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Women’s Health

Primary Care Corner with Geoffrey Modest MD: texas abortion law changes and its effects

3 Mar, 17 | by EBM

By Dr. Geoffrey Modest

This blog will not shock you: when Texas closed abortion facilities, decreasing access and making women travel further distances to get an abortion, there was a substantial decrease in the number of abortions done with a small increase in out-of-state abortions (see doi:10.1001/jama.2016.17026).

Details:

  • In 2013 Texas enacted a restrictive abortion law which was partially reversed by the Supreme Court in 2016 as being unconstitutional
  • After passage of the law, the number of abortion facilities declined, with the following changes:
    • 2012 (prior to the law): 66,098 abortions done in Texas, 97 done out-of-state. 41 abortion facilities in 17 counties in Texas
    • 2014: 53,882 abortions done in Texas, 254 done out-of-state. 21 abortion facilities in 6 counties in Texas
  • The median distance to a facility increased by 51 miles. There was a clear, consistent trend between the decrease in abortions and the distance to the nearest facility (p<0.001 for trend):
    • 0 distance assoc with 1.3% decline
    • 25-49 miles assoc with 25.3% decline
    • >100 miles assoc with 50.3% decline
  • Even counties with open facilities and minimal distance (within 5 miles)  had a 15.9% decline in abortions [perhaps from less local access, with the number of women seeking abortions being greater than the new capacity]

Commentary:

  • The above does not include abortions done in Mexico, or self-induced abortions
  • Adding together the in-state and out-of-state abortions confirms a 18.2% decline, despite the shift to more being out-of-state
  • None of this is terribly surprising. The concern now is that the new US president and vice-president, their Cabinet appointees, their likely Supreme Court appointees, and the Republican House and Senate are pretty likely to make matters much more difficult for women in the near future. And perhaps decrease funding for/access to birth control, making the situation even more untenable (g. closing Planned Parenthood or not funding abortion/contraceptive services). Especially for poorer women with fewer resources/alternatives.
  • I would just add that in Illinois in the late 1960s/early 1970s, when abortion was illegal, I was told that there were 2 full wards at Cook County Hospital (about 50 people) filled with women having septic abortions (serious uterine infections, in this case after “back-alley” abortions done by coat-hangers, ). And there was a 10% mortality rate….

Primary Care Corner with Geoffrey Modest MD: Is Mammography Useful?

14 Feb, 17 | by EBM

By Dr. Geoffrey Modest

This blog will bring up 2 recent studies suggesting the lack of efficacy of mammography screening coupled with significant overdiagnosis.

  1. An article a couple of years ago looked at screening mammography in the US, with 10 year follow-up of breast cancer incidence and mortality (see Harding C. JAMA Intern Med 2015; 175: 1483).

Details:

  • This was an ecological study of 16,120,349 women 40 years of older who resided in 547 counties reporting in the Surveillance, Epidemiology, and End Results (SEER) cancer registries during the year 2000.
  • 53,207 had a diagnosis of breast cancer and were followed for 10 years.
  • The researchers looked at the extent of the screening in each county, and the results of both breast cancer incidence and mortality (the latter being defined as women diagnosed with breast cancer in the year 2000 who had died from the disease during the 10 year follow-up period). Overall, in the 547 counties, the overall 10-year incidence based mortality was 47.2 per 100,000 cases diagnosed in 2000.

Results:

  • There was a strong positive correlation between the extent of mammography screening and the breast cancer incidence (P<0.001)
  • But, there was no relationship between screening and breast cancer mortality.
  • Each increase of 10 percentage points in the extent of screening was accompanied by:
    • A 16% increase in breast cancer diagnoses, RR 1.16 (1.13- 1.19)
    • Not even a trend to a change in breast cancer deaths, RR 1.01 (0.96-1.06)
  • Analyzing by tumor size, screening led to a higher incidence of small breast cancers (<= 2 cm), but not with a decreased incidence of larger breast cancers (>2 cm )
  • Each increase of 10 percentage points in screening is associated with:
    • A 25% increase in the incidence of small breast cancers, RR 1.25 (1.18- 1.32)
    • A 7% increase in the incidence of larger breast cancers, RR 1.07 (1.02- 1.12)
  • The following figure shows that as the proportion of women had a mammogram in the past two years, the incidence of breast cancer diagnoses increased significantly yet the 10-year mortality did not budge

Commentary:

  • So, pretty powerful large-scale epidemiologic study, finding that mammography led to a large increase in the diagnosis of small cancers, but there was no decline in the detection of larger cancers. This may be the reason why there was no significant difference in the overall death rate from breast cancer by doing mammography screening.
  • What does this mean? It may mean that there are a subset of very aggressive small cancers which spread and cause clinical disease and mortality, and that screening is didn’t help for these. And that a very large number of small cancers that are picked up by mammography are in fact “overdiagnosed” (defined as: tumors that would not have become clinically evident in the remaining lifetime without screening).
  • One would have expected that if screening did pick up small tumors earlier, that over time the diagnosis of larger and less treatable cancers should decrease. It is quite concerning that the number of larger breast cancers in fact continued to increase over the study. And, of course, the goal of screening is to reduce mortality, which was not found in the study. One additional finding was that increased screening would lead to more breast conserving surgical procedures; however they found no evidence of a decrease in extensive mastectomies.
  • Without getting into a lot of detail, the authors present reasonable arguments that this is not just lead-time bias, or ecological bias (this latter happens when looking at group data and assuming that it applies to the individual who may or may not have had a mammogram). Also, there was no association between mortality rates even comparing those counties with much higher breast cancer incidence, reducing the potential bias of comparing counties with very different incidences of breast cancer. But, they also did not have data on women who had therapy or what the risk factors were for the women who developed breast cancer. Also, this was just a 10-year follow-up, and patients may well live more than 10 years with newer therapies, but I would have expected some evident benefit of screening by 10 years (and at least a trend to benefit…)
  • There have been several important changes in technology over the past several decades, some of which may make older studies less applicable now (these older studies are the ones on which current mammogram recommendations are based). On the one hand, the sensitivity of our screening methods is greater and we are picking up much smaller tumors; and, perhaps these smaller tumors are more likely to regress than the larger ones picked up previous, leading to increased overdiagnosis. On the other hand, treatments have improved a lot, and the risk/benefit equation may have changed some. Given the potential harms of overdiagnosis (including surgery, radiotherapy, and chemotherapy), we should be looking at the new balance. In addition, there are interesting advances in genomic profiling, which are helpful in determining how aggressive a tumor is likely to be as well as how intensive therapy should be

So, a large study like this offers interesting insights, especially when looking at likely overdiagnosis (which one cannot determine in an individual patient). As with all screening tests (e.g. PSA), it would be really useful to figure out how to risk stratify patients, with more aggressive screening in those at higher risk. That is much more likely to show benefit for screening then with screening the general population.

