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Can Advanced Imaging Reduce Overdiagnosis and Overtreatment?
Can Advanced Imaging Reduce Overdiagnosis and Overtreatment? Saurabh Jha, MD Key Words: Advanced imaging; overdiagnosis; MRI; amyloid PET; Alzheimer’s disease; psychiatric substrates. ªAUR, 2015
A
t first glance, it is counterintuitive that imaging, the alleged instigator of overdiagnosis, can reduce overdiagnosis and overtreatment. Imaging can curb overdiagnosis if it juxtaposes between the gateway of overdiagnosis and biopsy or treatment or makes diagnosis prognostically meaningful. In this special issue, how imaging may affect overdiagnosis is discussed in relation to prostate cancer (1), Alzheimer disease (2), and psychiatric disorders (3).
MAGNETIC RESONANCE IMAGING (MRI) AND PROSTATE CANCER: OVERTESTING TO CURB OVERTREATMENT The gateway to the overdiagnosis of prostate cancer is the prostate-specific antigen (PSA) test. PSA is not at fault for its own sake but because the threshold for its positivity is so low and the population in which it is used is so broad that overdiagnosis is inevitable. Many believe that the strategies after a positive PSA are to blame for the overtreatment of prostate cancer (1). The scale of overdiagnosis is illustrated by a remarkable statistic—nearly 60% of 60-year-olds and 80% of 80-year-olds have prostate cancer at autopsy (4). Simply put, if we seek cancer in the prostate gland, we will likely find it. Biopsy not only finds innocuous tumors but does not confidently exclude high-grade tumors. This is one reason why so often the whole gland is treated, by surgery or radiation, for a localized low-grade tumor. Biopsy therefore overdiagnoses, increases uncertainty, and leads to overtreatment. For MRI to reduce overtreatment, it must gatekeep biopsy when PSA is positive or whole gland treatment when the biopsy is positive. Diffusion-weighted MRI detects high-grade tumors well but does not detect low-grade tumors as well. The differential sensitivity for consequential and innocuous tumors makes it plausible that MRI can reduce overdiagnosis, if biopsy is conditional on the positivity of MRI.
Acad Radiol 2015; 22:1007–1009 From the Department of Radiology, MRI Learning Center, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104. Received June 1, 2015; accepted June 1, 2015. Address correspondence to: S.J. e-mail: [email protected] ªAUR, 2015 http://dx.doi.org/10.1016/j.acra.2015.06.001
However, this paradigm has several challenges, which Rosenkrantz and Taneja discuss (1). The costs are notable even if only men with a positive PSA undergo MRI as well. Furthermore, because of indication drift, more people with a positive PSA could get an MRI than would have been sent for a biopsy. The negative predictive value of MRI for significant cancer is 90% (1). Will clinicians not biopsy the prostate if the MRI is negative? MRI could mirror PSA so completely that everyone who gets a PSA gets an MRI as well. This is not difficult to imagine in our medical culture where prudence is neither rewarded nor respected. However, MRI could persuade clinicians to adopt surveillance instead of whole gland treatment. Overtreatment of prostate cancer will be curbed at the expense of overtesting. PET AND DEMENTIA: BIOMARKER BECOMES THE DISEASE Both positron emission tomography (PET) and extended longevity are successes of modern medicine. One consequence of living longer is the emerging epidemic of dementia, and so it is ironic that PET is being tasked in predicting Alzheimer disease (AD), the most common cause of dementia. Advanced dementia is debilitating and exacts a toll on the patient, their caregivers, and the health care system. By logically extrapolating from this fact, one may make a case that there is an urgent imperative to diagnose predementia or mild cognitive impairment and predict who will proceed to advanced dementia. However, the utility in diagnosing predementia is unclear given the absence of a proven diseasemodifying agent. Although there may be satisfaction in knowing for the sake of knowing that one may develop dementia, there may be dissatisfaction as well, particularly if that knowing is a false positive or overdiagnosis. Amyloid is the most promising substrate in AD. However, amyloid is neither exclusive to AD nor exclusive in AD; there are other substrates in AD and amyloid can be found in the absence of AD. The methodologic challenge that PET and other tests for AD face is the lack of a single end point that is not a biomarker, which can verify the success of intervening before full-blown symptoms of dementia. 1007
JHA
