic characterization will hopefully lead to the identification of a subset of noninvasive cancers that can be treated less aggressively or even observed.
Harms
The harms and disadvantages of mammography screening include overdiagnosis, FP tests, FN tests, and the possibility of radiation-induced breast cancer.
The fact that mammography screening has increased the incidence of localized disease without a significant change in metastatic disease at the time of diagnosis suggests that there is some degree of overdiagnosis. The risk of overdiagnosis is greatest at the first screening3 and varies with patient age, tumor type, and grade of disease.
FP screening tests lead to substantial inconvenience and anxiety in addition to unnecessary invasive biopsies with their attendant complications. In the United States, about 10% of all women screened for breast cancer are called back for additional testing, and less than half of them will be diagnosed with breast cancer.39 The risk of a FP mammogram is greater for women under the age of 50.37
FN tests delay diagnosis and provide false reassurance. They are more common in younger women and in women with dense breasts.42,43 Certain histologic subtypes are also more difficult to see on mammogram. Mucinous and lobular tumors and rapidly growing tumors tend to blend in with normal breast architecture.44
A typical screening mammogram provides approximately 4 mSv of radiation. It has been estimated that annual mammographies will cause up to 1 case of breast cancer per 1,000 women screened from age 40 to age 80 years. Radiation exposure at younger ages causes a greater risk of breast cancer.45 There is also concern that ionizing radiation from mammographies might disproportionately increase the breast cancer risk for women with certain BRCA1or BRCA2 mutations, because these genes are related to DNA repair.46
Recommendations
Women at Average Risk
The ACS and most other medical groups recommend that average risk women undergo a CBE every 3 years starting at age 20 and that women 40 years of age and over should undergo CBEs and screening mammograms annually. Women should be informed of the benefits, limitations, and harms associated with breast cancer screening. A mammography will not detect all breast cancers, and some breast cancers detected with mammographies may still have a poor prognosis. The harms associated with breast cancer screening also include the potential for FP results, causing substantial anxiety. When abnormal findings cannot be resolved with additional imaging, a biopsy is required to rule out the possibility of breast cancer. A majority of biopsies are benign. Finally, some breast cancers detected by a mammography may be biologically indolent, meaning they would not have caused a problem or have been detected in a woman’s lifetime had she not undergone a mammography.
The USPSTF, the American College of Physicians, and the Canadian Task Force on the Periodic Health Examination recommend routine screening beginning at age 50 years.30,47,48 For women aged 40 to 49 years of age, these groups advise physicians to enter into a discussion with the patient. The physician and patient should take into account individual risks and concerns before deciding to screen.47
An Advisory Committee on Cancer Prevention in the European Union recommends that women between the ages of 50 and 69 years be offered mammogram screening in an organized screening program with quality assurance.49This committee says women aged 40 to 49 years should be advised of the potential harms of screening and, if mammographic screening is offered, it should be performed with strict quality standards and double reading.
Women at High Risk
The ACS has issued guidelines for women who were known or likely carriers of a BRCA mutation and other rarer high-risk genetic syndromes, or at high risk for other reasons.50 Annual screening mammographies and MRIs starting at age 30 is recommended for women:
With a known BRCA mutation
Who are untested but have a first-degree relative with a BRCA mutation
Who had been treated with radiation to the chest for Hodgkin disease
Who have an approximately 20% to 25% or greater lifetime risk of breast cancer based on specialized breast cancer risk estimation models.
COLON CANCER SCREENING
Colorectal cancer screening with the rigid sigmoidoscope dates back to the late 1960s. The desire to examine the entire colon led to the use of a barium enema and the development of fecal occult blood tests. With the development of fiber optics, flexible sigmoidoscopies and, later, colonoscopies were employed. Today, fecal occult blood testing (FOBT), stool DNA testing, flexible sigmoidoscopies, colonoscopies, and CT colonographies and, occasionally, barium enemas are all used in colorectal cancer screening. MRI colonoscopy is in development.
Screening examinations of the colon and rectum can find cancer early, but also find precancerous polyps. Randomized trials have demonstrated that endoscopic polypectomies reduce the incidence of colorectal cancer by about 20%.51–53
FOBT was the first colorectal screening test studied in a prospective randomized clinical trial. The Minnesota Colon Cancer Control Study randomized 46,551 adults to one of three arms: annual FOBTs, biennial screening, or usual care. A rehydrated guaiac test was used. With 13 years of follow-up, the annual screened arm had a 33% relative reduction in colorectal cancer mortality compared to the usual care group.54 At 18 years of follow-up, the biennially screened group had a 21% reduction in colorectal cancer mortality.55 This study would subsequently show that stool blood testing was associated with a 20% reduction in colon cancer incidence.51 These results were confirmed by two other randomized trials.56,57 A reduction in colon cancer–specific mortality persisted in the Minnesota trial through 30 years of follow-up. Overall mortality was not affected.
Rehydration increases the sensitivity of FOBT at the expense of lowering specificity.58 Indeed, rehydrated specimens have a very high FP rate. Overall, 1% to 5% of FOBTs are positive, but only 2% to 10% of those with a positive FOBT have cancer.
Fecal immunochemical tests (FIT) are stool tests that do not react to hemoglobin in dietary products. They appear to have higher sensitivity and specificity for colorectal cancer when compared to nonrehydrated FOBT tests.59
Fecal DNA testing is an emerging modality. These tests look for DNA sequences specific to colorectal polyps and colorectal cancer. They may have increased sensitivity and specificity compared to FOBT. Although fecal DNA tests appear to find cancer, the body of evidence on their ability to reduce colorectal cancer mortality is limited due to a lack of study. This test has been intermittently available.