—————————————–

  1. A more recent article look specifically at breast cancer overdiagnosis by mammography screening in Denmark (see doi:10.7326/M16-0270)). The study looked at women aged 35 to 84, from 1980 to 2010.

Details:

  • Denmark had a perhaps unique opportunity to look at the results of mammography screening both because it has rigorous databases (the Danish Breast Cancer Group, DBCG, and the Danish Cancer Registry, DCR) as well as a 17-year screening program which involved 20% of the population aged 50 to 69. This differential access to mammography screening allowed for real-world comparisons to a large, essentially randomized non-screening populations. Clinical breast exams were not included.
  • The DBCG database included 90,665 women aged 35 to 94 who were diagnosed with invasive breast cancer, and 4267 diagnosed with DCIS
  • For the mammography group in DBCG, they divided tumors into two groups: large (>20 mm) and small (<20 mm), considering the large tumors as “advanced” because they are equivalent to T2 or greater in the TNM classification system
  • The screening routine, somewhat different from what we do in the US, was biennial screening with a 2-view mammography on the first round, with 1-view mammography at subsequent screens except for women with dense breasts who always received a 2-view mammogram.
  • The DCR provided individual data on tumor size in women with invasive breast cancer.

Results:

  • For women aged 35 to 69: in non-screening areas the incidence of advanced cancer increased throughout the observation period.
  • For women 70 to 84: in the non-screening areas the incidence of advanced cancer also increased throughout the observation period, and was most pronounced in the later years.
  • The incidence of non-advanced tumors increased in the screening versus prescreening periods, incidence ratio 1.49 (1.43- 1.54), i.e. a 49% increase
  • Looking just at nonadvanced tumors, there were 711 invasive tumors and 180 cases of DCIS that were overdiagnosed in 2010 (overdiagnosis rate of 48.3% including DCIS and 38.6% excluding DCIS
  • There was no reduction in the incidence of advanced cancers through mammography screening.
  • Their conclusion: “it is likely that one in every three invasive tumors in cases of DCIS diagnosed and women offered screening represents overdiagnosis (incidence increase of 48.3%)”

Commentary:

  • This study is quite remarkable since it is reasonably close to a really large-scale randomized controlled trial, in which for 17 years 20% of women got mammograms and the rest didn’t. And there was no difference in advanced breast cancers through consistent mammography screening
  • See below for other blogs on the poor utility of mammography screening, also showing almost no decrease in breast cancer mortality but large numbers of overdiagnosed mammogram-detected cancer.
  • A lot of the “overdiagnosis” is from DCIS (about 25% of all new breast cancer diagnoses), which the National Cancer Institute now classifies as a “noninvasive condition” (an observational study of 108,196 women with DCIS in the SEER registries found an overall breast cancer death rate of 3.3% over 20 years, similar to the general population: see Narod SA. JAMA Oncol 2015; 1(7):888
  • All of this reinforces the fact that early detection of breast cancer is fraught. For breast cancer, there are 230,815 diagnoses/year in women, 2109 in men; and 40,860 breast cancers deaths/year in women and 464 in men, and affects 1 in 8 women!!!; yet mammography screening has perhaps minimal benefit. Which really brings up the issue of prevention (which, it turns out, does not get much funding). As noted in prior blogs, one big unknown is the prevalence of industrial toxins (many of which are estrogenic, including pesticides, BPA, others used in plastics, etc etc) which are in our environment and may well be carcinogenic. Large numbers of new chemicals are being used and thousands of new ones are introduced each year with minimal attempts to look at potential toxicity. In addition, it is reasonably clear from the studies that healthy diet, weight control, and exercise are helpful. It seems to me that it would likely be much more useful to devote our national resources into preventing breast cancer by regulating environmental toxins and promoting healthy lifestyles than attempting early detection.

See http://blogs.bmj.com/ebm/2016/10/13/primary-care-corner-with-geoffrey-modest-md-radiologist-variability-in-mammography-readings/ which documents the quite remarkable discordance in radiologists’ reading of breast densities

See http://blogs.bmj.com/ebm/2014/02/13/primary-care-corner-with-geoffrey-modest-md-mammography-another-hit/​ for the 25-year results from the Canadian National Breast Screening Study finding NO benefit from mammography screening but that 22% of mammography-detected breast cancers were overdiagnosed.

See http://blogs.bmj.com/ebm/2014/04/22/primary-care-corner-with-geoffrey-modest-md-mammograms-again/ for a 2014 meta-analysis, finding that mammography yielded very small changes in breast cancer mortality (e.g. screening women in their 50s would lead to 3-32/10,000 decrease in breast cancer mortality, but have 6130 false positive and 30-137 overdiagnoses)​. As mentioned above, these studies were older ones.

