hematuria workup: ??too much radiation

A theoretical analysis suggested that our current guidelines (via Am Urol Assn) to working up hematuria, vs guidelines in several other countries, may well lead to increased radiation-induced cancer (see hematuria avoid CT jamaintmed2019 in dropbox, or doi:10.1001/jamainternmed.2019.2280)

Details:

-- current guidelines for working up hematuria:

    -- American Urological Association (AUA): if >35 yo, cystoscopy plus CT urography

    -- Dutch: if >50 yo, cystoscopy plus ultrasonography

    -- Canadian Urological Association (CUA): if >40 yo, cystoscopy plus ultrasonography

    -- Kaiser Permanente (KP): if patients had gross hematuria, cystoscopy along with CT urography; smokers, males, or anyone >50yo had cystoscopy plus ultrasonography; non-smoking females <50yo had no workup

    -- Hematuria Risk Index (HRI): risk scores were calculated, and no workup if low-risk, cystoscopy plus ultrasound if moderate risk, cystoscopy and CT if high risk (see more on this below)

-- hypothetical cohort of 100,000 patients with hematuria aged 35 or older. they modeled the data from 2 large prospective hematuria cohorts on patients' ages, sex, smoking status and history of gross hematuria, and the statistical likelihood of different types of urinary tract. they included patients with both microhematuria and gross hematuria in their simulated grouping (based on the relative frequency of each in the population) vs just asymptomatic microhematuria (much more common but lower likelihood of cancer)

-- main outcome: urinary tract detection rates, radiation-induced secondary cancers from CT scans, procedural complications, false positive rates per 100,000 patients, and incremental cost per additional urinary tract cancer detected

Results:

-- 3514 patients in the simulated cohort had urinary tract cancers, estimated prevalence 3.5%: 2978 bladder cancer, 443 renal cell cancers (RCC), 93 upper tract urothelial cancers (UTUC)

-- AUA:

    -- cancers: 3432 detected/82 missed, 2.3% (ie 97.7% picked up); 2918 bladder cancers detected/60 missed, 425 RCC detected/19 missed, 89 UTUC detected/5 missed

    -- radiation-induced cancers: 575

    -- clinical outcomes: UTI from cystoscopy 1902, dysuria 11,003, false positive cases 22,189

    -- CT associated events: CT allergy 618, contrast nephropathy 4114

    -- total cost $939 per person, false positive cost from results of initial workup $94 (not including costs of downstream testing)

--Dutch:

    -- cancers: 3263 detected/251 missed, 7.1% (ie 92.9% picked up); 2838 bladder cancers detected/141 missed, 360 RCC detected/82 missed, 65 UTUC detected/28 missed

    -- radiation-induced cancers: none

    -- clinical outcomes: UTI from cystoscopy 1179, dysuria 6820, false positive cases 6452

    -- CT associated events: none

    -- total cost $442 per person, false positive cost from results of initial workup $2426

-- CUA:

    -- cancers: 3343 detected/172 missed, 4.9% (ie 95.1% picked up); 2906 bladder cancers detected/72 missed, 371 RCC detected/72 missed, 65 UTUC detected/28 missed

    -- radiation-induced cancers: none

    -- clinical outcomes: UTI from cystoscopy 1230, dysuria 7114, false positive cases 6740

    -- CT associated events: none

    -- total cost $462 per person, false positive cost from results of initial workup $25 per person

-- KP:

    -- cancers: 3385 detected/130 missed, 3.7% (ie 96.3% picked up); 2907 bladder cancers detected/71 missed, 397 RCC detected/46 missed, 80 UTUC detected/13 missed

    -- radiation-induced cancers: 108

    -- clinical outcomes: UTI from cystoscopy 1260, dysuria 7289, false positive cases 9099

    -- CT associated events: CT allergy 135, contrast nephropathy 898

    -- total cost $519 per person, false positive cost from results of initial workup $36 per person

-- HRI:

    -- cancers: 3399 detected/116 missed, 3.3% (ie 96.7% picked up); 2907 bladder cancers detected/71 missed, 404 RCC detected/39 missed, 87 UTUC detected/6 missed

    -- radiation-induced cancers: 136

    -- clinical outcomes: UTI from cystoscopy 1260, dysuria 7289, false positive cases 13,811

