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Screening for ovarian cancer
COMMENTARY
CORRESPONDENCE
Screening for ovarian cancer Sir—I would be grateful if Ian Jacobs and colleagues (April 10, p 1207)1 could clarify the following issues about their report on screening for ovarian cancer. It seems that the screened population they refer to had already been screened twice before by means of measurement of serum CA 125 antigen and ultrasonography. 2 4 1 women with abnormal screening underwent operations, and 11 ovarian cancers were discovered. There were altogether 19 ovarian cancers in the group of 22 000 women tested and those women were removed from the cohort. The rest of the women were then randomised to screening or no screening to make the sample of the new study. Do the authors think that this study is representative of the general population? There were 340 women with raised CA 125 among the 22 000 women tested,2 which amounts to 1·54% of the population with abnormal values. Among 8723 patients tested with CA 125,1 254 had abnormal values (2·9%). Any possible explanation for an almost two-fold increase in the second group, which—as mentioned before—had already been screened twice? Which are the true numbers: the numbers in the text—with 9364 women with one screen and 7743 women with three screens—or the numbers in figure 1 and table 1—with 8732 with one screen and 8455 with three screens? In view of what is said in the summary about survival and mortality, I find it difficult to interpret the following passage in the Discussion: “survival differed significantly between women with index cancer in the screened and control groups, but this finding is not definitive evidence for lack of benefit from screening for ovarian cancer.” The prevalence of ovarian cancer has been estimated at 50 per 100 000 women.3 There is evidence to suggest that the use of oral contraceptives may decrease the relative risk of ovarian cancer in ever users by 40%.4 This point should be taken into account
THE LANCET • Vol 354 • August 7, 1999
before resources are committed to a larger study of the feasibility of screening programmes for ovarian cancer. Nikolai Manassiev 58 Ollerton Road, Yardley, Birmingham, B26 1PN, UK 1
Jacobs I, Skates S, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: 1207–10. 2 Jacobs I, Davies A, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993; 306: 1030–34. 3 NIH Consensus Development Panel on Ovarian Cancer. Ovarian cancer: screening, treatment and follow-up. JAMA 1995; 273: 491–97. 4 Beral V, Hermon C, Kay C, et al. Mortality associated with oral contraceptive use: 25 year follow-up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study. BMJ 1999; 318: 96–100.
Sir—In the light of Woodman’s report 1 about Ian Jacobs and colleagues’ study,2 we disagree with the optimistic conclusion reached by the investigators and believe a more cautious interpretation is justified. Jacobs and colleagues specifically report only the positive-predictive value of the strategy (20·7%), and compare this with other current methods of screening for ovarian cancer. This single factor is sufficient to make decisions about a screening test. On the basis of the figures for women who completed at least one screen (9364), the strategy has a sensitivity of 37·5%, specificity of 99·75%, and negative-predictive value of 99·89%. A screening test should have high sensitivity (especially for rare disease) and be followed by a diagnostic test with high sensitivity and specificity, leading to a strategy with high sensitivity and high positivepredictive value. The reported strategy has low sensitivity and low positivepredictive value. Since the subsequent investigation of any positive test involves major abdominal surgery, a high positive-predictive value is particularly important. Although data on certain risk factors are presented for each group, family
history of ovarian cancer is not reported. Given the voluntary nature of recruitment to this study, we do not know if the population studied were representative, or if in fact they included a disproportionate number of women with increased genetic risk of ovarian cancer. This bias could potentially affect the uptake of the test and its detection rate. Jacob and colleagues conclude that this pilot study justifies a much larger trial to show an effect on mortality, and to assess economic and psychosocial factors. It is a pity that this study of 22 000 women d i d n o t include these additional assessments. It would be interesting to know the psychological and physical impact on the 23 women who underwent major abdominal surgery for a false-positive screen, and the effect on the ten women reassured by the test who subsequently developed ovarian cancer.3 We believe that this study shows the lack of an adequate population screening tool for ovarian cancer, and highlights the difficulties of searching for screening tools for r a r e diseases. Perhaps a more appropriate strategy will be shown from studies currently in progress of targeted screening for women at increased genetic risk of ovarian cancer, or from the development of more sensitive biological markers of the disease? *Jon Emery, John Yaphe, Patricia Priest, David Whiteman Division of Public Health and Primary Health Care, Institute of Health Sciences, Headington, Oxford OX3 7LF, UK 1
Woodman R. Ovarian cancer screening may increase survival. BMJ 1999; 318: 1027. 2 Jacobs I, Skates S, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: 1207–10. 3 Stewart-Brown S, Farmer A. Screening could seriously damage your health. BMJ 1997; 314: 533–34.