Primary Care Corner with Geoffrey Modest MD: pregnancy and congenital heart disease management

25 Jan, 17 | by EBM

By Dr. Geoffrey Modest

There was a new guideline from the American Heart Association on the management of congenital heart disease in pregnancy (see http://circ.ahajournals.org/content/early/2017/01/12/CIR.0000000000000458?sid=3d46cd93-3125-4db0-8f6c-a1002093e09d  ). Given that this is not a common primary care issue, I will broadly review their approach and defer to the article itself for the specifics

In (very) brief, this article has sections on:

  • Physiology of pregnancy and its effects on the heart/lungs (e.g. increased blood volume, increased cardiac output, decreased oncotic pressure, increased heart rate, increased B-type natriuretic peptide, vascular tree remodeling to accommodate the increased blood volume, increased pulmonary tidal volume/minute ventilation)
  • Preconception counseling/diagnostic evaluation
  • Estimating maternal and fetal risk, including some risk stratification calculators
  • Medications in pregnancy (with detailed chart on cardiac meds, pregnancy risk category, teratogenic risk, lactation suggestions, etc.
  • Fetal screening
  • Approach to obstetric care
  • Therapy for cardiac problems (arrhythmias, heart block, mechanical valves/anticoagulation, heart failure, cyanosis)
  • Interventional therapies (transcatheter interventions, cardiovascular surgery, cardioversion, ablation, implantable defibrillators/pacemakers)
  • Specific cardiac conditions (pulmonary hypertension, aortic stenosis/LV outlet tract obstruction, transposition of great arteries, etc.)

It seems to be a good reference to keep on hand for those of us doing prenatal care, or general medical care of women with congenital heart disease who are thinking of becoming pregnant

Primary Care Corner by Geoffrey Modest MD: pap in women with HPV vaccine jnci2016

19 Oct, 16 | by EBM

By Dr. Geoffrey Modest

Given the recent 2 articles on cervical cancer screening (http://blogs.bmj.com/ebm/2016/10/12/primary-care-corner-with-geoffrey-modest-md-cervical-cancer-screening-less-frequently/ and http://blogs.bmj.com/ebm/2016/10/17/primary-care-corner-with-geoffrey-modest-md-cervical-screening-guidelines-from-asco/), I thought I would add (briefly) a third to the troika (see doi: 10.1093/jnci/djw216). Funded by National Cancer Institute of the NIH and done by Harvard School of Public Health.

Details:

  • This is a mathematical modeling of the cost-effectiveness of different cervical cancer screening approaches in HPV-vaccinated women
  • They looked at different levels of cost-effectiveness thresholds: from $50K to $200K per quality-adjusted life-year (QALY) gained

Results:

  • In women who were fully vaccinated with either the bivalent or quadrivalent HPV vaccine, optimal screening strategies involved either cytology or HPV screening alone every 5 years starting at age 25 or 30 (cost-effectiveness ratios ranging from $34,680 to $138,560 per QALY gained
  • In women vaccinated with the nonavalent vaccine (that being: 9 HPV genotypes), only HPV testing by itself was efficient, with both decreased frequency (every 10 years) and starting later at age 35 ($40,210 per QALY) or age 30 ($127,010 per QALY)
  • If there were in reality decreased nonavalent vaccine efficacy, then the 10-year HPV screening should start at age 25 or 30.

Commentary:

  • This article does highlight the issue mentioned briefly in the prior 2 blogs: HPV vaccination might significantly change the cervical cancer screening algorithm
  • The nonavalent vaccine, the one we use now, covers 90% of the carcinogenic HPV types (including the biggies 16/18), as well as 2 of them (6/11) associated with noncarcinogenic genital warts
  • But, there are certainly concerns about directly applying the above:
    • The US rates of HPV vaccination remain <50%
    • There are very limited real-world data on the effectiveness of the vaccines in reducing HPV infection and, especially, the development of precancerous or cancerous lesions
    • This relies on mathematical modeling, which without any real data, is likely fraught with potential errors in assumptions
    • There is potential collateral benefit from screening less: fewer harms from unnecessary colposcopies (???though are we missing some of the “necessary” ones??)
  • So, this adds some to the argument that we need to screen less. The analysis/conclusions would be different if women did not receive the vaccine before they had sexual relations (though, important to remember that HPV can be transmitted without penetrative sexual relations), or did not receive the full series of shots. And the real issue is waiting for real data about the effects of vaccinations in the real world on the incidence of actual CIN and advanced cervical cancer and morbidity/mortality. I am also a little leery about the effect of doing many fewer pelvic exams: I find now that some newer clinicians are less confident doing them, and sometimes do not do them when there are clear clinical indications. This potential adverse effect should somehow be factored into the risk/benefit analysis…

Primary Care Corner with Geoffrey Modest MD: Cervical Screening Guidelines From ASCO

17 Oct, 16 | by EBM

By Dr. Geoffrey Modest

The American Society of Clinical Oncology just published guidelines for the secondary prevention of cervical cancer (see doi: 10.1200/JGO.2016.006577, or go to  http://ascopubs.org/doi/abs/10.1200/JGO.2016.006577 ). These guidelines were unusual in that they stratified the screening approach based on the country’s resources, reflecting a global initiative, and also had several differences from the current US guidelines.

Details:

  • HPV testing is recommended in all resource settings, though visual inspection with acetic acid may be used in countries with basic resources.
  • Frequency of testing:
    • For countries with maximal resources: should be from age 25 to 65, every five years if negative.
    • For countries with enhanced resources: age 30 to 65. If two consecutive negative tests at five-year intervals, then every 10 years. Stop at age 65 if consistently negative results for the past 15 years
    • For countries with limited resources: age 30 to 49 every 10 years
    • For countries with basic resources: age 30 to 49, 1 to 3 times per lifetime
  • Treatment options for patients with a positive screen:
    • In countries with more than basic resources: colposcopy, then loop electrosurgical excision (LEEP) if positive
    • For countries with basic resources: treat with cryotherapy or loop electrosurgical excision
  • Follow-up post-treatment:
    • 12 month follow-up is recommended in all settings
  • For HIV-positive women (also applies to women who are immunosuppressed for any reason):
    • Overall, screen with HPV testing twice as many times per lifetime as in the general population (as above). Screening should begin as soon as they get the HIV diagnosis [? when to start if they are born with the infection/or get it from a transfusion at age 8???].
      • In countries with maximal  resources: screen with HPV every 2-3 years
      • In countries with enhanced resources: screen with HPV at 2-3 year intervals; but if negative, every 5 years (approx 8 screenings in lifetime)
      • In countries with limited resources: twice as often as in general population (4-6 screenings per lifetime)
      • In countries with basic resources: begin screening with HPV if available, or with visual inspection with acetic acid, at age 25, then every 3 years if negative initially. [A bit unclear, since they then suggest it will be approximately twice per lifetime]. These recommendations are based on murky data…
    • Postpartum screening: overall no screening recommended during the pregnancy, partly because the normal immune changes in pregnancy can have increased HPV changes which subside after pregnancy.
      • Screen at six months in all countries other than those with only basic resources, where screen at 6 weeks since longer interval could lead to loss of follow-up [though this might apply to other countries, or areas in other countries as well…..]
    • No screening should be done in people who had a total hysterectomy for benign causes [though see blog http://blogs.bmj.com/ebm/2016/07/18/primary-care-corner-with-geoffrey-modest-md-pap-smears-post-hysterectomy-in-hiv-positive-women/, which would support general screenings in HIV-positive women who had hysterectomy]
    • And, in countries with basic resources without mass screening — infrastructure for HPV testing, diagnosis and treatment should be developed
    • Self-screening: there is evidence that women doing their own HPV sampling may improve screening coverage, though the pooled sensitivity and specificity are lower, especially for CIN2+. So, overall not suggested except in women who might otherwise not get tested at all [and the sensitivity and specificity are actually only a little lower].
    • Postulated effect of HPV vaccine: likely to decrease the incidence of HPV 16/18 cancers, and with approx 5 year later onset of disease as a result of decreasing these most-carcinogenic genotypes, so potentially can start screening later in life, and decrease screening to ages 30, 45, 60. Maybe no need to screen at all??? Or only once??  But all recommendations are pending actual data….

