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Screening for Ovarian Cancer: Part 1

Casey Parker, MD and David Cohn, MD
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Evidence suggests that screening asymptomatic, low risk women for ovarian cancer does not reduce the risk of cancer specific mortality.

 

PEARLS:

  • In 2015, a large European study showed that screening low-risk women for ovarian cancer did not significantly reduce ovarian cancer mortality.
  • Newspaper headlines covering this study reported a benefit, however. This was largely based on the results of secondary analyses and  convoluted statistics. Patients (and providers) were left confused.
  • Patients at low-risk for ovarian cancer should be informed that there is no data to show that screening will reduce her mortality from the disease.
  • Symptoms of ovarian cancer include the following:  unexplained gastrointestinal pain, bloating, and urinary complaints. Women with these complaints warrant an evaluation with pelvic ultrasound and bimanual examination. A CA-125 should be ordered only if the exam or ultrasound detect abnormalities.
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  • Reasonable options for women determined to be at high-risk of ovarian cancer include prophylactic BSO or surveillance with twice yearly CA-125 and pelvic ultrasounds. 
  • Ovarian cancer can be a devastating diagnosis, largely due to its 5-year survival rate which is dismal compared to other malignancies. Unfortunately, this is a neoplasm that is commonly diagnosed after it has already metastasized. The value of screening for ovarian cancer, in hopes of detecting the disease before it has reached an advanced stage, is the subject of debate, controversy, and this Primary Care RAP segment.

  • The 2011 PLCO Trial showed that screening for ovarian cancer using a combination of CA-215 and transvaginal ultrasound had no significant benefit in terms of ovarian cancer mortality rates. In this study, the screening group had a high false positive rate which sometimes led to significant complications when positive screening results were pursued.

    • Buys SS, et al; PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8;305(22):2295-303. PMID: 21642681

  • The results of a much larger and more recent European study have been interpreted in widely disparate ways, yielding mixed messages and creating confusion.  

    • Jacobs IJ,et al. Ovarian cancer screening and mortality in the UK
      Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised
      controlled trial. Lancet. 2015 Dec 17. pii: S0140-6736(15)01224-6. PMID: 26707054

    • One Australian headline covering the study read, “Evidence for Ovarian Cancer Screening, Not There Yet”, while the sister newspaper reported, “Blood Tests Could Reduce Ovarian Cancer Deaths by 20%”.  In the US, the CBS News headline was, “Blood Tests for Ovarian Cancer Saves Lives, Study Finds” whereas the New York Times was more circumspect and stated, “Early Detection of Ovarian Cancer May Become Possible”. The NYT article is recommended for patients who are interested in a relatively unbiased synopsis this study. Link to New York Times article.

    • Study design:  

      • This was a randomized controlled trial of 202,000 women between the ages of 50 and 74. Participants were largely postmenopausal and predominantly Caucasian.  

      • 1.2 million women were invited to volunteer for this study and only about 1 in 6 responded. This trial suffered from the healthy volunteer effect which occurs in many screening trials when primarily health-conscious people agree to participate. In this study, the mortality rate of participants over the period of follow-up was about 37% of predicted, implying that this was an incredibly healthy group of women.  

      • Women were excluded from this trial if they were at increased risk of ovarian cancer, defined as a greater than 10% lifetime risk. This determination was based on a complex algorithm which took into account the family history of specific cancers known to be associated with ovarian cancer (namely ovarian, breast, and colon) as well as a family history of certain genetic mutations, such as positive BRCA result.  

      • Women were randomized to three groups:

        • 100,000 had no screening (although about 4% of these did end up getting some type of screening test).

        • 50,000 had annual transvaginal ultrasounds.

        • 50,000 had multimodal screening using the serum CA-125 and the risk of ovarian cancer (ROCA) algorithm.  

          • Rather than using a standardized CA-125 cutoff, the authors used age, risk level, and changes in the individual’s CA-125 to generate a numerical score which gave a risk of ovarian cancer.

          • Patients were classified as either normal risk (with continued annual screening), intermediate risk (with repeat  CA-125 in 3 months), or elevated risk (with repeat CA-125 in 3 weeks plus a transvaginal ultrasound).  

          • A potential conflict of interest of this study is that the ROCA algorithm has been patented by the lead author of the trial.  This person also has a financial interest in Abcodia, the company that sells the ROCA test.  