Flexible sigmoidoscopies are, of course, limited to an examination of the rectum and sigmoid colon. A prospective randomized trial of once-only flexible sigmoidoscopies demonstrated a 23% reduction in colorectal cancer incidence and a 31% reduction in colorectal cancer mortality after a median 11.2 years of follow-up.60 In the NCI’s Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), there was a 21% reduction in colorectal cancer incidence and a 26% reduction in colorectal cancer mortality with two sigmoidoscopies done 3 to 5 years apart compared with the usual care group after a median follow-up of 11.9 years.53 In both studies, there was no effect on proximal lesions (i.e., right and transverse colon) due to the limited reach of the scope. It is estimated that flexible sigmoidoscopies can find 60% to 80% of cancers and polyps found by colonoscopies.61
In two meta-analyses of five randomized controlled trials of sigmoidoscopies, there was an 18% relative reduction in colorectal cancer incidence and a 28% relative reduction in colorectal cancer mortality.62,63Participants ranged in age from 50 to 74 years. Follow-up ranged from 6 to 13 years.
The colonoscopy has become the preferred screening method of many, although there have been no prospective, randomized trials of colonoscopy screening. A positive FOBT, FIT, fecal DNA test, or sigmoidoscopy warrants a follow-up diagnostic colonoscopy. Perhaps the best support for colonoscopy screening is indirect evidence from the Minnesota Colon Cancer Control Study, which required that all participants with a positive stool blood test have diagnostic imaging of the entire colon. In the Minnesota study, more than 40% of those screened annually eventually received a colonoscopy. One can also make the argument that the sigmoidoscopy studies indirectly support the efficacy of colonoscopy screening, although it can be argued that embryologic and epidemiologic evidence indicate that the right and left colon are biologically distinct and, therefore, the mortality benefits from sigmoidoscopies do not constitute proof that a colonoscopy would similarly reduce mortality from proximal colon lesions.
In studies involving repeat colonoscopies by a second physician, 21% of all adenomas were missed, including 26% of 1 to 5 mm adenomas and 2% of adenomas 10 mm or more in length.64 Other limitations of colonoscopies include the inconvenience of the bowel preparation and the risk of bowel perforation (about 3 out of 1,000 procedures, overall, with nearly all of the risk among patients who undergo colonoscopic polypectomies). The cost of the procedure and the limited number of physicians who can do the procedure are also of concern.
A CT colonography or virtual colonoscopy allows a physician to visually reproduce the endoscopic examination on a computer screen. A CT colonography involves the same prep as a colonoscopy, but is less invasive. It might have a higher compliance rate. In experienced hands, the sensitivity of a CT colonography for the detection of polyps ≥6 mm appears to be comparable to that of a colonoscopy. In a meta-analysis of 30 studies, 2-D and 3-D CT colonographies performed equally well.65
The disadvantages of a CT colonography include the fact that it requires a colonic prep and a finding on CT requires a follow-up diagnostic colonoscopy. The rate of extracolonic findings of uncertain significance is high (~15% to 30%), and each one must be evaluated, thereby contributing to additional expense and potential morbidity. The long-term, cumulative radiation risk of repeated colonography screenings is also a concern.
Current Recommendations
The ACS, the American College of Gastroenterology, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the American College of Radiology have issued joint colorectal cancer guidelines. These groups consider FOBT, FIT, rigid and flexible sigmoidoscopies, colonoscopies, and CT colonographies to all be reasonable screening methodologies.
They recommend the following: (1) Screening modalities be chosen based on personal preference and access, and (2) average risk adults should begin colorectal cancer screening at age 50 years with one of the following options:
1. Annual high sensitivity FOBT or FIT
2. A flexible sigmoidoscopy every 5 years
3. A colonoscopy every 10 years
4. A double contrast barium enema every 5 years
5. A CT colonography every 5 years
No test is of unequivocal superiority. Patient preferences should be incorporated into screening in order to increase compliance. The guidelines also stress that a single screening examination is far from optimal and that patients should be in a program of regular screening.
Although some colorectal cancers are diagnosed in persons under the age of 50 years, screening persons age 40 to 49 years has low yield.66 The guidelines also state that patients with less than a 10-year life expectancy should not be screened.
The USPSTF issued colorectal cancer screening guidelines in 2008.67 The guidelines were based on a systematic literature review and decision models. The task force concluded that three screening strategies appear to be equivalent for adults age 50 to 75 years:
1. An annual FOBT with a sensitive test
2. A flexible sigmoidoscopy every 5 years, with a sensitive FOBT every 3 years
3. A colonoscopy every 10 years
The task force recommends that patients age 76 to 85 years be evaluated individually for screening. They found “insufficient evidence” to recommend CT colonographies or fecal DNA testing.
Patients at Increased Risk of Colorectal Cancer
Patients can have higher than average risk of colorectal cancer due to familial or hereditary factors and clinical conditions such as inflammatory bowel disease. These patients technically undergo surveillance and not screening. Nevertheless, there are few clinical studies to guide recommendations. Guidelines have been created based on professional opinion and an understanding of the biology of colorectal cancer (Table 34.5).68
OTHER CANCERS OF THE GASTROINTESTINAL TRACT
There are no widely accepted screening guidelines for cancers of the esophagus, stomach, pancreas, and liver. However, surveillance is advocated for some patients at high risk.
Esophageal Cancer Screening
Esophageal cancer screening has centered on endoscopic examinations for those at high risk due to chronic, severe gastroesophageal reflux disease.69 Some physicians advocate routine endoscopic surveillance of patients with Barrett esophagus. At this time, there is no evidence that such surveillance is effective at reducing cancer mortality.
Gastric Cancer Screening
Barium-meal photofluorography, serum pepsinogen, and gastric endoscopy have been proposed as screening methods for the early detection of gastric cancer. There are no randomized trials evaluating the impact of these modalities on gastric cancer mortality. Indeed, screening with barium-meal photofluorography has been studied in high-risk populations for more than 40 years without clear evidence of benefit.
Time-trend analysis and case control studies of gastric endoscopy have suggested a decrease in gastric cancer mortality among those at high risk in screened versus unscreened individuals; however, a large observational study in a high-risk population failed to demonstrate a benefit.70,71
Although widespread gastric screenings cannot be advocated, there may be justification for endoscopic screenings of high-risk populations. Candidates for screening might include elderly individuals with atrophic gastritis or pernicious anemia, patients who have had partial gastrectomy,72 those with a history of sporadic adenomas, and patients with familial adenomatous polyposis or hereditary nonpolyposis colon cancer.