Commentary:

  • High-quality screening programs can lower the incidence of cervical cancer by up to 80%
  • HPV is the most frequent sexually-transmitted infection, with one study finding 43% of college women getting infected over 36 months (see Ho GYF. New Engl J Med 1998; 338:423)
  • As a point of reference, the US screening guidelines at this point are quite different from the above ASCO ones for countries with maximal resources (e.g. the USPSTF recommendations):
    • Begin at age 21, do cytology screening only until age 30, and then every 3 years if normal. HPV testing not recommended because of higher likelihood of unnecessary follow-up and procedures (HPV infection tends to be transient)
    • After age 30, either continue cytology only every 3 years, or do cytology/HPV co-testing every 5 years, if normal results
    • Stop at age 65 unless there is increased risk (history of abnormal screens, prior HPV-related disease, immunocompromise, DES exposure); and if there are 2 negative consecutive co-tests or 3 negative cytologies within prior 10 years; and no history of high-grade dysplasia or worse
  • Although ASCO cites the importance of HPV testing, they do not make formal recommendations about primary HPV testing vs co-testing, noting just that some countries and regions have moved towards adopting primary HPV testing (see http://blogs.bmj.com/ebm/2016/10/12/primary-care-corner-with-geoffrey-modest-md-cervical-cancer-screening-less-frequently/ )
  • The American College of Obstetricians and Gynecologists also just came out with their recommendations in 2016 (though, not sure what to make of this: but these guidelines were retracted from the January 2016 issue of their publication Obstetrics and Gynecology, and I could find only recommendations for HIV-positive women, though these were also retracted), with a few differences from ASCO. for HIV infected women:
    • Start screening within one year of onset of sexual activity, but no later than age 21
    • Screening should be continued throughout a woman’s lifetime and not stop at age 65
    • For women less than 30 years old:
      • Cytology screening (without HPV testing) should be repeated in 12 months (though some people feel it should be followed in six months)
      • If three consecutive cervical cytology tests and normal, follow-up cervical cytology should be done every three years
      • If ASCUS on cytology, and reflex HPV testing is positive, then colposcopy. If HPV testing results are not available, repeat cytology in 6 to 12 months if more advanced dysplasia is found, refer for colposcopy
    • For women older than 30 years old, do cervical cytology or co-testing:
      • If only cytology is done, follow-up is as for women less than 30 years old
      • If co-testing is done and negative, repeat at three years; if cytology is negative and HPV positive, repeat in one year (though if HPV 16/18 is present go directly to colposcopy). if either of the co-tests at one year is abnormal, colposcopy
    • The hope is that as HPV vaccination becomes more widespread, the incidence of cervical cancer will decrease significantly as well as the need to screen for it; though this is in the relatively distant future, given the high prevalence of HPV infections currently, and the vaccine does not help those currently infected or with abnormal cytology from infection
    • They do recommend starting screening at age 25, as is done in several countries in Europe for example, noting that there is lack of evidence of the benefit of decreased cancer risk in those under 25 (very uncommon), and potential harm or screening and overtreatment. The United States still recommends initiation of screening at age 21. And though HPV infections are remarkably common in women under 25 (as noted in study above), HPV infections clear spontaneously, and 90 to 95% of those with even LGSIL as well as many with high-grade lesions regress spontaneously
    • And they recommend HPV screening at age 25 in countries with maximal resources, different from the general recommendations in the US to start HPV screening at age 30
    • So, my guess is that the formal US recommendations will change significantly in their next iteration (the USPSTF recommendations date from 2012, with an anticipated update 2018). Perhaps internal controversy led to ACOG retracting their guidelines??  But it is pretty clear that recently the approach to cervical cancer screening has changed significantly in other countries.

Primary Care Corner with Geoffrey Modest MD: Radiologist Variability in Mammography Readings

13 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent article revealed the dramatic variability in radiologists’ interpretations of mammographic breast density (see Sprague BL. Ann Intern Med 2016; 165: 457). Determining breast density accurately is certainly important because increased breast density leads to difficulty in reading mammograms and is an independent risk factor for breast cancer. In this light, one prerequisite for us in primary care is that the radiologic determination of breast density is consistent and accurate. But, details, from an NIH supported study:

  • Data from 216,783 screening mammograms from 145,123 women aged 40 to 89 were included, from 30 radiology facilities within three breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium.
  • 83 radiologists were involved; each interpreted at least 500 screening mammograms from 2011-3, using the BIRADS reporting system, along with patients age, race, and BMI

Results:

  • 9% of mammograms were rated as showing dense breasts
  • Across radiologists, the finding of dense breasts ranged from 6.3% to 84.5% (median 38.7%, interquartile range 28.9% to 50.9%). !!!!
  • Variation in breast density assessment was pervasive in all but the most extreme patient age and BMI combinations
  • Among women with consecutive mammograms interpreted by different radiologists, 17.2% had discordant assessments of breast density.