    • Study results and weaknesses of the trial:

      • The primary outcome was ovarian cancer mortality, which tells you whether the screening intervention is picking up ovarian cancers.  In this study, deaths from ovarian cancer were not diminished by any of the screening strategies. This is an important outcome to know, but not the only one.  

        • Unfortunately, the study did not report all-cause mortality. All-cause mortality informs people as to whether the test will make people live longer. If screened women are dying due to complications of treatment or surgery for ovarian cancer, this would be reflected in the all-cause mortality. If the all-cause mortality is equivalent between all groups, then we may not be doing anyone a favor by earlier screening and diagnosis.

        • A recent BMJ article suggests that the primary metrics when analyzing the efficacy of cancer screening should not be cancer-specific deaths, but instead should be overall mortality. The article states, “Discrepancies between disease-specific and overall mortality were found in 7 of 12 randomized trials of cancer screening. Despite reductions in disease-specific mortality in the majority of studies, overall mortality was unchanged or increased. The overall effect of cancer screening and mortality is more complex than a disease-specific endpoint can capture, owing to the harms of further testing, overdiagnosis, and overtreatment.”

          • Prasad V, et al. Why cancer screening has never been shown to
            "save lives"-and what we can do about it. BMJ. 2016 Jan 6;352:h6080. PMID: 26740343

      • Although this study found that ovarian cancer screening yielded no benefit in terms of ovarian cancer mortality, newspaper headlines reported differently. This is largely based on the results of secondary analyses, convoluted statistics where models were changed, and after cases were excluded.  

      • In this study, secondary analyses used two statistical methods to better understand the effect of screening on mortality over time:  the Cox model and the Royston-Parmar model.

        • The Cox model looked at the progress of cancers over time to try to determine whether the screening was effective. In this study, the Cox model numbers were unimpressive, with no P values close to 0.05.  

        • The Royston-Parmar model is a slightly different model which was used by the authors’ statisticians. This model was not in the original trial protocol and was done on secondary analyses only. Using this model, some of the secondary outcomes did have P values which reached statistical significance. For instance, a subanalysis of women who died of both ovarian and primary peritoneal cancers were included in this model. These women were found to have a 20% reduction in ovarian cancer mortality. It was this finding (about a secondary outcome that wasn’t in the original model) that generated the major headline, “Blood Tests Could Reduce Ovarian Cancer Deaths by 20%”. It is concerning when the secondary analyses become the headline.

      • A weakness of this trial is that prevalent cases were excluded. This means that women who had a previously undiagnosed or had an asymptomatic ovarian tumor at the time of enrollment in the trial were removed from the data analyses. They did this by excluding women who had an upward trend in their CA-125s from the beginning of the study. By excluding these women, the authors were able to reach the magical 0.05 P value and find statistical significance.

      • This trial inadequately reported the harms of ovarian cancer treatment. In a screening program where a diagnostic study has many false positives (as in the serum CA-125), it is essential to understand the number needed to harm of the test, so that a primary care provider can weigh that against the potential benefit. This was hard to find by reading the paper.  In the supplementary appendix, the authors report that the surgical complication rate was 3.5%, but the actual harms of the surgery and any associated mortality was not documented.

    • What advice should a primary care provider give to a worried patient, concerned she might have ovarian cancer?

      • There is no right or wrong answer.

      • At this time, the evidence supports the fact that in a woman at a routine or baseline risk for developing ovarian cancer, there is no data to show that screening will reduce her mortality from the disease.

    • If a woman insists on screening, what is the best strategy?

      • Educate the patient regarding how rare ovarian cancer is, affecting only 1.5% of women in their lifetime.

      • Inform her that when a disease is uncommon, in order for a test to identify the disease in a low-risk population, it must be an incredibly powerful. The performance characteristics of the CA-125 and transvaginal ultrasound are not powerful enough for the early detection of ovarian cancer in low-risk populations.

      • Make sure that the patient understands that there has been no demonstrated value of screening for ovarian cancer in low-risk women.

      • Inform her of the risks of testing. This includes the potential for accruing unnecessary costs and expense,  not only for the patient but also for society. There is also the risk of screening tests leading to additional interventions which may have associated harm.

      • If a patient still requests  screening, despite the above information, the provider can either decline the test or agree to it. It is not unreasonable to agree to screening in a well-counselled patient who understands the risks of proceeding, is able to pay for the test (or has insurance that will), and realizes the lack of documented benefit.

    • For the provider who agrees to ovarian cancer screening for a low-risk patient, what test should be ordered initially? And does it require repeating?

