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Screening to improve ovarian cancer prognosis?
Comment
Screening to improve ovarian cancer prognosis? periods, allowing judgement on the efficacy of screening both in terms of detection of cancer at an earlier stage, and survival. The Shizuoka Cohort Study of Ovarian Cancer Screening (SCSOCS)8 was the first of these randomised controlled studies, recruiting participants until 1999, and reported that 63% of patients in the screened group had stage I tumours versus 38% in the non-screened group, 3 years after last enrolment. However, in this underpowered study the difference was not statistically significant. Survival data have not yet been published. The Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) randomised controlled trial9 enrolled patients until 2001, and its results showed neither a stage shift—which would indicate earlier detection of tumours—nor a survival benefit, for those women who underwent screening.9 A survival benefit was not achieved even when the risk of ovarian cancer algorithm, as used in the UKCTOCS study, was applied retrospectively to the data.10 The third and largest prospective randomised controlled trial is UKCTOCS.2 Jacobs and colleagues randomly assigned 202 638 postmenopausal women in a 1:1:2 ratio to two screening approaches or control. Besides being by far the largest study, UKCTOCS used a unique calculation to estimate risk of ovarian cancer rather than fixed cutoff values for CA125. Additionally, it tested two screening strategies: multimodal screening
Published Online December 17, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01236-2 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
Steve Gschmeissner/Science Photo Library
Despite increasingly radical surgical approaches and the huge efforts put into new and targeted therapeutic agents, prognosis for patients with ovarian cancer has hardly improved in the past three decades.1 Besides aiming to revolutionise treatment further, efforts need to focus on early detection of disease. In The Lancet, Ian Jacobs and colleagues2 report the results of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which has assessed whether screening improves diagnosis and prognosis of ovarian cancer. Less than 30% of patients with ovarian cancer are diagnosed at an early, potentially curable stage (ie, International Federation of Gynecology and Obstetrics stages I–II). Models using data from patients with hereditary cancer have estimated that ovarian cancer starts to develop 5·1 years before clinical diagnosis, and on average the tumour will take 0·8 years to progress from an early to an advanced stage, which potentially leaves a window of opportunity for early detection of 4·3 years. Additionally, a yearly screening test that could detect tumours below 0·5 cm in diameter has been estimated to reduce mortality from serous ovarian cancer by 50%.3 Early diagnosis is hampered by the absence of early and specific symptoms. Although studies in primary care have indicated independent predictors of disease (eg, abdominal bloating, abdominal or pelvic pain, abdominal lump, urinary urge, and abnormal vaginal blood loss), these predictors are all unspecific.4,5 Therefore, their predictive value or the predictive value of indices based upon them is low.6 Nevertheless, whether the resulting delay in diagnosis will actually affect survival remains a matter of debate, because no difference in survival was noted between a cohort of patients with a delay between first symptoms and diagnosis of longer than 12 months, or shorter than 1 month.7 Research aimed at developing presymptomatic detection of ovarian cancer by screening seems to be warranted, and trials have been done comparing women screened on the basis of concentration of serum CA125 and ultrasound with women in the general population who were not screened. Only three large randomised studies,2,8,9 one of which is the UKCTOCS study,2 have been done so far. The studies have long follow-up
Ovarian cancer cells
www.thelancet.com Published online December 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01236-2
1
Comment
(ie, primary CA125 screening followed by transvaginal ultrasound); or primary ultrasound screening only. The primary endpoint of ovarian cancer death by study end showed no significant differences between the study groups (mortality reduction compared with no screening over years 0–14 was 15% [95% CI –3 to 30], p=0·10, with CA125 screening plus ultrasound; and 11% [–7 to 27], p=0·21, with ultrasound alone). However, the results showed earlier detection of ovarian cancer with screening, and a significant mortality reduction in the long term (ie, after 7 years). Specifically, multimodal screening could detect cancer at an early stage in a greater number of patients (118 [39%] of 299 patients in the multimodal screening group vs 148 [26%] of 574 patients with no screening, p<0·0001); and mortality was reduced by 23% (95% CI 1–46) in years 7–14. Despite these encouraging results in a trial with more than 200 000 participants, detection of cancers by screening in both study groups was limited (59% in the multimodal screening group and 51% in