Pancreatic Cancer Screening
At this time, there are no data from prospective clinical trials to support a role for pancreatic cancer screening. Some patients with an extensive family history have undergone periodic CT scanning of the abdomen, but this approach has not been shown to reduce pancreatic cancer mortality. There is an ongoing search for screening biomarkers. There is a need to follow large cohorts prospectively after collecting and storing biologic samples to identify biomarkers of risk.73
Liver Cancer Screening
Screening for liver cancer or hepatocellular carcinoma (HCC) has focused on very high-risk individuals, such as those with cirrhosis.54 To date, trial results are unreliable due to small study sizes and a lack of randomization.
Serum alpha-fetoprotein (AFP), a fetal-specific glycoprotein antigen, is an HCC tumor marker used in screening. It is not specific to HCC because it may be elevated in hepatitis, pregnancy, and some germ cell tumors. AFP has variable sensitivity and has not been tested in any randomized clinical trial with a mortality end point.
In one prospective, 16-year, population-based observational study, screening was done on 1,487 Alaska natives with chronic hepatis B virus (HBV) infection. The survival of those with screen-detected HCC was compared with a historical group of clinically diagnosed HCC patients.74 With a target of AFP determination every 6 months, there was a 97% sensitivity and 95% specificity for HCC. Such high sensitivity and specificity have not been found in other studies. It is not known if AFP screening decreases HCC mortality.75
Hepatic ultrasound has been used as an additional method for detection of HCC. This procedure is operator dependent with variable sensitivity and specificity. Ultrasound screening is commonly used in patients with hepatitis and cirrhosis.76,77
Interest in CT scanning has grown due to the limitations of AFP and ultrasound. CT scans may be a more sensitive test for HCC than ultrasound or AFP.75
GYNECOLOGIC CANCER
Cervical Cancer Screening
Dr. George Papanicolaou first introduced the Pap smear or Pap test in the early 1940s. The test was widely adopted based on its ability to identify squamous premalignancies and malignancies (from the ectodermal cervix) and glandular dysplasia and adenocarcinomas (from the endocervix). It is, however, more sensitive at detecting squamous lesions.
The Pap test was introduced before the advent of the prospective, randomized clinical trial and, therefore, has never been so tested. However, a number of observational studies over the past 60 years support the effectiveness of this screening test.78,79 Multiple ecologic studies have shown an inverse correlation between the introduction of Pap testing in a given country and reductions in both cervical cancer incidence and mortality.80 Importantly, mortality reductions in these studies have been proportional to the intensity of screening. In one series, more than half of women diagnosed with cervical cancer either had never had a Pap test or had not been screened within 5 years of diagnosis.80
Cervical cytology has evolved over the years. The original Pap smear used an ectocervical spatula to apply a specimen (“smear”) to glass slides. It later included an endocervical brush. The smear was fixed, stained, and manually examined under a microscope. That method is still used today, but a liquid-based/thin-layer system capable of being analyzed by computer is gaining in popularity.81
Human papillomavirus (HPV) 16 and 18 are the cause of more than 70% of cervical cancers. Thirteen other HPV subtypes are known to be associated with cervical cancer. With increasing understanding of the role of HPV in cervical disease, interest in developing tests to determine the presence of HPV DNA and RNA has grown. HPV screening can be used along with cytology (cotesting), in response to an abnormal cytologic test (reflexive testing), or as a stand-alone test. One advantage of the liquid-based/thin-layer tests over the older smears is that it makes reflexive testing easier to perform. An abnormal cytology screen can be objectively verified by testing for the presence of the HPV virus without calling the patient back.
HPV testing is especially useful because of its negative predictive value. Although a positive test for HPV infection is not diagnostic of cervical disease, a negative HPV test strongly suggests that the abnormal Pap does not represent a premalignant condition.
The utility of the HPV test is limited in younger women because one-third or more of women in their 20s have active cervical infections at any given time. The overwhelming majority of these infections and resultant dysplasia will regress and resolve within 8 to 24 months. For women over the age of 30, screening for the presence of HPV DNA or RNA appears to be superior to cytology in identifying women at risk for cervical dysplasia and cancer.82 An HPV infection in women over the age of 30 is more likely to be persistent and clinically significant.83 The risk of cervical cancer also increases with age, and most cervical cancer deaths occur in women over 50 years of age.
Cytologic Terminology
The terminology of the Pap smear has changed over time. The traditional cytologic categories were mild, moderate, and severe dysplasia and carcinoma in situ. Mild correlated with cervical intraepithelial neoplasia (CIN)1 histology on biopsy; moderate usually indicated CIN2; and severe dysplasia indicated CIN3 or carcinoma in situ.
There was some subjectivity and some overlap, especially in the area of mild and moderate dysplasia. The NCI sponsored the development of the Bethesda system in 1988. This system provides an assessment of the adequacy of the cervical specimen and a way of categorizing and describing the Pap smear findings. It more effectively and uniformly communicates cytology results from the laboratory to the patient caregiver. The Bethesda system was modified in 1991 and again in 2001.84 Today, more than 40 international professional societies have endorsed the Bethesda system.
The Bethesda system recognizes both squamous and glandular cytologic abnormalities.
Squamous cell abnormalities include:
Atypical squamous cells (ASC), which are categorized as either:
Of undetermined significance (ASC-US)
Cannot exclude high-grade squamous intraepithelial lesions (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL), which correlates with histologic CIN1
High-grade squamous intraepithelial lesion (HSIL), which correlates with histologic CIN2, CIN3, and carcinoma in situ
Glandular cell abnormalities (features suggestive of adenocarcinoma) include:
Atypical glandular cells (AGC): endocervical, endometrial, or not otherwise specified
AGCs, favor neoplastic
Endocervical or not otherwise specified
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
ASCs differ from normal cells but do not meet criteria for LSIL or HSIL. A small proportion of ASC-US smears are from CIN1 lesions; a smaller proportion are from CIN2 or 3. LSILs are usually due to a transient HPV infection. HSILs are more likely to be due to a persistent HPV infection and are more likely to progress to cervical cancer than LSILs.
The Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathology and the American Society for Colposcopy and Cervical Pathology has proposed that histologic cervical findings be described using the same terminology as cytologic findings.85
Women under the age of 30 who have not received the HPV vaccine have a high incidence of HPV infection86 and the highest prevalence of CIN. However, the overwhelming majority of these HPV infections and associated CIN will spontaneously regress.87,88 Due to the high regression rates, cervical screening and treatment in women aged 20 to 24 years appear to have little or no impact on the incidence of invasive cervical cancer. It is estimated that about 6% of CIN1 lesions progress to CIN3, and 10% to 20% of CIN3 lesions progress to invasive cancer.89
The Atypical Squamous Cells of Undetermined Significance (ASCUS)-LSIL Triage Study (ALTS) evaluated women with abnormal Pap smears.90 The investigators concluded that women with ASC-US should be tested for HPV. Those who are HPV positive should receive a colposcopy. In addition, because most women with LSIL or HSIL had an HPV infection, an immediate colposcopy and a biopsy of lesions was recommended.91 HPV DNA testing is very sensitive for identifying CIN2 or worse pathology. Among women 30 to 69 years of age, the sensitivity of the Pap test with HPV testing was 95% compared with 55% for the Pap test alone.92
Performance Characteristics of Cervical Cytology
The sensitivity of cytology varies and is a function of the adequacy of the cervical specimen. It is also affected by the age of the woman and the experience of the cytologist. The addition of HPV testing increases the number of women referred for a colposcopy. Not surprisingly, sensitivity is improved by serial examinations over time versus a single screen.
Screening Recommendations
Cervical screening, like other screening tests, is associated with some degree of overdiagnosis as evidenced by the phenomenon of spontaneous regression (see previous) and, therefore, potential harm from overtreatment, such as cervical incompetence, which may reduce fertility and the ability to carry a pregnancy to term. Because dysplasia takes years to progress to cervical cancer, increasing the screening interval can reduce overdiagnosis and excessive treatment without decreasing screening efficacy.
In 2012, the ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) issued joint screening guidelines.93 These guidelines recommend different surveillance strategies and options based on a woman’s age, screening history, risk factors, and choice of screening tests. The following are the recommendations for a woman at average risk.
Screening for cervical cancer should begin at 21 years of age. Women aged 21 to 29 years should receive cytology screening (with either conventional cervical cytology smears or liquid-based cytology) every 3 years. HPV testing should not be performed in this age group (although it can be used to follow-up a diagnosis of ASC-US). Women under 21 years of age should not be screened regardless of their age of sexual initiation.
For women aged 30 to 65 years, the preferred approach is to be screened every 5 years with both HPV testing and cytology (cotesting). It is also acceptable to continue screening every 3 years with cytology alone.
Women should discontinue screening after age 65 years if they have had three consecutive negative cytology tests or two consecutive negative HPV test results within the 10-year period before ceasing screening, with the most recent test occurring within the last 5 years.
Women who have undergone a hysterectomy for noncancerous conditions do not need to undergo cervical cancer screening.
Women, regardless of age, should NOT be screened annually by any screening method.
Women who have received HPV vaccinations should still be screened according to the previously listed schedule.
Screening in Low Resource Countries
Cytology and HPV testing is not widely available in much of the world. Cervical cancer remains a leading cause of death in many of these areas. Visual inspection of the cervix is a low-tech method of screening that is now recognized as having the potential to save thousands of lives per year. A clustered, randomized trial in India compared one-time cervical visual inspection and immediate colposcopy, biopsy, and/or cryotherapy (where indicated) versus counseling on cervical cancer deaths in women aged 30 to 59 years. After 7 years of follow-up, the age-standardized rate of death due to cervical cancer was 39.6 per 100,000 person-years in the intervention group versus 56.7 per 100,000 person-years in unscreened controls.94,95 This was the first prospective randomized clinical trial to evaluate cervical cancer screening.
Ovarian Cancer Screening
Modalities proposed for ovarian cancer screening include the bimanual pelvic examination, serum CA-125 antigen measurement, and transvaginal ultrasound (TVU). The bimanual pelvic examination is subjective and not very reproducible, but serum CA-125 can be objectively measured. Unfortunately, CA-125 is neither sensitive nor specific. It is elevated in only about half of women with ovarian cancer and may be elevated in a number of nonmalignant diseases (e.g., diverticulosis, endometriosis, cirrhosis, normal menstruation, pregnancy, uterine fibroids).96–98 TVU has shown poor performance in the detection of ovarian cancer in average and high-risk women.99 There is interest in the analysis of serum proteomic patterns, but this should be considered experimental.100,101
The combination of CA-125 and TVU has been assessed in two large, prospective randomized trials. The U.S. trial, the Prostate Lung Colorectal and Ovarian trial (PLCO), enrolled 78,216 women of average risk age 55 to 74 years.102,103 Participants were randomized to receive annual examinations with CA-125 (at entry and then annually for 5 years) and TVU (at entry and then annually for 3 years) (n = 39,105), or usual care (n = 39,111). Participants were followed for a maximum of 13 years, with mortality from ovarian cancer as the main study outcome. At the conclusion of the study, the number of deaths from ovarian cancer was similar in each group. There were 3.1 ovarian cancer deaths per 10,000 women years in the screened group versus 2.6 deaths per 10,000 women years in the control group (RR = 1.18; 95% CI, 0.82 to 1.71).103
The U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomized trial assessing the efficacy of CA-125 and TVU in more than 200,000 postmenopausal women. In this trial, CA-125 is being used as a first-line test and TVU as a follow-up test using a risk of ovarian cancer algorithm (ROCA).104 The ROCA measures changes in CA-125 over time rather than using a predefined cut point.105ROCA is believed to improve sensitivity for smaller tumors without measurably increasing the FP rate. A mortality assessment is expected in 2015.106
No organization currently recommends screening average risk women for ovarian cancer. In 2012, the USPSTF recommended against screening for ovarian cancer, concluding that there was “adequate evidence” that (1) annual screening with TVU and CA-125 does not reduce ovarian cancer mortality and (2) screening for ovarian cancer can lead to important harms, mainly surgical interventions in women without ovarian cancer.107
Women at High Risk for Ovarian Cancer
Although no study has shown a mortality benefit for ovarian cancer screening of high-risk individuals, a National Institutes of Health (NIH) consensus panel concluded that it was prudent for women with a known hereditary ovarian cancer syndrome, such as BRCA1/2 mutations or HNPCC, to have annual rectovaginal pelvic examinations, CA-125 determinations, and TVU until childbearing is completed or at least until age 35 years, at which time a prophylactic bilateral oophorectomy is recommended.108
Endometrial Cancer Screening
There is insufficient evidence to recommend endometrial cancer screening either for women at average risk or for those at increased risk due to a history of unopposed estrogen therapy, tamoxifen therapy, late menopause, nulliparity, infertility or failure to ovulate, obesity, diabetes, or hypertension.109 The ACS recommends that women be informed about the symptoms of endometrial cancer—in particular, vaginal bleeding and spotting—after the onset of menopause. Women should be encouraged to immediately report these symptoms to their physician.
