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Assessing the risk of ovarian malignancy in asymptomatic women with abnormal findings: “Tilting at windmills”
Gynecologic Oncology 135 (2014) 1–2
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Editorial
Assessing the risk of ovarian malignancy in asymptomatic women with abnormal findings: “Tilting at windmills”
The University of Kentucky group has once again added to our knowledge of the use of transvaginal ultrasonography (TVU) and a morphology index (MI) to predict the risk of ovarian malignancy in asymptomatic women with abnormal findings. In this issue of Gynecologic Oncology, they present the evolution of 25 years of experience using a morphology index to predict risk. The group has enrolled 38,983 women in the University of Kentucky Ovarian Cancer Screening Program since 1987. The current report is an evaluation of 7104 women who had abnormalities, 6758 observed without surgery, and 472 who had surgery. Several important observations can be made from this significant contribution to transvaginal ultrasound evaluation. First, a MI of ≥5 was present in 85% of the 74 malignant tumors. Second, the risk of malignancy increased with MI score increase. Third, a change in the MI score over time either defined as mean delta change per month or per scan was also predictive of malignancy. Fourth, the positive predictive value (PPV) improved substantially over the two and one-half decades of the screening program. Unfortunately for the University of Kentucky group, a randomized unscreened control group has never been added; therefore, the impact on ovarian cancer specific mortality of screening asymptomatic women cannot be evaluated in this study group. However, the group has significantly improved the PPV of TVU screening from 8.10% in the years 1987–2000, 19.20% from 2000 to 2008, to 24.70% from 2008 to 2012. This increase in PPV reduces the number of surgical procedures for non-malignant tumors. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) evaluated the impact of CA125 and TVU screening in asymptomatic women between the ages of 55 and 74 on ovarian specific mortality and found no difference in mortality between the screened and unscreened group [1]. Currently, no professional groups recommend routine screening for asymptomatic women. The PLCO trial group also evaluated the risk of ovarian malignancy among asymptomatic women with an abnormal transvaginal ultrasound or CA125 to help guide physicians managing these women in the future. For the initial screen, two high risk categories were identified: CA125 of 70 or more with negative ultrasound (PPV 15.9 CI 14.7%–17.7%) and positive for both CA 125 and transvaginal ultrasound (PPV 25.0%, CI 23.3%–27.3%). For follow-up screens, three high risk categories were identified: negative transvaginal ultrasound with change in CA125 of 45 or more (PPV 29.0%, CI 28.3–30.3%); increase in size of cyst 6 cm or greater with negative CA125 (PPV 13.3%, CI 10.5%–18.0%) and positive for both tests (PPV 42.9%, CI 40.0%–46%) [2]. Although the increase in PPV using either the University of Kentucky MI or the criteria of the PLCO group is notable, for now we are all “tilting at windmills” [3].
http://dx.doi.org/10.1016/j.ygyno.2014.08.038 0090-8258/© 2014 Elsevier Inc. All rights reserved.