the ultrasound only group). The limited stage shift and survival benefit needed a reasonable number of patients (641) to be screened to prevent one cancer death, and an acceptable number (three) of operations were needed to detect one cancer case. If only 59% of ovarian cancer cases are detected by screening plus ultrasound, we will need to focus on why and how screening—as undertaken within UKCTOCS—still has a significant, but delayed, survival effect. Trying to unravel the mechanism behind this effect so that it can be improved should have a high priority. Looking for new tumour markers is most probably not such a high priority, because, for example, none of 28 new biomarkers tested on samples from the PLCO trial were better than CA125 at predicting ovarian cancer risk.11
2
Awareness and symptom recognition for diagnosis of ovarian cancer at an early stage will be difficult to improve upon. Screening will not be warranted until the UKCTOCS outcome2 has been validated in daily practice. But careful studies such as that of Jacobs and colleagues show that we must and can focus on mechanisms of early cancer detection. *René H M Verheijen, Ronald P Zweemer Department of Gynaecological Oncology, Division of Surgical Oncology, UMC Utrecht Cancer Center, 3584 CX Utrecht, Netherlands [email protected] We declare no competing interests. 1
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Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011; 11: 719–25. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 2015; published online Dec 17. http://dx.doi.org/10.1016/S0140-6736(15)01224-6. Brown PO, Palmer C. The preclinical natural history of serous ovarian cancer: defining the target for early detection. PLoS Med 2009; 6: e1000114. Hippisley-Cox J, Coupland C. Identifying women with suspected ovarian cancer in primary care: derivation and validation of algorithm. BMJ 2012; 344: d8009. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 2007; 109: 221–27. Hamilton W, Peters TJ, Bankhead C, Sharp D. Risk of ovarian cancer in women with symptoms in primary care: population based case-control study. BMJ 2009; 339: b2998. Nagle CM, Francis JE, Nelson AE, et al. Reducing time to diagnosis does not improve outcomes for women with symptomatic ovarian cancer: a report from the Australian ovarian cancer study group. J Clin Oncol 2011; 29: 2253–58. Kobayashi H, Yamada Y, Sado T, et al. A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer 2008; 18: 414–20. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA 2011; 305: 2295–303. Pinsky PF, Zhu C, Skates SJ, et al. Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial. Int J Cancer 2013; 132: 2127–33. Zhu CS, Pinsky PF, Cramer DW, et al. A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer. Cancer Prev Res (Phila) 2011; 4: 375–83.
www.thelancet.com Published online December 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01236-2
Screening to improve ovarian cancer prognosis? periods, allowing judgement on the efficacy of screening both in terms of detection of cancer at an earlier stage, and survival. The Shizuoka Cohort Study of Ovarian Cancer Screening (SCSOCS)8 was the first of these randomised controlled studies, recruiting participants until 1999, and reported that 63% of patients in the screened group had stage I tumours versus 38% in the non-screened group, 3 years after last enrolment. However, in this underpowered study the difference was not statistically significant. Survival data have not yet been published. The Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) randomised controlled trial9 enrolled patients until 2001, and its results showed neither a stage shift—which would indicate earlier detection of tumours—nor a survival benefit, for those women who underwent screening.9 A survival benefit was not achieved even when the risk of ovarian cancer algorithm, as used in the UKCTOCS study, was applied retrospectively to the data.10 The third and largest prospective randomised controlled trial is UKCTOCS.2 Jacobs and colleagues randomly assigned 202 638 postmenopausal women in a 1:1:2 ratio to two screening approaches or control. Besides being by far the largest study, UKCTOCS used a unique calculation to estimate risk of ovarian cancer rather than fixed cutoff values for CA125. Additionally, it tested two screening strategies: multimodal screening
Published Online December 17, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01236-2 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
Steve Gschmeissner/Science Photo Library