    -- CT associated events: CT allergy 151, contrast nephropathy 1009

    -- total cost $598, false positive cost from results of initial workup $59

-- cost per additional cancer case detected, as compared to the least expensive Dutch guidelines as the reference (costs in 2017 US$) [these are the increased costs to detect one case over what would have been detected following the Dutch guidelines]

    -- CUA: $23,864

    -- KP: $137,063

    -- HRI: $559,378

    -- AUA: $1,034,374

Commentary:

--so, this study found that through mathematical modeling, the least invasive strategy (via the Dutch recommendations) does pretty well (picking up 93% of cancers) with zero radiation-induced cancer [though, it should be noted, this “zero” rate is only for the initial screen, and any concerning finding on ultrasound is likely followed up by radiologic imaging]

--raising the age from 40 to 50yo per the CUA over the Dutch guidelines had an incremental cost of $23,864 per additional cancer detected

--the AUA guidelines had the highest detection rate for cancers, but many more adverse events related to CT scanning including induced cancers, and by far the highest cost per additional cancer detected. And lots more false positive results

    -- And the AUA, unlike some other guidelines, suggest workup of a single urinalysis with >3 RBCs/hpf (vs repeatedly positive tests) [per the 2012 AUA guidelines: asymptomatice microhematuria "is defined as 3 or greater RBCs/hpf on a properly collected urinary specimen in the absence of an obvious benign cause", though they also note that there is variability in microhematuria from one time to the next (see hematuria guidelines AUA 2012.pdf in dropbox, or doi.org/10.1016/j.juro.2012.09.078)

--the HRI approach evolved from a prospective cohort study of 2630 patients with microscopic hematuria seen by urologists in Kaiser-Permanente over a 2-year period, finding that 55 (2.1%) had a neoplasm and 50 (1.9%) had pathologically-confirmed cancer, more so in those with recent diagnosis of gross hematuria, in men, and those >50yo, though smoking history and >25 RBC per high power field were not statistically significant (see hematuria cancer HRI in dropbox, or doi.org/10.1016/j.mayocp.2012.10.004)

--the current authors comment that the guidelines often conflate microhematuria and gross hematuria as if they should have the same approach, though gross hematuria is more predictive of cancer

 --the major concern here is that:

    --the use of CT scans is increasing dramatically (6-fold in the past 3 decades)

    --analyses have found that about 1/2 of the ordered CT scans may be unnecessary

    --about 2 million Americans annually are referred to urologists for hematuria (and this does not include the number of patients having CT scans for hematuria but ordered by non-urologists, like us in primary care)

    --CT scans pick up lots of incidental findings, which often beget more CT scans (and more radiation), plus also patient anxiety, subjection to more tests, possibly invasive procedures, possible adverse effects of these tests/procedures, and often unclear benefit of these incidental detections and array of interventions

            --i have found several patients with "incidental" renal cell cancers, a not so uncommon issue since the increased use of abdominal imaging. are these real cancers that behave the same way as ones picked up through symptoms?? are they more similar to prostate cancers, where some are really bad actors but others are indolent and people die late in life from other causes? do these patients need pretty urgent surgery, as my patients had? are these simply overdiagnoses (are some/many of the cancers picked up through a few RBCs in the urine really just incidental findings unrelated to the hematuria?)? are we really saving lots of lives by cutting the cancers out?????

    --the Choosing Wisely campaign to decrease unnecessary medical tests, treatments and procedures has disproportionately targeted medical imaging as unnecessary

    --abdominal and pelvic CTs confer the highest radiation dose of commonly performed CT scans

    --and, there is remarkably/shockingly high variability of the actual dose of radiation given with an abdominal/pelvic CT: from 6.4 to 90 mSv per exam [in the current study they comment that the actual range in the community may be from 3.5-144 mSv, which per the AUA guidelines would increase the number of radiation-induced cancers from 575 to 782/100,000

    --and, significantly, radiation-induced cancer has a case fatality rate of >50%

--one side issue of interest (at least to me) in conceptualizing cancer is that there is a complex interplay between the genetic mutations and the environment:

    --as several blogs have noted, there is typically not a genetic imperative to developing cancer; genes are not determinant even in mututions such as BRCA