Commentary:

  • One of the scariest issues to me as a clinician is that I need to rely on an accurate interpretation of medical tests in order to inform my patient management. The sheer magnitude of the variation in breast density assessment is quite striking.
  • There are also other studies, mostly 10-20 years old, showing that the general radiologic interpretation of mammograms has considerable variability as well.
  • There are certainly other tests that have significant variability andhighlight this issue more broadly — for example finding significant spine MRI abnormalities in totally asymptomatic patients:
    • One study (see Jensen MC. N Engl J Med 1994; 331: 69) looked at 98 people without back pain, where their MRI scans were interpreted by two experienced neuroradiologists at the Cleveland Clinic, finding that 52% had a bulge in at least one intervertebral disc, 27% had a protrusion, and 1% had an extrusion. 38% had multilevel abnormalities. Only 36% had a normal MRI.
    • A systematic review (see Brinjikji W. AJNR2015 36: 811-816) found dramatic MRI or CT changes in asymptomatic people, which increased with age.  For example, the prevalence of disc degeneration went from 37% at age 20 to 96% at age 80, bulges went from 30% at age 20 to 84% at age 80, disc protrusion from 29% age 20 to 43% at age 80, annular fissure from 19% age 20 to 29% at age 80.  so, lots and lots of impressive disc changes even in asymptomatic 20 year olds……
  • Another issue, which we tend to understand more intuitively, is that of ultrasounds, which are clearly operator-dependent. But we had a patient with chronic hepatitis B, who had a “normal” screening RUQ ultrasound for hepatocellular cancer, but a CT revealed a 9cm cancer!! I spoke with a trusted hepatologist who commented that he used a CT to scan to screen for really high-risk patients because of the variability of ultrasounds (though that is not exactly a clear-cut, or generally accepted algorithm….)
  • One major concern about over-reading breast density (as well as potentially scaring patients that they might be at higher breast cancer risk) is that this findingoften leads to further studies such as ultrasound, digital breast tomosynthesis, and MRI examination (though there is minimal evidence to support these tests, and they may well lead to unnecessary biopsies, more radiation exposure, etc. And the USPSTF formally gives these procedures an “I” rating, for insufficient evidence)
  • And, another issue:  half of the United States has legislation currently requiring disclosure of mammographic breast density, in some cases advising women to discuss supplemental screening tests with their providers if they have dense breasts (again without supportive medical evidence). And even theFDA is considering a legislative requirement to report breast density information to patients. I think there is a real concern about non-medical legislators enacting medical legislation, where legislators may be swayed by patients pleading for unproved treatments, perhaps with the support of an “expert witness”. Or, perhaps the legislature decides to require a certain treatment based on small or flawed studies, writes the treatment into law, but then new and better studies contradict this legislative imperative. One recent example is in Massachusetts, where a law was passed requiring insurance to cover long-term antibiotic therapy for chronic Lyme disease, though several studies, including a new one (see Berende . N Engl J Med2016;374:1209-1220), have not found benefit from long-term antibiotics. Or, in the past, there has been legislation supporting the availability of bone marrow transplants for women with breast cancer, but without any evidence of benefit (and pretty clear harm). I do realize that there have been egregious, inappropriate treatment denials by some health insurers in the past which has led to some of this legislation and public/medical community outrage. But legislating medical diagnostics and therapies is fraught…..
  • So, this inconsistency/unreliability in breast density interpretation may subject many people to potentially dangerous interventions. I think it is really important that we as clinicians understand that many procedures we order are subject to large variability, as above. So, what can we do??
    • Whenever possible, we should interpret these “objective” data in the context of the clinical situation of the patient, and not always reflexively respond to the test results (it is just another piece of data, such as from the history or physical, which should be put in the overall gestalt of what is going on with the patient). Of course, some of these objective findings, even unsuspected, may be very important and not dismissed (e.g., the incidental finding of early pancreatic or renal cancers).
    • Maybe we should consider getting second opinions more often than we currently do, to assess interobserver agreement
    • Perhaps there should be triggers in place for certain findings (such as dense breasts on mammogram), requiring a blinded read by another radiologist, or?? always having mammograms automatically re-read by another radiologist??, or having an automatic second-read whenever a radiologist comments “should be repeated in 3-6 months by another test”, which puts the medicolegal imperative on us in primary care to do yet another test with potentially more radiation exposure, cost, possible unnecessary procedures, etc.
    • Perhaps there needs to be much more transparency in the system overall, maybe requiring those reporting on these results to have regular standardized testing themselves and posting the results (sort of like requiring hospitals to report their C-section rates).
    • Perhaps we need a good computer program????
  • I realize this blog is more tangential than others, but i do think this issue of inconsistency in mammography reading does bring up a slew of general issues in clinical medicine…..

Primary Care Corner with Geoffrey Modest MD: Cervical Cancer Screening Less Frequently?

12 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent review of cervical HPV screenings in the Netherlands found that those with negative screening could potentially be screened less frequently than every 5 years (see doi.org/10.1136/bmj.i4924).

Details:

  • 43,339 women aged 29-61 with a negative HPV and/or cytology were randomly assigned to HPV and cytology co-testing (intervention group) or cytology testing alone (control group); with 3 screens: at baseline, 5 years and 10 years; and with followup at 14 years. Those in the cytology only group also got HPV testing but this was blinded to all.
  • Mean age 43
  • Their triage approach (different from US recommendations):
    • For intervention group (cytology plus HPV):
      • Normal HPV and cytology: repeat in 5 years
      • At least moderate dyskaryosis on cytology: colposcopy
      • HPV positive, and neg or borderline/mild dyskaryosis (eg ASCUS or LGSIL) on cytology: repeat HPV/cytology at 6 and 18 months. refer to colposcopy if continued HPV positive or cytology worse
    • For control group (cytology only)
      • Normal cytology: cont routine screen
      • At least moderate dyskaryosis on cytology: colposcopy
      • Borderline/mild dyskaryosis (eg ASCUS or LGSIL) on cytology: repeat cytology at 6 and 18 months. refer to colposcopy if cytology same or worse