Sir—Ian Jacobs and colleagues 1 report the results of a population-based randomised trial of screening for ovarian cancer in postmenopausal women. The women were first screened by measurement of serum CA 125, and those who had had a
509
raised value were offered screening by transabdominal (and later endovaginal) ultrasonography. Women were screened each year for 3 years and followed up for at least 7 years. There were 18 deaths from ovarian cancer in the control group and nine deaths in the women who were screened. Treated as a cohort, ovarian cancer mortality was lower in the screened group than in the controls (p=0·08). The goal of screening is to reduce death from cancer by allowing diagnosis of the cancer at an early stage. 11 of the 16 women with ovarian cancer in the screened group had a diagnosis made at stages III or IV, and these 11 women will likely succumb to their disease. The observed survival benefit of screening was clinically important, and if the comparison in this study had been between two different treatments, then the increase in survival would have been notable. However, if most of the screendetected cancers ultimately prove to be fatal, then this study cannot be viewed as encouraging. We recommend prophylactic oophorectomy by age 45 years for women who carry a germline mutation in BRCA1 or BRCA2.2,3 The results of the Jacobs study do not encourage us to modify this policy. *Pierre O Chappuis, Steven A Narod, William D Foulkes Departments of Medicine, *Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada H3G 1A4; and Centre for Research in Women’s Health, University of Toronto, Toronto, Ontario, Canada 1
Jacobs IJ, Skates SJ, McDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: 1207–10. 2 Eisen A, Weber BL. Primary peritoneal carcinoma can have multifocal origins: implications for prophylactic oophorectomy. J Natl Cancer Inst 1998; 90: 797–99. 3 Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRAC1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277: 997–1003.
Authors’ reply Sir—We share the enthusiasm of all the correspondents for exploring other methods to reduce mortality from ovarian cancer, including chemoprevention, prophylactic oophorectomy, and identification of individuals at high risk of the disease. Hopefully effective prevention will eventually make screening unnecessary, but this is not the case at present. Nikolai Manassiev and Jon Emery and colleagues were concerned that t h e study population may not be representive of the general population.
510
Number of women who underwent annual screening 7743 women underwent all three screens; 9364 underwent at least one screen.
The population was similar to the UK population in terms of ovarian-cancer incidence.1 Of the 22 000 participants, only 587 had a first-degree relative with ovarian cancer and women with two or more first-degree relatives with ovarian cancer were not eligible. As far as the impact of the prevalence screen is concerned, there is no perfect design for a randomised trial of cancer screening. We chose to randomise after the prevalence screen, because this approach is more likely to reflect the situation in a regular screening programme. Randomisation before an initial screen dilutes the effect of screening, because prevalence cases of cancer are included. Manassiev and colleagues also commented on the difference in increased CA 125 serum concentration at different screens. This difference may be partly attributable to assay and biological variation or to various benign and malignant disorders.2 The figure clarifies the apparent discrepancy between the text and table pointed out by Manassiev and colleagues. The figure was removed in The Lancet’s editorial process, which also failed to incorporate our correction on the proofs to the sentence that should have read: “but this finding is not definitive evidence for a benefit from screening for ovarian cancer”. We share Chappuis and colleagues’ concern regarding the lack of a significant stage shift. This result may simply reflect the size and power of our study, because there was a trend to earlier stage cancer. Alternatively, the survival benefit noted may be caused by a shift in substage (eg, from stage IIIc to stage IIIa), rather than stage. These and other uncertainties underscore the need for a larger definitive randomised trial of screening for ovarian cancer. As far as women with germline B R C A 1 or B R C A 2