Screening for cancer is judged by the reduction of deaths from that cancer. It is unclear what single parameter can judge screening for a disease with as wide ranging an effect (biological, psychological, and economic) as dementia, which affects quality more than quantity of life. The implication is that it will be tempting to verify amyloid PET, to give one example, by specimens of brain rather than a hard outcome for dementia. This will really be testing PET’s ability to detect amyloid, not AD, against pathology. This would be fine if the amount of amyloid in the brain was synonymous with the presence and severity of dementia in AD, but it is not. This could lead to future therapies for AD being refereed by PET. Such therapies may truly alter the burden and natural history of substrates, such as amyloid, in the brain without improving outcomes for AD. Substrates, such as amyloid, are imperfect biomarkers for AD, not diseases in their own right. Dubroff and Nasrallah laud the high negative predictive value of amyloid PET (2). They say that amyloid PET is almost never negative in patients with pathologically proven AD. Even so, the only way to judge screening for or therapy in predementia is a well-designed randomized controlled trial with a follow-up longer than the lead time of predementia, which can be 17 years. Will PEToverdiagnose fewer cases of dementia than memory tests? One must not assume that an advanced diagnostic test is less likely to overdiagnose just because it has a greater area under the curve, meaning a higher sensitivity and specificity. A more sensitive test, particularly one that is more sensitive at detecting predementia, can lead to more overdiagnosis if its higher sensitivity comes from detecting pseudodisease. It is uncertain if PET will overdiagnose more dementia than a noninvasive screening test. However, it is fair to say that there are cheaper ways to overdiagnose dementia than PET.
NEUROIMAGING AND PSYCHIATRIC DISORDERS: THE GAUSSIAN TRAP The emerging role of neuroimaging in the evaluation of psychiatric disorders comes from two temporally related trends: an imperative to seek biological substrates for psychiatric illness and an imperative to counter the expanding, even if objective, definition of mental disorders. The latter created a new level of controversy with the fifth edition of the Diagnostic and Statistical Manual (DSM-5), which the National Institute of Mental Health rejected for want of greater exposition of pathogenesis of mental illnesses (5). The lack of biological substrates is psychiatry’s b^ete noire. This was highlighted by the eminent psychiatrist, Thomas Szasz, in Myth of Mental Illness (6). Szasz’s position was extreme, whereas the truth is closer to the middle, and there are many structural and metabolic changes which correlate with the presence of psychiatric disorders that are uncovered by neuroimaging. An example is hippocampal atrophy in ma1008
Academic Radiology, Vol 22, No 8, August 2015
jor depression (7). Although evidence, such as this, counters Szasz’s assertion of the nonorganic basis of mental illness, it could introduce new problems through a process of reasoning which is entirely logical. The reasoning starts with the premise that hippocampal atrophy, to choose one example, is associated with depression. One then correlates the degree of measurable atrophy with the severity of (severe) depression. The logician then argues that by measuring hippocampal volume, we can detect early disease and predict severe disease. This is a fallacy of extrapolation. The fallacy is not in extrapolating but in failing to understand that although severe disease leads to detectable loss of hippocampal volume, mild disease may not lead to a measurable loss of volume, or if it does, the diminished volume could reside in a spectrum that overlaps considerably with normals. The quest to biologically rationalize mental illness will, for most parts, find associations with substrates which are not unique to the mentally ill. Extrapolating is problematic because the methodologic challenges in detecting tiny effects from mild disease, even if they exist, cannot be linearly projected from the relative methodologic ease in detecting modest effects from severe disease. What is the utility of advanced neuroimaging in suspected mental illness? For those with full-blown depression, a negative imaging test is as meaningless as a positive one because neither changes management. In the mildly symptomatic, neither may the positivity of a test sufficiently justify treatment nor may its negativity sufficiently dissuade from treatment, if the clinician, based on experience or the diagnostic criteria she follows, thinks otherwise. Nucifora conjectures that neuroimaging may reduce overtreatment by legitimizing the cessation of treatment in nonresponders (3). This is not just theoretical, but the author has the directionality reversed. The patient must, first, be deemed a nonresponder and will be deemed as thus on clinical symptoms, not substrates, by the psychiatrist in the office, not imagers. The psychiatrist will likely have decided to stop the treatment by the time the patient is imaged. Neuroimaging will either support the decision to stop treatment or challenge it but will unlikely persuade the psychiatrist to stop treatment if she does not wish for it to be halted. In other words, neuroimaging will, at best, leave overtreatment unchanged and, at worst, increase it. Neuroimaging will likely legitimize an organic basis to mental illness. It may, however, defer to symptom-based criteria, such as DSM-4 and DSM-5, for its own legitimacy, to verify that substrates are correctly calling mild phenotypes of illness. This will be ironic because it is the imperfections in symptom-based criteria that make one seek biological substrates for mental illnesses. The relationship between imaging and DSM may be akin to two drunkards propping up each other.