      • Screening options include a CA-125 and a transvaginal ultrasound. If both are normal, hopefully the patient will be reassured and concur that further screening going forward is unnecessary.

    • If patients have signs or symptoms that are worrisome for ovarian cancer, then a diagnostic evaluation (and not a screening test) is required.  

      • Symptoms that may herald ovarian cancer include unexplained gastrointestinal pain or symptoms, bloating, and urinary complaints.

      • A strategy for symptomatic patients is to start with a  pelvic examination and a transvaginal ultrasound. If these are entirely normal, the CA-125 has limited additional value.

      • Cohn does not recommend starting with a serum CA-125 in a symptomatic patient.

    • What is the sensitivity of a bimanual examination for detecting small ovarian cysts or tumors?

      • Studies have shown that medical residents and students are almost as good at OB/Gyn faculty at detecting a pelvic mass when one is present and the patient is examined while anesthetized.  

      • The sensitivity and specificity of the bimanual exam is relatively low.  

      • If a mass is felt but not seen on ultrasound, options include:  continued surveillance with ultrasound (if symptomatic), nothing (if no symptoms and you can explain what you feel by constipation, etc), or further imaging (CT).

    • Only 10% of ovarian cancers are diagnosed in stage 1 disease; most women have metastatic disease at the time of diagnosis.  What symptoms might prompt evaluation, so that the disease is detected earlier?

      • The current thinking is that for many patients there are some signs and symptoms that may be present with early stage disease.

      • Consider ovarian cancer in women who have a constellation of nonspecific symptoms such as abdominal pain, bloating, gastrointestinal dysfunction, urinary tract dysfunction, nausea, or vomiting.  It is particularly concerning when these symptoms do not improve, or actually worsen, over time.

      • One study found that the combination of bloating, increased abdominal size, and urinary symptoms was found in 43% of those with ovarian cancer.  This constellation of symptoms is uncommon, however, affecting only 8% of those presenting to primary care clinics.

        • Goff BA, et al. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA. 2004 Jun 9;291(22):2705-12. PubMed PMID: 15187051

    • Given the dismal prognosis of ovarian cancer, for which patients should prophylactic bilateral salpingo-oophorectomy (BSO) be considered?  Does it reduce mortality?

      • There is no indication for prophylactic salpingo-oophorectomy for women who have a baseline, or low, risk of ovarian cancer.

      • There is evolving data that shows that ovarian cancer may arise from the distal edge of the fallopian tubes. This provides an opportunity for women who are undergoing tubal ligation to actually undergo tubal removal, even if they’re at low risk for developing ovarian cancer.

      • For women at higher risk for cancer (namely those with a mutation in one of the BRCA genes or PALB2) who have completed childbearing, it would be appropriate to consider prophylactic salpingo-oophorectomy.

        • The earlier that a high-risk woman undergoes a BSO, the more protection there is against the development of ovarian cancer.  

        • These women should be referred to a genetic counsellor to determine the ovarian cancer risk.  

        • If genetic testing determines that the risk is elevated, then a discussion should follow, introducing the increased risk of osteoporosis and cardiac disease when a BSO is performed before menopause.

    • What screening alternatives are recommended for high-risk women who are concerned about the direct surgical or long-term medical risks of a prophylactic BSO? Or for those who desire future pregnancy?

      • Surveillance with CA-125, pelvic examination and pelvic ultrasound is a reasonable alternative for these high-risk women. The usual practice is to repeat these twice a year.

    • How does Cohn interpret CA-125 levels and use these results to determine if more aggressive intervention is needed for high-risk women?

      • Every woman has their “normal” CA-125 value, independent of the presence or absence of ovarian cancer. That number varies between women.   

      • The CA-125 normal range was established for postmenopausal women who had no other pathologic abnormalities, like uterine fibroids, endometriosis, or other nonmalignant gynecologic conditions.  

      • Unless it is substantially elevated, single CA-125 level is usually not sufficient to trigger an intervention, such as a BSO.  

      • Cohn usually follows the delta, or change, in CA-125 levels.  He looks for a deflection where the rate of change is significantly increasing.  

      • When women have small increases in the CA-125 (with no concerning symptoms or pelvic ultrasound findings), the physician’s judgement and the patient’s level of concern determine what is the appropriate next step. Some women will elect to have a risk-reducing BSO even if their CA-125 is only minimally elevated.  

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Hernias and Ovaries Full episode audio for MD edition 183:26 min - 86 MB - M4AHippo Primary Care RAP April 2016 Summary 882 KB - PDF

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