The bottom line and only credible endpoint for any type of cancer screening in an asymptomatic population is a reduction in cancer specific mortality. To date, no screening modality has been able to demonstrate such a reduction for ovarian cancer mortality. Screening, almost always, increases morbidity. There are false positives which lead to anxiety and further evaluation including biopsies and/or surgical procedures. In addition, so called malignancies will be detected and treated that were so indolent that death from the specific disease is unlikely, as seen in prostate and other cancer screens including ovarian. In addition, some cancers will be detected but are so aggressive that the patients die in spite of early detection. In fact, when one undergoes a screen for any cancer, there are five possibilities — one helpful and four not so helpful. For screening, the one helpful possibility is a true positive early detection that leads to decreased cancer specific mortality. The four not so helpful are (1) a false negative which does not help anyone, (2) a false positive leading to morbidity from diagnostic and therapeutic procedures not to mention increased cost, (3) a true positive but the “cancer” is so indolent that mortality was never an issue but morbidity is associated with the treatment, and (4) a true positive but so aggressive that mortality is not affected. Lead time bias which always improves five year survival in the screened population and over diagnosis bias which leads to down staging in the screened population leaves cancer specific mortality as the only valid endpoint for evaluation of screening [4]. This brings us full circle to the issue at hand. There are only two ways in which an asymptomatic woman can have an adnexal mass detected — an imaging procedure and/or bi-manual or internal pelvic examination. As noted previously, there is currently no professional group that recommends pelvic imaging for ovarian screening in an asymptomatic woman; in fact, the harm outweigh any benefit in the trials that have been conducted [5]. The PLCO group determined that the pelvic bi-manual examination was not helpful in diagnosing ovarian malignancy in that no cancer was detected solely by this examination [1]. The American College of Physicians recommends against performing a screening internal pelvic examination in an asymptomatic woman. This is based on the lack of evidence that the pelvic examination is beneficial and some evidence that it is harmful — fear, anxiety, embarrassment, pain and discomfort, over treatment, and unnecessary surgery [6]. The American Congress of Obstetricians and Gynecologists recommends that pelvic examination should be done only when indicated in women less than 21 and the internal examination should be a shared decision in asymptomatic women 21 or older and notes lack of evidence either refuting or supporting the internal examination [7]. This is a
2
Editorial
rather “timid” recommendation. The bottom line at this point is that pelvic imaging and internal pelvic examination in asymptomatic women cause net harm. And, thus, we continue to “tilt at windmills” trying to improve the PPV of screening tests that do not reduce mortality. An increasing PPV does not affect ultimate mortality from the specific cancer being screened but only reduces the unnecessary surgery. A high PPV is truly useful only when cancer specific mortality is reduced by the screen and the increasing PPV reduces unnecessary surgery. In a value based versus volume based payment system, one would be hard pressed to support either TVU or internal pelvic examinations in asymptomatic women as adding value to the care of these women. If transvaginal ultrasound and pelvic examinations are not done in asymptomatic women, and with current knowledge they should not, there would be little need of a MI or other methods to predict malignancy for this indication. Until we have a screen that reduces mortality, the MI in asymptomatic women should be a moot point and rarely necessary to be utilized. In this nation, we over and inappropriately screen and as a result, over diagnose and over treat in some populations and for some cancers while never screening or under screening other populations when the screen is clearly beneficial. We could do better, and I think we eventually will. References [1] Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA Jun 8 2011;305(22):2295–303. http:// dx.doi.org/10.1001/jama.2011.766.
[2] Partridge EE, Greenlee RT, Riley TL, Commins J, Ragard L, Xu JL, et al. Assessing the risk of ovarian malignancy in asymptomatic women with abnormal CA 125 and transvaginal ultrasound scans in the prostate, lung, colorectal, and ovarian screening trial. Obstet Gynecol Jan 2013;121(1):25–31. http://dx.doi.org/10.1097/AOG. 0b013e3182755e14. [3] DeCervantes M. Don Quixote; 1605. [4] Wegwarth O, Schwartz LM, Woloshin S, Gaissmaier W, Gigerenzer G. Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med Mar 6 2012;156(5):340–9. http://dx.doi.org/10. 7326/0003-4819-156-5-201203060-00005. [5] U.S. Preventive Services Task Force: Screening for Ovarian Cancer. http://www. uspreventiveservicestaskforce.org/uspstf/uspsovar.htm. [6] Qaseem A, Humphrey LL, Harris R, Starkey M, Denberg TD. Clinical Guidelines Committee of the American College of Physicians. Screening pelvic examination in adult women: a clinical practice guideline from the American College of Physicians. Ann Intern Med Jul 1 2014;161(1):67–72. http://dx.doi.org/10.7326/M14-0701. [7] Committee on Gynecologic Practice. Committee opinion No. 534: well-woman visit. Obstet Gynecol Aug 2012;120(2 Pt 1):421–4. http://dx.doi.org/10.1097/AOG. 0b013e3182680517.