CONCLUSIONS Theoretically, advanced imaging can curb overdiagnosis and overtreatment. There are methodologic challenges. Arguably,
Academic Radiology, Vol 22, No 8, August 2015
MRI can reduce overtreatment of prostate cancer but at considerable costs. The best ways to reduce overdiagnosis and overtreatment are to raise the threshold for defining disease and the bar for its suspicion.
REFERENCES 1. Rosenkrantz AB and Taneja SS. Prostate MRI Can reduce overdiagnosis and overtreatment of prostate cancer. Acad Radiol 2015; 22:1000–1006.
ADVANCED IMAGING AND OVERDIAGNOSIS
2. Dubroff J and Nasrallah IM. Will PET amyloid imaging lead to overdiagnosis of Alzheimer’s disease? Acad Radiol 2015; 22:988–994. 3. Nucifora P. Overdiagnosis in the era of neuropsychiatric imaging. Acad Radiol 2015; 22:995–999. 4. Sakr WA, Grignon DJ, Haas GP, et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996; 30:138–144. 5. Insel TR. The NIMH Research Domain Criteria Project (RDoC) Project: precision medicine for psychiatry. Am. J. Psychiatry 2014; 171(4):395–397. 6. Szasz TS. The myth of mental illness. New York: Harper Perennial, 2010. Anv. Edition. 7. Sheline YI, Wang PW, Csernansky JG, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 1996; 93(9):3908–3913.
1009
A
t first glance, it is counterintuitive that imaging, the alleged instigator of overdiagnosis, can reduce overdiagnosis and overtreatment. Imaging can curb overdiagnosis if it juxtaposes between the gateway of overdiagnosis and biopsy or treatment or makes diagnosis prognostically meaningful. In this special issue, how imaging may affect overdiagnosis is discussed in relation to prostate cancer (1), Alzheimer disease (2), and psychiatric disorders (3).
MAGNETIC RESONANCE IMAGING (MRI) AND PROSTATE CANCER: OVERTESTING TO CURB OVERTREATMENT The gateway to the overdiagnosis of prostate cancer is the prostate-specific antigen (PSA) test. PSA is not at fault for its own sake but because the threshold for its positivity is so low and the population in which it is used is so broad that overdiagnosis is inevitable. Many believe that the strategies after a positive PSA are to blame for the overtreatment of prostate cancer (1). The scale of overdiagnosis is illustrated by a remarkable statistic—nearly 60% of 60-year-olds and 80% of 80-year-olds have prostate cancer at autopsy (4). Simply put, if we seek cancer in the prostate gland, we will likely find it. Biopsy not only finds innocuous tumors but does not confidently exclude high-grade tumors. This is one reason why so often the whole gland is treated, by surgery or radiation, for a localized low-grade tumor. Biopsy therefore overdiagnoses, increases uncertainty, and leads to overtreatment. For MRI to reduce overtreatment, it must gatekeep biopsy when PSA is positive or whole gland treatment when the biopsy is positive. Diffusion-weighted MRI detects high-grade tumors well but does not detect low-grade tumors as well. The differential sensitivity for consequential and innocuous tumors makes it plausible that MRI can reduce overdiagnosis, if biopsy is conditional on the positivity of MRI.