        --analysis of the 23andMe genetic evaluations have found remarkably poor sensitivity and specificity for clinical disease (see http://gmodestmedblogs.blogspot.com/2017/04/23andme-genetic-analysis-approved-for.html )

        --we all develop potentially serious mutations with aging, more so with exposure to such things as radiation or smoking

        --several studies have found a lower risk of cancer with a healthier lifestyle. one factor that may well be involved is inflammation (eg see http://gmodestmedblogs.blogspot.com/2016/08/normal-bmiexercise-lower-cancer-risk-2.html for decreased cancer with exercise; http://gmodestmedblogs.blogspot.com/2015/11/breast-cancer-risk-and-mediterranean.html for decreased breast cancer with Mediterranean diet )

            --a healthy lifestyle does decrease inflammation: see http://gmodestmedblogs.blogspot.com/2019/01/non-animal-protein-diet-dec-inflammation.html , or http://gmodestmedblogs.blogspot.com/2018/12/mediterranean-diet-dec-cad-and.html

            --studies have shown that inflammation increases the growth of tumor cells and the risk of metastatic disease, eg see cancer and inflammation cell2010 in dropbox or doi 10.1016/j.cell.2010.01.025 or https://www.cell.com/action/showPdf?pii=S0092-8674%2810%2900060-7 )

          --aspirin has been shown to decrease the risk of metastatic cancer and cancer deaths, moreso in smokers: see aspirin cancer mets lancet 2012 in dropbox, or Rothwell PM. lancet. 2012; 379: 1591

-- One basic concern with mathematical modeling for radiation exposure is the rather limited database to derive the estimates. The most studied involve the effects of atomic bomb blasts in Hiroshima and Nagasaki, looking at distance from the blast (a surrogate for differences in radiation exposure) and cancer incidence. As a model, this is very approximate: the study involves a single ethnic group, different baseline environmental exposures from other groups, and the application of results from a “normal” population (for example, those with hematuria may well have underlying noncancerous pathology, and the addition of ionizing radiation to that pathology may increase the risk of cancer more than in a normal population). eg see https://www.pnas.org/content/pnas/100/24/13761.full.pdf , or radiation and cancer risk lancet2015 in dropbox, or Kamiya K. Lancet. 2015; 386:469

--note that the above false positive costs include the monetary costs only,  not include the cost of downstream testing, including workup of incidental findings (found in >30% of CTs), anxiety, patient/family burden, physical risks, patient costs (out-of pocket, esp)

so, seems to me that the Am Urol Assn guidelines are a bit on the aggressive side. A few % higher pickup of cancers, but lots more radiation and likely radiation-induced cancers. And lots more false positive results (likely leading to even more radiation exposure as a followup).  probably makes sense to:

--check on the local CT scanner used (eg in the hospital) and see what the actual radiation exposure is (by reference, a chest CT yields 8 mSv), given the very huge apparent variation in the community. And we should advocate strongly for newer CT scanners if the radiation exposure is high

--the patients should understand that radiation can be associated with creating cancer, and that there is this potential downside with pretty much all xrays and their use should be minimized. my experience is that xrays have been so normalized in our culture that patients do not understand that there really are any risks. and when i mention the risks, the patients are often surprised and less interested in getting xrays (this has been particularly successful in discussing risks of biennial vs annual mammograms)

--the Canadian guidelines do seem to be a reasonable approach, with its lower age group inclusion (40yo, vs 50yo in the Dutch guidelines), especially since the effects of missing a cancer in the 40-50yo probably has a higher overall social value than in an 80-90yo, esp in terms of potential years of life lost and family/community  effects.

For some prior blogs on radiation-induced cancer:

http://gmodestmedblogs.blogspot.com/2018/06/low-dose-radiation-and-subsequent.html looks at adults with congenital heart disease, finding a significant increase in cancer years after exposure to ionizing radiation, with higher rates associated with more exposure

http://gmodestmedblogs.blogspot.com/2014/01/ct-and-radiation.html

http://gmodestmedblogs.blogspot.com/2013/07/ct-scanning-in-kids-and-radiation.html for projected effects of CT scanning in kids on cancer risk

geoff

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