Edward E. Partridge, M.D., Director Comprehensive Cancer Center, Professor of Gynecologic Oncology Evalina B. Spencer, Chair in Oncology University of Alabama at Birmingham, 1824 Sixth Avenue South, WTI 202 Birmingham, AL 35294-3300, USA
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Editorial
Assessing the risk of ovarian malignancy in asymptomatic women with abnormal findings: “Tilting at windmills”
The University of Kentucky group has once again added to our knowledge of the use of transvaginal ultrasonography (TVU) and a morphology index (MI) to predict the risk of ovarian malignancy in asymptomatic women with abnormal findings. In this issue of Gynecologic Oncology, they present the evolution of 25 years of experience using a morphology index to predict risk. The group has enrolled 38,983 women in the University of Kentucky Ovarian Cancer Screening Program since 1987. The current report is an evaluation of 7104 women who had abnormalities, 6758 observed without surgery, and 472 who had surgery. Several important observations can be made from this significant contribution to transvaginal ultrasound evaluation. First, a MI of ≥5 was present in 85% of the 74 malignant tumors. Second, the risk of malignancy increased with MI score increase. Third, a change in the MI score over time either defined as mean delta change per month or per scan was also predictive of malignancy. Fourth, the positive predictive value (PPV) improved substantially over the two and one-half decades of the screening program. Unfortunately for the University of Kentucky group, a randomized unscreened control group has never been added; therefore, the impact on ovarian cancer specific mortality of screening asymptomatic women cannot be evaluated in this study group. However, the group has significantly improved the PPV of TVU screening from 8.10% in the years 1987–2000, 19.20% from 2000 to 2008, to 24.70% from 2008 to 2012. This increase in PPV reduces the number of surgical procedures for non-malignant tumors. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) evaluated the impact of CA125 and TVU screening in asymptomatic women between the ages of 55 and 74 on ovarian specific mortality and found no difference in mortality between the screened and unscreened group [1]. Currently, no professional groups recommend routine screening for asymptomatic women. The PLCO trial group also evaluated the risk of ovarian malignancy among asymptomatic women with an abnormal transvaginal ultrasound or CA125 to help guide physicians managing these women in the future. For the initial screen, two high risk categories were identified: CA125 of 70 or more with negative ultrasound (PPV 15.9 CI 14.7%–17.7%) and positive for both CA 125 and transvaginal ultrasound (PPV 25.0%, CI 23.3%–27.3%). For follow-up screens, three high risk categories were identified: negative transvaginal ultrasound with change in CA125 of 45 or more (PPV 29.0%, CI 28.3–30.3%); increase in size of cyst 6 cm or greater with negative CA125 (PPV 13.3%, CI 10.5%–18.0%) and positive for both tests (PPV 42.9%, CI 40.0%–46%) [2]. Although the increase in PPV using either the University of Kentucky MI or the criteria of the PLCO group is notable, for now we are all “tilting at windmills” [3].
http://dx.doi.org/10.1016/j.ygyno.2014.08.038 0090-8258/© 2014 Elsevier Inc. All rights reserved.