Results:

  • Co-testing group: 20,490 of 21,623 women had double negative HPV/cytology, 764 had pos HPV/neg cytology, 369 pos cytology/neg HPV
  • Cytology only group: 20,533 of 21,716 had negative cytology, 814 had pos HPV/neg cytology (the HPV results were blinded), 369 pos cytology/neg HPV
  • During 14 years of followup:
    • Co-testing: 149 CIN2, 152 CIN3 (including 5 adenoca in situ), 8 squamous cell and 6 adeno carcinomas
    • Cytology only: 126 CIN2, 169 CIN3 (including 5 adenoca in situ), 17 squamous cell and 10 adeno carcinomas
  • Breakdown of the 14 year followup according to cytology and HPV status (again, HPV results were blinded for the control group)
    • Cancer:
      • Cytology neg/HPV neg: 7 in intervention, 12 control; 3.3 vs 5.7/100,000 women, incidence ratio 0.58 (0.23-1.48), nonsignficant
      • Cytology neg/HPV pos: 4 in intervention, 15 control; 55.4 vs 190.9/100,000 women, incidence ratio 0.29 (0.10-0.87)
      • Cytology pos/HPV neg: 3 in intervention, 0 control; 79.7 vs 13.4/100,000 women, incidence ratio 5.97 (0.30-119.22), nonsignficant [but they had to use 0.5 instead of 0 for the cancer count, in order to do the math]
    • CIN3+ (the combination of cervical cancer and precancer):
      • Cytology neg/HPV neg: 74 in intervention, 86 control; 35.0 vs 40.7/100,000 women, incidence ratio 0.86 (0.63-1.17), nonsignficant
      • Cytology neg/HPV pos: 82 in intervention, 94 control; 1135.1 vs 1196.1/100,000 women, incidence ratio 0.95 (0.71-1.28), nonsignificant
      • Cytology pos/HPV neg: 10 in intervention, 16 control; 265.7 vs 427.1/100,000 women, incidence ratio 0.62 (0.28-1.37), nonsignficant
    • The cumulative incidence of cervical cancer 14 years after the initial negative cytology/negative HPV screen in the co-testing group (0.09%) was the same as in the cytology negative patients in the cytology-only group after 9 years
    • The cumulative incidence of CIN3+ was 0.56% 14 years after the initial negative/negative screen in the co-testing group, but 0.69% in the cytology negative patients in the cytology-only group after 9 years
    • Combining both groups, the incidence of CIN3+ was 72.1% lower (60.5-80.4%) in women >40 years old vs younger; no statistically significant difference in cervical cancer

Commentary:

  • Several studies have supported using only HPV screening without cytology (primary HPV screening) for detection of cervical dysplasia/cancer (g., see doi.org/10.1136/bmj.e670 from BMJ or Ronco G. Lancet 2014; 383 (9916): 524); the latter study found that there was 60-70% better protection with primary HPV screening over cytology screening. And primary HPV screening might avoid over-referral to colposcopy and biopsies. And decrease the number of screens done/longer intervals between screenings. Several countries now do primary HPV screening including Australia, Italy, Netherlands, New Zealand, Sweden and the UK. The current study looked not just at cervical cancer, which may take years to manifest itself, but also to high-grade precancerous lesions (CIN3+) to try to ascertain if the longer screening interval could miss women with evolving cancers (which it didn’t: those with combined screening had the same incidence at 14 years as the cytology only group at 14 years).
  • So, this study suggests several things:
    • It confirms the superiority of HPV/cytology screening over cytology alone
    • The very low incidence of CIN3+ in the overall combined groups (including the blinded HPV testing of the cytology-only group) who had negative HPV testing (independent of cytology) was quite low: 84 events in 20,859 patients (e.g., as compared to those who were HPV positive but cytology negative, with CIN3+ in 82 of 764 patients), affirming that HPV testing is superior to cytology testing
    • The study also confirmed the utility of testing more than just the highest risk HPV 16/18 types, since there were 30 of 501 patients with CIN3+ who were HPV positive/cytology negative and HPV 16/18 negative
    • And the big conclusion was the very low risk of CIN3+ and cervical cancer itself in patients who were >40yo and had dually negative initial HPV/cytology
    • Putting this all together, in 2017 the Netherlands will implement the strategy of every 10-year screening for HPV negative women at least 40 years old
  • So, there really seems to be increasing data suggesting that primary HPV is a superior screening test (adding cytology seems to add more false positives than providing real clinical benefit), though i would imagine there need to be more studies in different populations to see what the optimal screening interval should be.

Primary Care Corner with Geoffrey Modest MD: Pap Smears Post-Hysterectomy in HIV Positive Women

18 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A rather striking retrospective study was just published from 2 clinics in Texas, showing a high rate of vaginal intraepithelial neoplasia (VAIN) and vaginal cancer in HIV-infected women with no prior history of abnormal cytologic screening and who had a hysterectomy for conditions other than cervical dysplasia and cancer (see Smeltzer S. Obstet Gynecol 2016; 128: 52).

Details:

  • 68 providers, 4 of whom did regular pap screening, with 1827 HIV-positive women seen in 2015. Rate of pap testing was 47%
  • 238 women were seen between 2000-2015 with a history of HIV, previous hysterectomy, and no previous abnormal Pap test results
  • Median follow-up time for the Pap test was 16 years.
  • Results:
    • 164 (69%) had normal Pap test results
    • 12 (5%) had results showing atypical cells of undermined significance and human papillomavirus-positive
    • 55 (23.1%) had results showing low-grade squamous intraepithelial lesion
    • 7 (2.9%) had results showing high-grade squamous intraepithelial lesion
    • Of those who underwent biopsy for abnormal pap tests:
      • 15 (28%) had normal results
      • 23 (43%) had VAIN 1
      • 9 (16%) had VAIN 2
      • 7 (13%) had VAIN 3
      • No patients had invasive vaginal cancer.
    • No demographic risk factor was associated with the abnormal Pap test results after hysterectomy (race, smoking history, alcohol history, illegal drug use). Also no association with a specific indication for the hysterectomy (fibroids vs pelvic pain vs bleeding). The story was mixed on HIV-related risk factor (though overall there was not much difference in CD4 or viral load between those with normal vs abnormal paps, within 6 months of the pap abnormalities there was a significant deterioration: median CD4 was 573 vs 364, and viral load was 248 vs 400, all values with p<0.001)
    • Older patients and higher viral load significantly increased the risk of development of an abnormal Pap test result. For example, the patients with viral load values greater than 400 had approximately two times the risk of developing an abnormal Pap test result than those lower than 400; the adjusted hazard ratio of 2.1 (95% CI 1.2–3.5). In terms of age: 30-38yo HR 2.2, 38-44yo HR 3.8, >44yo HR 6.3
    • No difference in time to abnormal Pap test result was noted with antiretroviral use, or by CD4.