mutations are concerned, we agree that prophylactic oophorectomy is an important option. However, in the absence of definitive data about the effect of oophorectomy or screening, we prefer to avoid a dogmatic approach and offer counselling about all options so that women can make a balanced and individualised decision. We agree with Emery and colleagues that various factors need to be considered when making decisions about screening tests. The report focused on one factor—the outcome of screening. Our research continues to address other important issues including screening performance, quality of life, morbidity, and health economics. The performance of the screening strategy was consistent with our previous reports of specificity (99·9%) and positive-predictive value (20%), 1,3 which compare favourably with screening for breast and cervical cancer. It is noteworthy that there was no major surgical morbidity in our study among women with falsepositive results. The sensitivity of our strategy for annual screening was 54·5% (six of 11 women). Although 16 cancers developed in the screened women during 8 years, only 11 women developed cancer during the year after a screen. We are exploring a number of approaches to improve on this sensitivity. The most encouraging incorporates changes in serial serum concentrations of CA 1254 and seems to increase sensitivity to 80% while maintaining high specificity. Emery and colleagues advocate targeting screening at women with a genetic predisposition to ovarian cancer. Since only 5–10% of all ovarian cancers occur in this group of women, this approach would have a limited impact on overall mortality from ovarian cancer. *Ian J Jacobs, Usha Menon, Nicola D MacDonald, Adam N Rosenthal Department of Gynaecological Oncology, St Bartholomew’s and Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London EC1A 7BE, UK 1
Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993; 306: 1030–34. 2 Jeyarajah AR, Ind TEJ, Skates SJ, et al. Serum CA 125 elevation and risk of clinical detection of cancer in asymptomatic postmenopausal women. Cancer 1999; 86: 2068–72. 3 Jacobs I, Stabile I, Bridges J, et al. Multimodal approach to screening for ovarian cancer. Lancet 1988; i: 268–71. 4 Skates SJ, Xu JF, Yu YH, et al. Toward an optimal algorithm for ovarian cancer screening with longitudinal tumour markers. Cancer 1995; 76: 2004–10.
THE LANCET • Vol 354 • August 7, 1999
CORRESPONDENCE
Screening for ovarian cancer Sir—I would be grateful if Ian Jacobs and colleagues (April 10, p 1207)1 could clarify the following issues about their report on screening for ovarian cancer. It seems that the screened population they refer to had already been screened twice before by means of measurement of serum CA 125 antigen and ultrasonography. 2 4 1 women with abnormal screening underwent operations, and 11 ovarian cancers were discovered. There were altogether 19 ovarian cancers in the group of 22 000 women tested and those women were removed from the cohort. The rest of the women were then randomised to screening or no screening to make the sample of the new study. Do the authors think that this study is representative of the general population? There were 340 women with raised CA 125 among the 22 000 women tested,2 which amounts to 1·54% of the population with abnormal values. Among 8723 patients tested with CA 125,1 254 had abnormal values (2·9%). Any possible explanation for an almost two-fold increase in the second group, which—as mentioned before—had already been screened twice? Which are the true numbers: the numbers in the text—with 9364 women with one screen and 7743 women with three screens—or the numbers in figure 1 and table 1—with 8732 with one screen and 8455 with three screens? In view of what is said in the summary about survival and mortality, I find it difficult to interpret the following passage in the Discussion: “survival differed significantly between women with index cancer in the screened and control groups, but this finding is not definitive evidence for lack of benefit from screening for ovarian cancer.” The prevalence of ovarian cancer has been estimated at 50 per 100 000 women.3 There is evidence to suggest that the use of oral contraceptives may decrease the relative risk of ovarian cancer in ever users by 40%.4 This point should be taken into account
THE LANCET • Vol 354 • August 7, 1999
before resources are committed to a larger study of the feasibility of screening programmes for ovarian cancer. Nikolai Manassiev 58 Ollerton Road, Yardley, Birmingham, B26 1PN, UK 1
Jacobs I, Skates S, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: 1207–10. 2 Jacobs I, Davies A, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993; 306: 1030–34. 3 NIH Consensus Development Panel on Ovarian Cancer. Ovarian cancer: screening, treatment and follow-up. JAMA 1995; 273: 491–97. 4 Beral V, Hermon C, Kay C, et al. Mortality associated with oral contraceptive use: 25 year follow-up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study. BMJ 1999; 318: 96–100.