The bottom line and only credible endpoint for any type of cancer screening in an asymptomatic population is a reduction in cancer specific mortality. To date, no screening modality has been able to demonstrate such a reduction for ovarian cancer mortality. Screening, almost always, increases morbidity. There are false positives which lead to anxiety and further evaluation including biopsies and/or surgical procedures. In addition, so called malignancies will be detected and treated that were so indolent that death from the specific disease is unlikely, as seen in prostate and other cancer screens including ovarian. In addition, some cancers will be detected but are so aggressive that the patients die in spite of early detection. In fact, when one undergoes a screen for any cancer, there are five possibilities — one helpful and four not so helpful. For screening, the one helpful possibility is a true positive early detection that leads to decreased cancer specific mortality. The four not so helpful are (1) a false negative which does not help anyone, (2) a false positive leading to morbidity from diagnostic and therapeutic procedures not to mention increased cost, (3) a true positive but the “cancer” is so indolent that mortality was never an issue but morbidity is associated with the treatment, and (4) a true positive but so aggressive that mortality is not affected. Lead time bias which always improves five year survival in the screened population and over diagnosis bias which leads to down staging in the screened population leaves cancer specific mortality as the only valid endpoint for evaluation of screening [4]. This brings us full circle to the issue at hand. There are only two ways in which an asymptomatic woman can have an adnexal mass detected — an imaging procedure and/or bi-manual or internal pelvic examination. As noted previously, there is currently no professional group that recommends pelvic imaging for ovarian screening in an asymptomatic woman; in fact, the harm outweigh any benefit in the trials that have been conducted [5]. The PLCO group determined that the pelvic bi-manual examination was not helpful in diagnosing ovarian malignancy in that no cancer was detected solely by this examination [1]. The American College of Physicians recommends against performing a screening internal pelvic examination in an asymptomatic woman. This is based on the lack of evidence that the pelvic examination is beneficial and some evidence that it is harmful — fear, anxiety, embarrassment, pain and discomfort, over treatment, and unnecessary surgery [6]. The American Congress of Obstetricians and Gynecologists recommends that pelvic examination should be done only when indicated in women less than 21 and the internal examination should be a shared decision in asymptomatic women 21 or older and notes lack of evidence either refuting or supporting the internal examination [7]. This is a
2
Editorial
rather “timid” recommendation. The bottom line at this point is that pelvic imaging and internal pelvic examination in asymptomatic women cause net harm. And, thus, we continue to “tilt at windmills” trying to improve the PPV of screening tests that do not reduce mortality. An increasing PPV does not affect ultimate mortality from the specific cancer being screened but only reduces the unnecessary surgery. A high PPV is truly useful only when cancer specific mortality is reduced by the screen and the increasing PPV reduces unnecessary surgery. In a value based versus volume based payment system, one would be hard pressed to support either TVU or internal pelvic examinations in asymptomatic women as adding value to the care of these women. If transvaginal ultrasound and pelvic examinations are not done in asymptomatic women, and with current knowledge they should not, there would be little need of a MI or other methods to predict malignancy for this indication. Until we have a screen that reduces mortality, the MI in asymptomatic women should be a moot point and rarely necessary to be utilized. In this nation, we over and inappropriately screen and as a result, over diagnose and over treat in some populations and for some cancers while never screening or under screening other populations when the screen is clearly beneficial. We could do better, and I think we eventually will. References [1] Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA Jun 8 2011;305(22):2295–303. http:// dx.doi.org/10.1001/jama.2011.766.
[2] Partridge EE, Greenlee RT, Riley TL, Commins J, Ragard L, Xu JL, et al. Assessing the risk of ovarian malignancy in asymptomatic women with abnormal CA 125 and transvaginal ultrasound scans in the prostate, lung, colorectal, and ovarian screening trial. Obstet Gynecol Jan 2013;121(1):25–31. http://dx.doi.org/10.1097/AOG. 0b013e3182755e14. [3] DeCervantes M. Don Quixote; 1605. [4] Wegwarth O, Schwartz LM, Woloshin S, Gaissmaier W, Gigerenzer G. Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med Mar 6 2012;156(5):340–9. http://dx.doi.org/10. 7326/0003-4819-156-5-201203060-00005. [5] U.S. Preventive Services Task Force: Screening for Ovarian Cancer. http://www. uspreventiveservicestaskforce.org/uspstf/uspsovar.htm. [6] Qaseem A, Humphrey LL, Harris R, Starkey M, Denberg TD. Clinical Guidelines Committee of the American College of Physicians. Screening pelvic examination in adult women: a clinical practice guideline from the American College of Physicians. Ann Intern Med Jul 1 2014;161(1):67–72. http://dx.doi.org/10.7326/M14-0701. [7] Committee on Gynecologic Practice. Committee opinion No. 534: well-woman visit. Obstet Gynecol Aug 2012;120(2 Pt 1):421–4. http://dx.doi.org/10.1097/AOG. 0b013e3182680517.
Edward E. Partridge, M.D., Director Comprehensive Cancer Center, Professor of Gynecologic Oncology Evalina B. Spencer, Chair in Oncology University of Alabama at Birmingham, 1824 Sixth Avenue South, WTI 202 Birmingham, AL 35294-3300, USA