Commentary:

  • No guidelines suggest regular pap screening for women with a hysterectomy, unless the hysterectomy was done for cancer or precancerous lesions
    • USPSTF, Am Cancer Society, ACOG, etc are against routine screening in these women overall:  “The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer”, giving it a “D” recommendation
      • However, I should add that old studies did find a non-zero but low risk of vaginal abnormalities in women in the general population getting a pap smear post-hysterectomy for benign causes (see Pearce KF. N Engl J Med 1996; 335: 1559, which noted that of 9610 vaginal smears, atypical squamous cells of undetermined significance (ASCUS) occurred in 52 (0.5%); low-grade squamous intraepithelial lesion in 44 (0.5%); high-grade squamous intraepithelial lesion in 6 (0.1%); and squamous-cell carcinoma in 2 (0.02%). In 5 women, biopsies revealed vaginal intraepithelial neoplasia type I or II; there were no biopsy-proved cases of vaginal cancer. The probability of an abnormal Pap smear in this group of women was 1.1 percent, and the positive predictive value of the Pap test for detecting vaginal cancer was 0.Mean time to get potentially significant intraepithelial lesions was 19 yrs. Because of the age of this study, there was no information about HIV or HPV status.
    • There are very limited data and no clear recommendations on pap testing in HIV-positive women having a hysterectomy for benign reasons.
  • There are several unanswered questions (which really should be studied).
    • This Texas study was a retrospective analysis with limited data collected and there are no data I’ve seen on the effect of interventions on changing actual clinical outcomes in abnormalities picked up by routine screening
    • We know that HPV infection tends to persist in HIV-positive men and women, with attendant increased risk of anal and cervical cancers. It would be great if there were prospective data looking at HPV status and vaginal paps in women. In the above study, the ASCUS findings were associated with HPV. My guess is that HPV is the culprit and that it seems reasonable to consider HPV and/or pap screening in women with HPV infection at the time of hysterectomy and later if at risk for getting an HPV infection. But this should be studied. And it is really important that we pursue HPV vaccination rigorously in young women (and men).
      • Since there was a deterioration of HIV markers (CD4 and viral load) within 6 months of the abnormal pap, perhaps should we be doing selective paps on those with HIV deterioration, or at certain levels of these counts. Again, it would be good to know prospectively if changes in HIV markers consistently preceded vaginal cytology abnormalities.
      • This study was done in a single population/demographic area. Is it generalizable?
      • Is there any relationship between numbers of sexual partners, partners infected with HIV, etc. and the development of VAIN?
    • So, this study does throw a bit of a wrench into conventional wisdom. It is pretty clear that there is more of a risk for vaginal cytologic abnormalities in women with HIV who get a hysterectomy for benign reasons than we had thought, and that recommendations be reconsidered given the relatively benign test (pap), and further work-up (biopsy). To me, it is not unreasonable to assume that for a woman with significant abnormalities on vaginal biopsy and with pathological deterioration on observation/local therapy, that definitive therapy be considered.
    • But, at this point, it does seem reasonable to do vaginal pap smears on women with HIV and hysterectomy for benign reasons. Unclear what interval. But it seems from the data that these are not very aggressive or rapidly progressive evolution from VAIN to cancer, so likely that they could be done every several years.

Primary Care Corner with Geoffrey Modest MD: Oral Contraceptives

3 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A huge observational study was done in France looking at women on oral contraceptives (OCs), looking at the relative dose of the hormones and the risk of pulmonary embolism (PE), ischemic stroke and MI (http://www.bmj.com/content/353/bmj.i2002 ).

Details:

  • 4,945,088 women aged 15-49 with at least one reimbursement for OCs and no prior history of cancer, PE, ischemic stroke or MI, between 2010-2012
  • Mean age 28, 34% used oral contraceptive with 20 mg estrogen,
  • Risk factors used in models: age, socioeconomic data (SES), hypertension, diabetes, and some indirect measures of smoking (e.g., getting nicotine replacement therapy) though smoking was not directly assessed in the database. The incidence of hypertension, diabetes or being prescribed nicotine replacement therapy were each <2%.

Results:

  • 5,443,916 women-years of OC use
  • 1800 PEs (33/100K women-years), 1046 ischemic strokes (19/100K women-years), 407 MIs (7/100K women-years)
  • Women >35 yo had 26.1% of all OC usage and 56.7% of these serious adverse events
  • Women in the lowest SES had 1.4-fold higher risk of PE, 1.5-fold increase in stroke and 2.5-fold increase in MI
  • By estrogen dose (ethinyl-estradiol), adjusting for progestogen and risk factors, and compared to levonorgestrel:
  • Low dose (20 mg vs 30-40 mg): 25% decrease PEs [RR 0.75 (0.67-0.85)]; 18% decrease ischemic strokes [RR 0.82(0.70-0.96)]; 46% decrease in MI [RR 0.56 (0.39-0.79)]
  • By progestin type, adjusting for estrogen dose and risk factors:
  • Desogestrel associated with 116% higher risk for PE [RR 2.16 (1.93-2.41)]; gestodene 63% higher risk [RR 1.63 (1.34-1.97)]; no significant difference for MI or stroke
  • Levonorgestrel combined with 20 mg estrogen was statistically better than levonorgestrel combined with 30-40 mg estrogen