Acad Radiol 2015; 22:1007–1009 From the Department of Radiology, MRI Learning Center, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104. Received June 1, 2015; accepted June 1, 2015. Address correspondence to: S.J. e-mail: [email protected] ªAUR, 2015 http://dx.doi.org/10.1016/j.acra.2015.06.001
However, this paradigm has several challenges, which Rosenkrantz and Taneja discuss (1). The costs are notable even if only men with a positive PSA undergo MRI as well. Furthermore, because of indication drift, more people with a positive PSA could get an MRI than would have been sent for a biopsy. The negative predictive value of MRI for significant cancer is 90% (1). Will clinicians not biopsy the prostate if the MRI is negative? MRI could mirror PSA so completely that everyone who gets a PSA gets an MRI as well. This is not difficult to imagine in our medical culture where prudence is neither rewarded nor respected. However, MRI could persuade clinicians to adopt surveillance instead of whole gland treatment. Overtreatment of prostate cancer will be curbed at the expense of overtesting. PET AND DEMENTIA: BIOMARKER BECOMES THE DISEASE Both positron emission tomography (PET) and extended longevity are successes of modern medicine. One consequence of living longer is the emerging epidemic of dementia, and so it is ironic that PET is being tasked in predicting Alzheimer disease (AD), the most common cause of dementia. Advanced dementia is debilitating and exacts a toll on the patient, their caregivers, and the health care system. By logically extrapolating from this fact, one may make a case that there is an urgent imperative to diagnose predementia or mild cognitive impairment and predict who will proceed to advanced dementia. However, the utility in diagnosing predementia is unclear given the absence of a proven diseasemodifying agent. Although there may be satisfaction in knowing for the sake of knowing that one may develop dementia, there may be dissatisfaction as well, particularly if that knowing is a false positive or overdiagnosis. Amyloid is the most promising substrate in AD. However, amyloid is neither exclusive to AD nor exclusive in AD; there are other substrates in AD and amyloid can be found in the absence of AD. The methodologic challenge that PET and other tests for AD face is the lack of a single end point that is not a biomarker, which can verify the success of intervening before full-blown symptoms of dementia. 1007
JHA
Screening for cancer is judged by the reduction of deaths from that cancer. It is unclear what single parameter can judge screening for a disease with as wide ranging an effect (biological, psychological, and economic) as dementia, which affects quality more than quantity of life. The implication is that it will be tempting to verify amyloid PET, to give one example, by specimens of brain rather than a hard outcome for dementia. This will really be testing PET’s ability to detect amyloid, not AD, against pathology. This would be fine if the amount of amyloid in the brain was synonymous with the presence and severity of dementia in AD, but it is not. This could lead to future therapies for AD being refereed by PET. Such therapies may truly alter the burden and natural history of substrates, such as amyloid, in the brain without improving outcomes for AD. Substrates, such as amyloid, are imperfect biomarkers for AD, not diseases in their own right. Dubroff and Nasrallah laud the high negative predictive value of amyloid PET (2). They say that amyloid PET is almost never negative in patients with pathologically proven AD. Even so, the only way to judge screening for or therapy in predementia is a well-designed randomized controlled trial with a follow-up longer than the lead time of predementia, which can be 17 years. Will PEToverdiagnose fewer cases of dementia than memory tests? One must not assume that an advanced diagnostic test is less likely to overdiagnose just because it has a greater area under the curve, meaning a higher sensitivity and specificity. A more sensitive test, particularly one that is more sensitive at detecting predementia, can lead to more overdiagnosis if its higher sensitivity comes from detecting pseudodisease. It is uncertain if PET will overdiagnose more dementia than a noninvasive screening test. However, it is fair to say that there are cheaper ways to overdiagnose dementia than PET.