Sir—In the light of Woodman’s report 1 about Ian Jacobs and colleagues’ study,2 we disagree with the optimistic conclusion reached by the investigators and believe a more cautious interpretation is justified. Jacobs and colleagues specifically report only the positive-predictive value of the strategy (20·7%), and compare this with other current methods of screening for ovarian cancer. This single factor is sufficient to make decisions about a screening test. On the basis of the figures for women who completed at least one screen (9364), the strategy has a sensitivity of 37·5%, specificity of 99·75%, and negative-predictive value of 99·89%. A screening test should have high sensitivity (especially for rare disease) and be followed by a diagnostic test with high sensitivity and specificity, leading to a strategy with high sensitivity and high positivepredictive value. The reported strategy has low sensitivity and low positivepredictive value. Since the subsequent investigation of any positive test involves major abdominal surgery, a high positive-predictive value is particularly important. Although data on certain risk factors are presented for each group, family
history of ovarian cancer is not reported. Given the voluntary nature of recruitment to this study, we do not know if the population studied were representative, or if in fact they included a disproportionate number of women with increased genetic risk of ovarian cancer. This bias could potentially affect the uptake of the test and its detection rate. Jacob and colleagues conclude that this pilot study justifies a much larger trial to show an effect on mortality, and to assess economic and psychosocial factors. It is a pity that this study of 22 000 women d i d n o t include these additional assessments. It would be interesting to know the psychological and physical impact on the 23 women who underwent major abdominal surgery for a false-positive screen, and the effect on the ten women reassured by the test who subsequently developed ovarian cancer.3 We believe that this study shows the lack of an adequate population screening tool for ovarian cancer, and highlights the difficulties of searching for screening tools for r a r e diseases. Perhaps a more appropriate strategy will be shown from studies currently in progress of targeted screening for women at increased genetic risk of ovarian cancer, or from the development of more sensitive biological markers of the disease? *Jon Emery, John Yaphe, Patricia Priest, David Whiteman Division of Public Health and Primary Health Care, Institute of Health Sciences, Headington, Oxford OX3 7LF, UK 1
Woodman R. Ovarian cancer screening may increase survival. BMJ 1999; 318: 1027. 2 Jacobs I, Skates S, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: 1207–10. 3 Stewart-Brown S, Farmer A. Screening could seriously damage your health. BMJ 1997; 314: 533–34.
Sir—Ian Jacobs and colleagues 1 report the results of a population-based randomised trial of screening for ovarian cancer in postmenopausal women. The women were first screened by measurement of serum CA 125, and those who had had a
509
raised value were offered screening by transabdominal (and later endovaginal) ultrasonography. Women were screened each year for 3 years and followed up for at least 7 years. There were 18 deaths from ovarian cancer in the control group and nine deaths in the women who were screened. Treated as a cohort, ovarian cancer mortality was lower in the screened group than in the controls (p=0·08). The goal of screening is to reduce death from cancer by allowing diagnosis of the cancer at an early stage. 11 of the 16 women with ovarian cancer in the screened group had a diagnosis made at stages III or IV, and these 11 women will likely succumb to their disease. The observed survival benefit of screening was clinically important, and if the comparison in this study had been between two different treatments, then the increase in survival would have been notable. However, if most of the screendetected cancers ultimately prove to be fatal, then this study cannot be viewed as encouraging. We recommend prophylactic oophorectomy by age 45 years for women who carry a germline mutation in BRCA1 or BRCA2.2,3 The results of the Jacobs study do not encourage us to modify this policy. *Pierre O Chappuis, Steven A Narod, William D Foulkes Departments of Medicine, *Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada H3G 1A4; and Centre for Research in Women’s Health, University of Toronto, Toronto, Ontario, Canada 1
Jacobs IJ, Skates SJ, McDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: 1207–10. 2 Eisen A, Weber BL. Primary peritoneal carcinoma can have multifocal origins: implications for prophylactic oophorectomy. J Natl Cancer Inst 1998; 90: 797–99. 3 Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRAC1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277: 997–1003.