This is an observational study, but a really large one, with several inherent limitations:

  • Short follow-up period of max 2 years, 3 months. Likely that the arterial events (MI and stroke) take longer to manifest themselves than PE (which might suggest that longer follow-up may have produced even more bad events with the higher doses estrogen/use of desogestrel or gestodene)
  • No start dates (a concern since the incidence of PE is highest early on, esp in the first 3 months). So, unclear when people were started on the low dose estrogens, and in fact these were available in France only more recently. However, when analysis was limited to postpartum women who have a pretty clear start date, the results were similar to the overall group
  • Possible confounding by indication: did doctors choose different OCs depending on BMI, or family predisposition to venous/arterial disease? Or those they felt to be at higher cardiovascular risk? This bias would, however, lead to more use of lower dose OCs and would therefore likely decrease the magnitude of the protective effect found with low-dose OCs.
  • One of the biggest deficiencies is the lack of clear smoking data, but again these women were likely to be put on the lowest dose OCs, which would tend to understate their risk (of note, other studies have not found that smoking modified the risk much)
  • Also, they only looked at PE, not other venous thrombotic events (e.g., DVTs)
  • So, it seems that the stars continue to align on this (and, see blog from last year on another large study finding that the newer OCs had much higher rates of venous thromboembolic disease: http://blogs.bmj.com/ebm/2015/06/23/primary-care-corner-with-geoffrey-modest-md-new-vs-old-ocps-and-thromboembolism/ . To me, it makes sense to use OCs with levonorgestrel unless there is a pretty compelling reason not to, and with whatever progestogen, use the lowest dose of estrogen one can.

Primary Care Corner with Geoffrey Modest MD: Dropping Teen Birthrates

18 May, 16 | by EBM

By Dr. Geoffrey Modest

MMWR found a decrease in teen birth rates and prior disparities for those aged 15-19, comparing 2013-14 with 2006-7  (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6516a1.htm?s_cid=mm6516a1_w ).

Findings:

  • From 1991-2014, the overall birth rate among those 15-19 yo declined 61% !!!, from 61.8 to 24.2 births/1000 women, and is currently the lowest ever recorded
  • Nationally, from 2006 – 2014 the teen birthrate decreased 41% overall, comparing 2006-7 and 2013-14:
    • 35% among whites (from 26.7 to 17.3/1000 teens)
    • 51% decrease among Hispanics (from 77.4 to 38.0/1000 teens), with the birth rate ratio vs whites declining from 2.9 to 2.2
    • 44% decrease among blacks (from 61.9 to 34.9/1000 teens), with the birth rate ratio vs whites declining from 2.3 to 2.0
  • By states, all had pretty dramatic decreases, the least in N Dakota at 13.4% and West Virginia at 14.9%, the most in Arizona at 47.8%, Connecticut at 47.6% and Colorado at 47.6%; almost all the other states are in the 30-40% range
  • There was huge variation of teen birth rates by county: from 3.1 to 119.0/1000 females aged 15-19. The highest birth rates being in Texas and much of the south (New Mexico, Oklahoma, Arkansas, Louisiana, Mississippi, Kentucky, Georgia)
  • For the states in the highest quintile of teen birth rates, the mean % of the population >15yo who are unemployed, mean % of population >24yo with an associates degree or higher, and mean family income were 10.5%, 19.9% and $46,005; in the lowest quintile, those numbers were 7.6%, 40.4%, and $73,967 and p<0.001 for all comparisons

So, a few observations:

  • It is certainly welcoming that the racial disparity gap is improving, but it has a long way to go
  • In some states this reflected a cross-ethnic consistency – e.g. in New Jersey: the teen birth rate in 2013-4 among whites was 4.8/1000 (below the national average of 18.0), for blacks was 27.4/1000 and Hispanics 31.3/1000 (also below the national averages of 37.0 and 39.8), though still a pretty staggering 6-7 fold higher than for whites
  • But in others, the disparities diverged: e.g. Nebraska, birth rate for whites was 16.2 (approx the national average) whereas the rates for black and Hispanic (42.6 and 53.9) were far above the national average for these groups.
  • The county-by-county map basically shows the highest teen birth rates are in the South, and largely coincides with those states there that refused to expand Medicaid through Obamacare
  • And, not so surprisingly, high teen birth rates also coincide with those states with the highest poverty rates and (somewhat less impressively, though pretty clearly) with highest numbers of African-Americans and Hispanics (see: map for poverty:  http://www.povertyusa.org/the-state-of-poverty/poverty-map-state/# ; map for racial disparities: https://www.google.com/search?safe=active&espv=2&biw=1280&bih=899&site=imghp&tbm=isch&source=hp&biw=&bih=&q=map+of+ethnicities&oq=ethnicities+map&gs_l=img.1.0.0i8i30.15110.19529.0.22183.19.13.3.3.3.0.151.960.10j2.12.0….0…1ac.1.64.img..1.18.983…0j0i24.p9s7jYX4pj8#safe=active&tbm=isch&q=map+of+ethnicities&chips=q:map+of+ethnicities,g_1:usa&imgrc=WU9o2tjooIVI-M%3A )
  • The US Dept of Health and Human Services has been funding community-wide initiatives in 9 communities with some of the highest teen birth rates, focusing on black and Hispanic teens, with a goal to address the social determinants of health at the community level. Mostly these have focused on access to health care services and pregnancy prevention programs [but, not really looking at the fundamental issues of poverty, unemployment, inadequate education, etc.]
  • As a reference point, the adolescent birth rate is 34.2/1000 females in the US, 25.1 in the UK, 15.5 in Australia, and pretty much under 10 in the rest of Europe (see http://internationalcomparisons.org/intl_comp_files/sheet010.htm )
  • So, to put this together: teen pregnancy is clearly decreasing in the US, with decreasing racial/ethnic disparities, but the US overall has the highest rate as compared to other resource-rich countries, and there are large discrepancies in different regions of the US, largely tracking those areas of poverty, racial disparities, and fewer federal resources (which in some cases are those states have chosen to reject). Again, this really speaks to the need for a national, coherent approach to the inequities in our society, as a basis to improve public health outcomes overall.

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