NEUROIMAGING AND PSYCHIATRIC DISORDERS: THE GAUSSIAN TRAP The emerging role of neuroimaging in the evaluation of psychiatric disorders comes from two temporally related trends: an imperative to seek biological substrates for psychiatric illness and an imperative to counter the expanding, even if objective, definition of mental disorders. The latter created a new level of controversy with the fifth edition of the Diagnostic and Statistical Manual (DSM-5), which the National Institute of Mental Health rejected for want of greater exposition of pathogenesis of mental illnesses (5). The lack of biological substrates is psychiatry’s b^ete noire. This was highlighted by the eminent psychiatrist, Thomas Szasz, in Myth of Mental Illness (6). Szasz’s position was extreme, whereas the truth is closer to the middle, and there are many structural and metabolic changes which correlate with the presence of psychiatric disorders that are uncovered by neuroimaging. An example is hippocampal atrophy in ma1008
Academic Radiology, Vol 22, No 8, August 2015
jor depression (7). Although evidence, such as this, counters Szasz’s assertion of the nonorganic basis of mental illness, it could introduce new problems through a process of reasoning which is entirely logical. The reasoning starts with the premise that hippocampal atrophy, to choose one example, is associated with depression. One then correlates the degree of measurable atrophy with the severity of (severe) depression. The logician then argues that by measuring hippocampal volume, we can detect early disease and predict severe disease. This is a fallacy of extrapolation. The fallacy is not in extrapolating but in failing to understand that although severe disease leads to detectable loss of hippocampal volume, mild disease may not lead to a measurable loss of volume, or if it does, the diminished volume could reside in a spectrum that overlaps considerably with normals. The quest to biologically rationalize mental illness will, for most parts, find associations with substrates which are not unique to the mentally ill. Extrapolating is problematic because the methodologic challenges in detecting tiny effects from mild disease, even if they exist, cannot be linearly projected from the relative methodologic ease in detecting modest effects from severe disease. What is the utility of advanced neuroimaging in suspected mental illness? For those with full-blown depression, a negative imaging test is as meaningless as a positive one because neither changes management. In the mildly symptomatic, neither may the positivity of a test sufficiently justify treatment nor may its negativity sufficiently dissuade from treatment, if the clinician, based on experience or the diagnostic criteria she follows, thinks otherwise. Nucifora conjectures that neuroimaging may reduce overtreatment by legitimizing the cessation of treatment in nonresponders (3). This is not just theoretical, but the author has the directionality reversed. The patient must, first, be deemed a nonresponder and will be deemed as thus on clinical symptoms, not substrates, by the psychiatrist in the office, not imagers. The psychiatrist will likely have decided to stop the treatment by the time the patient is imaged. Neuroimaging will either support the decision to stop treatment or challenge it but will unlikely persuade the psychiatrist to stop treatment if she does not wish for it to be halted. In other words, neuroimaging will, at best, leave overtreatment unchanged and, at worst, increase it. Neuroimaging will likely legitimize an organic basis to mental illness. It may, however, defer to symptom-based criteria, such as DSM-4 and DSM-5, for its own legitimacy, to verify that substrates are correctly calling mild phenotypes of illness. This will be ironic because it is the imperfections in symptom-based criteria that make one seek biological substrates for mental illnesses. The relationship between imaging and DSM may be akin to two drunkards propping up each other.
CONCLUSIONS Theoretically, advanced imaging can curb overdiagnosis and overtreatment. There are methodologic challenges. Arguably,
Academic Radiology, Vol 22, No 8, August 2015
MRI can reduce overtreatment of prostate cancer but at considerable costs. The best ways to reduce overdiagnosis and overtreatment are to raise the threshold for defining disease and the bar for its suspicion.
REFERENCES 1. Rosenkrantz AB and Taneja SS. Prostate MRI Can reduce overdiagnosis and overtreatment of prostate cancer. Acad Radiol 2015; 22:1000–1006.
ADVANCED IMAGING AND OVERDIAGNOSIS
2. Dubroff J and Nasrallah IM. Will PET amyloid imaging lead to overdiagnosis of Alzheimer’s disease? Acad Radiol 2015; 22:988–994. 3. Nucifora P. Overdiagnosis in the era of neuropsychiatric imaging. Acad Radiol 2015; 22:995–999. 4. Sakr WA, Grignon DJ, Haas GP, et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996; 30:138–144. 5. Insel TR. The NIMH Research Domain Criteria Project (RDoC) Project: precision medicine for psychiatry. Am. J. Psychiatry 2014; 171(4):395–397. 6. Szasz TS. The myth of mental illness. New York: Harper Perennial, 2010. Anv. Edition. 7. Sheline YI, Wang PW, Csernansky JG, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 1996; 93(9):3908–3913.
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