Women at High Risk for Endometrial Cancer
Women with a suspected autosomal-dominant predisposition to colon cancer (e.g. Lynch syndrome), should consider undergoing an annual endometrial biopsy to evaluate endometrial histology, beginning at age 35 years.110,111 This is based only on expert opinion, given the paucity of clinical trial data. Women should be informed about the potential benefits, harms, and limitations of testing for early endometrial cancer.
LUNG CANCER SCREENING
Lung cancer screening programs using chest radiographs (CXR) and sputum cytology began in the late 1940s.112 An evaluation of these programs showed that screening led to the diagnosis of an increased number of cancers, an increased proportion of early stage cancers, and a larger proportion of screen-diagnosed patients surviving more than 5 years.
These findings led many to advocate for mass lung cancer screening, whereas others called for a prospective, randomized trial with a lung cancer mortality endpoint.113 The Mayo Lung Project (MLP), which began in 1971, was such a trial. More than 9,200 male smokers were enrolled and randomized to either have sputum cytology collected and CXRs done every 4 months for 6 years or to have these same tests performed annually.
At 13 years of follow-up, there were more early stage cancers in the intensively screened arm (n = 99) than in the control arm (n = 51), but the number of advanced tumors was nearly identical (107 versus 109, respectively).114Despite an increase in 5-year survival (35% versus 15%) intensive screening was not associated with a reduction in lung cancer mortality (3.2 versus 3.0 deaths per 1,000 person-years, respectively).115
The impact of screening on cancer incidence persisted through nearly 20 years of follow-up. There were 585 lung cancers diagnosed on the intensive screening arm versus 500 on the control arm (p = 0.009) and intensive screening continued to be associated with a significant increase in disease-specific survival. However, a concomitant decrease in lung-cancer mortality did not emerge with long-term follow-up (4.4 lung cancer deaths per 1,000 person-years in the intensively screened arm versus 3.9 per 1,000 person-years in the control arm).116 This suggests that some lung cancers diagnosed by screening would not have resulted in death had they not been detected (i.e., overdiagnosis).116
Two other large, randomized studies of CXR and sputum cytology were conducted in the United States during the same time period. All three studies evaluated different screening schedules rather than screening versus no screening. Paradoxically, a meta-analysis of the three studies found that more frequent screening was associated with an increase (albeit not statistically significant), rather than a decrease, in lung cancer mortality when compared with less frequent screening.117 A study conducted in Czechoslovakia in the 1980s also failed to show a reduction in lung cancer mortality with CXR screening.118
More recently, the NCI conducted the PLCO trial at 10 sites across the United States. This was a prospective, randomized trial of nearly 155,000 men and women, aged 55 to 74 years. Participants were randomized to receive annual, single-view, posteroanterior CXRs for 4 years versus routine care. With 13 years of follow-up, no significant difference in lung cancer mortality was observed. A total of 1,213 lung cancer deaths occurred on the intervention arm versus 1,230 in the control group (RR, 0.99; 95% CI, 0.87 to 1.22).119
Low-dose computerized tomography (LDCT) is an appealing technology for lung cancer screening. It uses an average of 1.5 mSv of radiation to perform a lung scan in 15 seconds. A conventional CT scan uses 8 mSv of radiation and takes several minutes. The LDCT image is not as sharp as the conventional image, but sensitivity and specificity for the detection of lung lesions are similar.
As in the early chest radiograph trials, a number of single-arm LDCT studies reported a substantial increase in the number of early stage lung cancers diagnosed. These studies also demonstrated that 5-year survival rates were increased in screened compared to unscreened populations.
These findings led to the conduct of several randomized trials of LDCT for the early detection of lung cancer. The largest, longest, and first to report a mortality end point is the National Lung Screening Trial (NLST). In this trial, approximately 53,000 persons were randomized to receive three annual LDCT scans or single-view posteroanterior CXRs. Eligible participants were current and former smokers between 55 and 74 years of age at the time of randomization with at least a 30 pack-year smoking history; former smokers were eligible if they had quit smoking within the previous 15 years.
With a median follow-up of 6.5 years, 13% more lung cancers were diagnosed and a 20% (95% CI, 6.8 to 26.7; p = 0.004) relative reduction in lung cancer mortality was observed in the LDCT arm compared to the CXR arm.11This corresponds to rates of death from lung cancer of 247 and 309 per 100,000 person-years, respectively.11 Another important finding from the NLST was a 6.7% (95% CI, 1.2 to 13.6; p = 0.02) decrease in death from any cause in the LDCT group.
NLST participants were at high risk for developing lung cancer based on their smoking history. Indeed, 25% of all participant deaths were due to lung cancer. A further analysis of the NLST shows that screening prevented the greatest number of lung cancer deaths among participants who were at the highest risk but prevented very few deaths among those at the lowest risk. These findings provide empirical support for risk-based screening.120
LDCT screening is clearly promising, but there are some notable caveats. The risk of a FP finding in the first screen was 21%. Overall, after three CT scans, 39.1% of participants had at least one positive screening result. Of those who screened positive, the FP rate was 96.4% in the LDCT group.11 Positive results require additional workup, which can include conventional CT scans, a needle biopsy, bronchoscopy, mediastinoscopy, or thoracotomy. These diagnostic procedures are associated with anxiety, expense, and complications (e.g., pneumo- or hemothorax after a lung biopsy). In the LDCT study arm, there were 16 deaths within 60 days of an invasive diagnostic procedure. Of the 16 deaths, 6 ultimately did not have cancer. Although it is not known whether these deaths were directly caused by the invasive procedure, such findings do give pause. Although the radiation dose from LDCT is low, the possibility that this screening test could cause radiation-induced cancers is at least a theoretical concern. The possibility of this long-term phenomenon will have to be assessed in future analyses.