Authors’ reply Sir—We share the enthusiasm of all the correspondents for exploring other methods to reduce mortality from ovarian cancer, including chemoprevention, prophylactic oophorectomy, and identification of individuals at high risk of the disease. Hopefully effective prevention will eventually make screening unnecessary, but this is not the case at present. Nikolai Manassiev and Jon Emery and colleagues were concerned that t h e study population may not be representive of the general population.
510
Number of women who underwent annual screening 7743 women underwent all three screens; 9364 underwent at least one screen.
The population was similar to the UK population in terms of ovarian-cancer incidence.1 Of the 22 000 participants, only 587 had a first-degree relative with ovarian cancer and women with two or more first-degree relatives with ovarian cancer were not eligible. As far as the impact of the prevalence screen is concerned, there is no perfect design for a randomised trial of cancer screening. We chose to randomise after the prevalence screen, because this approach is more likely to reflect the situation in a regular screening programme. Randomisation before an initial screen dilutes the effect of screening, because prevalence cases of cancer are included. Manassiev and colleagues also commented on the difference in increased CA 125 serum concentration at different screens. This difference may be partly attributable to assay and biological variation or to various benign and malignant disorders.2 The figure clarifies the apparent discrepancy between the text and table pointed out by Manassiev and colleagues. The figure was removed in The Lancet’s editorial process, which also failed to incorporate our correction on the proofs to the sentence that should have read: “but this finding is not definitive evidence for a benefit from screening for ovarian cancer”. We share Chappuis and colleagues’ concern regarding the lack of a significant stage shift. This result may simply reflect the size and power of our study, because there was a trend to earlier stage cancer. Alternatively, the survival benefit noted may be caused by a shift in substage (eg, from stage IIIc to stage IIIa), rather than stage. These and other uncertainties underscore the need for a larger definitive randomised trial of screening for ovarian cancer. As far as women with germline B R C A 1 or B R C A 2
mutations are concerned, we agree that prophylactic oophorectomy is an important option. However, in the absence of definitive data about the effect of oophorectomy or screening, we prefer to avoid a dogmatic approach and offer counselling about all options so that women can make a balanced and individualised decision. We agree with Emery and colleagues that various factors need to be considered when making decisions about screening tests. The report focused on one factor—the outcome of screening. Our research continues to address other important issues including screening performance, quality of life, morbidity, and health economics. The performance of the screening strategy was consistent with our previous reports of specificity (99·9%) and positive-predictive value (20%), 1,3 which compare favourably with screening for breast and cervical cancer. It is noteworthy that there was no major surgical morbidity in our study among women with falsepositive results. The sensitivity of our strategy for annual screening was 54·5% (six of 11 women). Although 16 cancers developed in the screened women during 8 years, only 11 women developed cancer during the year after a screen. We are exploring a number of approaches to improve on this sensitivity. The most encouraging incorporates changes in serial serum concentrations of CA 1254 and seems to increase sensitivity to 80% while maintaining high specificity. Emery and colleagues advocate targeting screening at women with a genetic predisposition to ovarian cancer. Since only 5–10% of all ovarian cancers occur in this group of women, this approach would have a limited impact on overall mortality from ovarian cancer. *Ian J Jacobs, Usha Menon, Nicola D MacDonald, Adam N Rosenthal Department of Gynaecological Oncology, St Bartholomew’s and Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London EC1A 7BE, UK 1
Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993; 306: 1030–34. 2 Jeyarajah AR, Ind TEJ, Skates SJ, et al. Serum CA 125 elevation and risk of clinical detection of cancer in asymptomatic postmenopausal women. Cancer 1999; 86: 2068–72. 3 Jacobs I, Stabile I, Bridges J, et al. Multimodal approach to screening for ovarian cancer. Lancet 1988; i: 268–71. 4 Skates SJ, Xu JF, Yu YH, et al. Toward an optimal algorithm for ovarian cancer screening with longitudinal tumour markers. Cancer 1995; 76: 2004–10.
THE LANCET • Vol 354 • August 7, 1999