The CXR lung screening studies suggested that there is a reservoir of biologically indolent lung cancer and that a percentage of screen-detected lung cancers represent overdiagnosis. The estimated rate of overdiagnosis in the long-term follow-up of the Mayo Lung Study and the other CXR studies was 17 to 18.5%.121 Similarly, it is estimated that 18.5% of the cancers diagnosed on the LDCT arm of the NLST represented overdiagnosis.122
There are estimates that widespread, high-quality screening has the potential to prevent 12,000 lung cancer deaths per year in the United States.123 However, the NLST was performed at 33 centers specifically chosen for their expertise in the screening, diagnosis, and treatment of lung cancer. It is not known whether the widespread adoption of LDCT lung cancer screening will result in higher complication rates and a less favorable risk–benefit ratio.
Although LDCT lung cancer screening should clearly be considered for those at high risk of the disease, those at lower risk are equally likely to suffer the harms associated with screening but less likely to reap the benefits.
Following the announcement of the NLST results, the ACS, the American College of Chest Physicians (AACP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) recommended that clinicians should initiate a discussion about lung cancer screening with patients who would have qualified for the trial. That is:
Age 55 to 74 years
At least a 30 pack-year smoking history
Currently smoke or have quit within the past 15 years
Relatively good health
Core elements of this discussion should include the benefits, uncertainties, and harms associated with screening for lung cancer with LDCT. Adults who choose to be screened should enter an organized screening program at an institution with expertise in LDCT screening, with access to a multidisciplinary team skilled in the evaluation, diagnosis, and treatment of abnormal lung lesions. If such a program is not available, the risks of harm due to screening may be greater than the benefits.124,125 The guidelines recommend an annual LDCT screening with the caveat that participants in NLST had only three annual screens.
The USPSTF guidelines give LDCT a grade B recommendation, concluding that there is moderate certainty that annual screening for lung cancer with LDCT is of moderate net benefit in asymptomatic persons at high risk for lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting.
PROSTATE CANCER SCREENING
Hugh Hampton Young first advocated the early detection of prostate cancer with a careful digital rectal examination (DRE) in 1903. Screening for prostate cancer with the DRE and serum PSA was first advocated in the mid 1980s and became commonplace by 1992. PSA screening is directly responsible for prostate cancer becoming the most common nonskin cancer in American men.
PSA is a glycoprotein produced almost exclusively by the epithelial component of the prostate gland. This protein was discovered in the late 1970s, and a serum test to measure circulating levels was developed in the early 1980s. Although PSA is prostate specific, it is not prostate cancer specific and may be elevated in a variety of conditions (e.g., benign prostatic hyperplasia, inflammation and following trauma to the gland, the presence of prostate cancer).
The PSA test has been widely advocated for prostate cancer screening because it is objective, easily measured, reproducible, noninvasive, and inexpensive. Although PSA screening increases the detection of potentially curable disease, there is substantial debate about the overall utility of the test. This is because PSA screening introduces substantial lead time and length bias as well as being associated with a high FN and FP rates and having a low positive predictive value. The prostate cancer conundrum was best summarized by the distinguished urologist, Willet Whitmore when he said, “Is cure necessary for those in whom it is possible? Is cure possible for those in whom it is necessary?”126
Observational studies suggest that the problem of prostate cancer overdiagnosis precedes the PSA era. In a landmark analysis with 20-year follow-up, only a small proportion of 767 men, diagnosed with localized prostate cancer in the 1970s and early 1980s and followed expectantly, died from prostate cancer: 4% to 7% of those with Gleason 2 to 4 tumors, 6% to 11% of those with Gleason 5 disease, and 18% to 30% of men with Gleason 6 cancer.127
Although obviously present in the pre-PSA era, overdiagnosis increased substantially after the introduction of PSA screening. This is illustrated by an examination of the prostate cancer incidence and mortality rates in Washington state and Connecticut. Due to the earlier uptake of PSA screening, the incidence of prostate cancer in Washington increased to twice that of Connecticut during the 1990s. However, mortality rates remained similar throughout the decade and, in fact, have remained similar to this day. The Surveillance, Epidemiology, and End Results (SEER) cancer registries show that, over the last 2 decades, a larger proportion of men living in western Washington have been diagnosed with prostate cancer and definitively treated, without a concomitant reduction in prostate cancer mortality compared to that of men living in Connecticut.128
Additional evidence of the potential for overdiagnosis comes from the unexpectedly large number of men diagnosed with prostate cancer in the Prostate Cancer Prevention Trial (PCPT). The PCPT was a prospective, randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Men were screened annually during this trial, and those who had not been diagnosed with prostate cancer after 7 years on-study were asked to undergo an end-of-study prostate biopsy. Of 4,692 men on the placebo arm whose prostate cancer status had been determined by biopsy or transurethral resection (TURP), 24.4% were diagnosed with prostate cancer. Given that the lifetime risk of prostate cancer mortality in the United States is less than 3%, it is clear that many men harbor indolent prostate cancer and, therefore, are at risk of being overdiagnosed.
The unexpectantly high rate of positive end-of-study biopsies in men with PSA levels less than or equal to 4.0 ng/mL provided a more accurate assessment of disease prevalence and thus a more accurate assessment of PSA sensitivity than was previously possible. Of the 2,950 men on the placebo arm of the PCPT with PSA levels consistently less than or equal to 4 ng/mL who underwent end-of-study biopsies, 449 (15.2%) were diagnosed with prostate cancer. Accordingly, a PSA level <4.0 ng/mL is more likely to be a false negative. Because Sensitivity = True Positives / (True Positives + False Negatives), a higher FN rate means a lower sensitivity at any given PSA threshold. This has prompted some to advocate using a lower PSA threshold for recommending biopsies. However, although lowering the PSA threshold from 4.0 to 2.5 ng/mL increases the sensitivity from 24% to 42.8%, it reduces specificity from 92.7% to an unacceptably low 80%.129
In the PCPT, cancer was found on end-of-study biopsies at all PSA levels (e.g., including 10% of biopsies in men with PSA levels between 0.6 and 1.0 ng/mL and 6% of biopsies in men with PSA levels between 0 and 0.6 were positive), suggesting a continuum of prostate cancer risk and no cut point with simultaneously high sensitivity and high specificity. High-grade disease was also documented at all PSA levels, albeit at an overall frequency of only 2.3% of men with PSAs <4 ng/mL.130,131
Does Prostate Cancer Treatment Prevent Deaths?
In order for screening to work, treatment has to work. The first prospective, randomized studies showing that any prostate cancer treatment saves lives were published in the late 1990s. These studies demonstrated an overall survival benefit for the addition of long-term androgen deprivation to radiation therapy in men with locally advanced, high-risk prostate cancer.132
The value of surgery for localized disease was assessed by the Scandinavian Prostate Cancer Group 4 study (SPCG-4). In this trial, 695 men with clinically localized prostate cancer were prospectively randomized to receive radical prostatectomy (RP) or watchful waiting (WW). In the expectant management group, hormonal therapy was given at the time of symptomatic metastases. About 60% of those enrolled had low-grade, 23% had moderate-grade, 5% had high-grade tumors, and 12% had tumors of unknown grade. At a median follow-up of 12.8 years, the RP group had significantly lower overall (RR 0.75; p = 0.007) and prostate cancer–specific mortality (RR 0.62; p = 0.01), with 14.6% of the PR group and 20.7% of the WW group having died of prostate cancer. The number needed to treat or prevent one prostate cancer death was 15. The survival benefit associated with RP was similar before and after 9 years of follow-up and for men with low and high-risk disease. However, a subset analysis suggested that the mortality benefit of surgery was limited to men less than 65 years of age. An important limitation of this trial is that 75% of the study participants had palpable disease, only 12% had nonpalpable disease, and only 5% of the cancers had been screen detected. It is, therefore, difficult to apply these data to the US prostate cancer population, which is dominated by nonpalpable, screen-detected disease.133
In contrast to the SPCG-4, the Prostate Intervention versus Observation Trial (PIVOT) was conducted in the United States during the early PSA era. In this study, 731 men with screen-detected prostate cancer were randomized to receive RP or WW. Of the participants, 50% had nonpalpable disease and, using established criteria for PSA levels, grade, and tumor stage, 43% of men had low-risk, 36% had intermediate-risk, and 21% had high-risk prostate cancer. With a median follow-up of 12 years, during which time 48.4% (354 of 731) of the study participants had died, RP was associated with statistically insignificant 2.9% and 2.6% absolute reductions in overall and prostate cancer–specific mortality, respectively. Subgroup analyses suggested mortality benefits for men with PSA values greater than 10 ng/mL and for those with intermediate- and high-risk disease.134
The Prospective Randomized Screening Trials
The PLCO Cancer Screening Trial was a multicenter, phase III trial conducted in the United States by the NCI. In this trial, nearly 77,000 men age 55 to 74 years were randomized to receive annual PSA testing for 6 years or usual care. At 13 years of follow-up, a nonsignificant increase in cumulative prostate cancer mortality was observed among men randomized to annual screening (RR, 1.09; 95% CI, 0.87 to 1.36).135 The most important limitation of this trial was the high rate of PSA testing among men randomized to the control arm. This drop-in or contamination served to reduce the statistical power of the study to detect differences in outcome between the two arms. It has also been argued that, due to the high rate of PSA screening on the control arm, PLCO effectively compared regular prostate cancer screening to opportunistic screening rather than comparing screening to no screening.
The ERSPC is a multicenter trial initiated in 1991 in the Netherlands and Belgium; five additional European countries joined between 1994 and 1998.136,137 The frequency of PSA testing was every 4 years in all countries except Sweden, in which it was every 2 years. The study results were initially reported in 2009 and updated in 2012.136,137 Although the overall analysis of 182,160 men, aged 50 to 74, did not show a reduction in prostate cancer–specific mortality, screening was associated with a significant decrease in prostate cancer mortality in the prespecified core age group, 55 to 69 years, which included 162,243 men. After a median follow-up of 11 years, a 21% relative reduction of prostate cancer death (RR, 0.79; 95% CI, 0.68 to 0.91) was observed in this group. In absolute terms, prostate cancer mortality was reduced from 5 to 4 men per 1,000 screened and 37 men had to be diagnosed to avert one prostate cancer death. It remains to be seen whether the benefits of screening will increase with continued follow-up.
The recruitment and randomization procedures of the ERSPC differed among countries. Notably, potential participants in Finland, Sweden, and Italy were identified from population registries and underwent randomization beforewritten informed consent was obtained. In some trials, men on the control arm were not aware they were in the study. Therefore, men on the intervention arm in these countries were more likely to be cared for at high-volume referral centers. This may have contributed to the higher proportion of men on the screening arm, with clinically localized cancer being treated with RPs.138
In a separate report on 20,000 men randomized to screening or a control group in Göteborg, Sweden, there was a 40% (95% CI, 1.50 to 1.80) risk reduction at 14 years of follow-up.139 They reported 293 (95% CI, 177 to 799) needed to be screened and 12 needed to be diagnosed in order to prevent one prostate cancer death. Three-fourths of the men in this report and 89% of the prostate cancer deaths were included in the published ERSPC analysis. Given this, these data do not constitute independent evidence of the efficacy of prostate cancer screening.
The other site to report separately was in Finland. A total of 80,144 men were randomized to a screening or usual care arm. At 12 years after randomization, there was no statistical difference in risk of prostate cancer death (hazard ratio [HR] = 0.85; 95% CI, 0.69 to 1.04).140 Possible explanations as to why Sweden and Finland would have such different outcomes include differences in the frequency of screening (every 2 years versus every 4 years, respectively) and the higher background rate of death from prostate cancer in the control group in the Goteborg cohort. Given that the mortality data from these two cohorts have been largely included in the ERSPC analyses, they do not provide independent evidence of the efficacy of prostate cancer screening.
The decline in prostate cancer mortality in the United States since the introduction of PSA screening 2 decades ago is often offered as evidence supporting a mortality benefit for prostate cancer screening. However, prostate cancer mortality rates have also declined in many countries that have not widely adopted screening.141 Thus, it is likely that improvements in treatment have contributed, at least in part, to the observed decline in prostate cancer mortality. Another possible contributing factor may be the World Health Organization (WHO) algorithm for adjudicating cause of death. A change occurred just as mortality rates began to go up in the late 1970s, and WHO changed back to the older algorithm in 1991 when prostate cancer mortality began declining in many countries.142 All of these factors, including a beneficial effect from screening, may be contributing to the declining prostate cancer mortality rates in the United States.
Screening Recommendations
The topic of prostate cancer screening tends to evoke strong emotional reactions. Although the intuitive appeal of early detection is undeniable and screening may save some lives, the magnitude of the mortality reduction is relatively small, whereas the harms associated with screening can be substantial. Whether the potential benefits outweigh the known harms is a question that each man must answer for himself based on his individual preferences.
Several professional organizations in the United States, Europe, and Canada have recently reviewed the screening data and issued screening guidelines. All acknowledge that legitimate concerns remain regarding the risk–benefit ratio of prostate cancer screening. There is also general agreement that prostate cancer screening should only be done in the context of fully informed consent and that men should know that experts do not agree as to whether the benefits of screening for this disease outweigh the harms. Most recommend against mass screening in public meeting places, malls, churches, etc.
In 2009, the American Urological Association (AUA) PSA Best Practice Statement was published, which stated, “Given the uncertainty that PSA testing results in more benefit than harm, a thoughtful and broad approach to PSA is critical. Patients need to be informed of the risks and the benefits of testing before it is undertaken. The risks of over-detection and over-treatment should be included in this discussion.”143
In 2010, the ACS updated their guidelines, stating that the balance of benefits and harms related to prostate cancer early detection are uncertain and the existing evidence is insufficient to support a recommendation for or against the routine use of PSA screening.144 The ACS called for discussion and shared decision making within the physician–patient relationship.
The most recent 2012 USPSTF guidelines recommend against the use of PSA screening on the basis that there is moderate certainty that the harms of PSA testing outweigh the benefits and, on that basis, recommended against PSA-based screening for all men.14 The task force did acknowledge that some men will continue to request screening and some physicians will continue to offer it. Like the ACS and AUA, they state that screening under such circumstances should respect patient preferences.
In 2013, the AUA conducted a systematic review of over 300 studies. They recommended against screening men younger than 40 years of age, and against screening average-risk men age 40 to 54 years, most men over 70 years of age, and men with a life expectancy of less than 10 to 15 years. They recommend that screening decisions be individualized for higher risk men ages 40 to 54 years and men over 70 years of age who are in excellent health. They placed primacy on shared decision making versus physician judgments about the balance of benefits and harms at the population level.145 Even for men aged 55 to 69 years, the AUA concluded that the quality of evidence for benefits associated with screening was moderate, whereas the quality of the evidence for harm was high. They recommended shared decision making for this group, in whom they have concluded the benefits may outweigh the harm.
SKIN CANCER SCREENING
Assessments of skin cancer screening have focused on melanoma end points with very little attention to screening for nonmelanoma skin cancer. A systematic review of skin cancer screening studies examining the available evidence through mid 2005 concluded that direct evidence of improved health outcomes associated with skin cancer screening is lacking.146
No randomized, clinical trial of skin cancer screening has been attempted. However, several observational studies have suggested that melanoma screening might reduce mortality. For example, a decrease in melanoma mortality did occur after a Scottish campaign to promote awareness of the signs of suspicious skin lesions and encourage early self-referral. However, uncontrolled, ecologic studies such as this provide a relatively low level of evidence, because it is not possible to determine whether the observed mortality reduction was due to screening or other factors.
More recently, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening project, or SCREEN project, compared a region of Germany in which intensive skin cancer screening was performed to areas of Germany without intensive screening. Approximately 360,000 residents of the Schleswig-Holstein region aged 20 years and older participated. They chose either to be screened by a nondermatologist physician trained in skin examinations or by a dermatologist. Almost 16,000 biopsies were performed and 585 melanomas were diagnosed. Overall, 1 in 23 participants had an excisional skin biopsy and 620 persons needed to be screened to detect one melanoma. This screening effort led to a 16% and 38% increase in melanoma incidence among men and women, respectively, compared to 2 years earlier. The melanoma incidence rate returned to preprogram levels after the program ended. Of the screen-detected melanomas, 90% were less than 1 mm thick. Screening was performed in 2003 to 2004, and melanoma mortality in this region subsequently declined. In 2008, it was nearly 50% lower in both men and women compared to the rest of Germany.147,148
Recommendations of Experts
Skin cancer screening recommendations are based on expert opinion, given the absence of a randomized clinical trial data and limited observational studies. The ACS recommends monthly skin self-examinations and a yearly clinical skin examination as part of a routine cancer-related checkup.149 The USPSTF finds insufficient evidence to recommend for or against either routine skin cancer screening of the general population by primary care providers or counseling patients to perform periodic skin self-examinations. The task force does recommend that clinicians “remain alert” for skin lesions with malignant features when performing a physical examination for other purposes, particularly in high-risk individuals. The American Academy of Dermatology recommends that persons at highest risk (i.e., those with a strong family history of melanoma and multiple atypical nevi), perform frequent self-examination and seek a professional evaluation of the skin at least once per year.150
High-risk individuals are persons with multiple nevi or atypical moles. There is consensus they should be educated about the need for frequent surveillance by a trained health-care provider beginning at an early age. In the United States, Australia, and Western Europe, Caucasian men age 50 years and over account for nearly half of all melanoma cases. There is some discussion that melanoma early detection efforts should be focused on this population.
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