Despite increasingly radical surgical approaches and the huge efforts put into new and targeted therapeutic agents, prognosis for patients with ovarian cancer has hardly improved in the past three decades.1 Besides aiming to revolutionise treatment further, efforts need to focus on early detection of disease. In The Lancet, Ian Jacobs and colleagues2 report the results of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which has assessed whether screening improves diagnosis and prognosis of ovarian cancer. Less than 30% of patients with ovarian cancer are diagnosed at an early, potentially curable stage (ie, International Federation of Gynecology and Obstetrics stages I–II). Models using data from patients with hereditary cancer have estimated that ovarian cancer starts to develop 5·1 years before clinical diagnosis, and on average the tumour will take 0·8 years to progress from an early to an advanced stage, which potentially leaves a window of opportunity for early detection of 4·3 years. Additionally, a yearly screening test that could detect tumours below 0·5 cm in diameter has been estimated to reduce mortality from serous ovarian cancer by 50%.3 Early diagnosis is hampered by the absence of early and specific symptoms. Although studies in primary care have indicated independent predictors of disease (eg, abdominal bloating, abdominal or pelvic pain, abdominal lump, urinary urge, and abnormal vaginal blood loss), these predictors are all unspecific.4,5 Therefore, their predictive value or the predictive value of indices based upon them is low.6 Nevertheless, whether the resulting delay in diagnosis will actually affect survival remains a matter of debate, because no difference in survival was noted between a cohort of patients with a delay between first symptoms and diagnosis of longer than 12 months, or shorter than 1 month.7 Research aimed at developing presymptomatic detection of ovarian cancer by screening seems to be warranted, and trials have been done comparing women screened on the basis of concentration of serum CA125 and ultrasound with women in the general population who were not screened. Only three large randomised studies,2,8,9 one of which is the UKCTOCS study,2 have been done so far. The studies have long follow-up
Ovarian cancer cells
www.thelancet.com Published online December 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01236-2
1
Comment
(ie, primary CA125 screening followed by transvaginal ultrasound); or primary ultrasound screening only. The primary endpoint of ovarian cancer death by study end showed no significant differences between the study groups (mortality reduction compared with no screening over years 0–14 was 15% [95% CI –3 to 30], p=0·10, with CA125 screening plus ultrasound; and 11% [–7 to 27], p=0·21, with ultrasound alone). However, the results showed earlier detection of ovarian cancer with screening, and a significant mortality reduction in the long term (ie, after 7 years). Specifically, multimodal screening could detect cancer at an early stage in a greater number of patients (118 [39%] of 299 patients in the multimodal screening group vs 148 [26%] of 574 patients with no screening, p<0·0001); and mortality was reduced by 23% (95% CI 1–46) in years 7–14. Despite these encouraging results in a trial with more than 200 000 participants, detection of cancers by screening in both study groups was limited (59% in the multimodal screening group and 51% in the ultrasound only group). The limited stage shift and survival benefit needed a reasonable number of patients (641) to be screened to prevent one cancer death, and an acceptable number (three) of operations were needed to detect one cancer case. If only 59% of ovarian cancer cases are detected by screening plus ultrasound, we will need to focus on why and how screening—as undertaken within UKCTOCS—still has a significant, but delayed, survival effect. Trying to unravel the mechanism behind this effect so that it can be improved should have a high priority. Looking for new tumour markers is most probably not such a high priority, because, for example, none of 28 new biomarkers tested on samples from the PLCO trial were better than CA125 at predicting ovarian cancer risk.11
2
Awareness and symptom recognition for diagnosis of ovarian cancer at an early stage will be difficult to improve upon. Screening will not be warranted until the UKCTOCS outcome2 has been validated in daily practice. But careful studies such as that of Jacobs and colleagues show that we must and can focus on mechanisms of early cancer detection. *René H M Verheijen, Ronald P Zweemer Department of Gynaecological Oncology, Division of Surgical Oncology, UMC Utrecht Cancer Center, 3584 CX Utrecht, Netherlands [email protected] We declare no competing interests. 1
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4
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Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011; 11: 719–25. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 2015; published online Dec 17. http://dx.doi.org/10.1016/S0140-6736(15)01224-6. Brown PO, Palmer C. The preclinical natural history of serous ovarian cancer: defining the target for early detection. PLoS Med 2009; 6: e1000114. Hippisley-Cox J, Coupland C. Identifying women with suspected ovarian cancer in primary care: derivation and validation of algorithm. BMJ 2012; 344: d8009. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 2007; 109: 221–27. Hamilton W, Peters TJ, Bankhead C, Sharp D. Risk of ovarian cancer in women with symptoms in primary care: population based case-control study. BMJ 2009; 339: b2998. Nagle CM, Francis JE, Nelson AE, et al. Reducing time to diagnosis does not improve outcomes for women with symptomatic ovarian cancer: a report from the Australian ovarian cancer study group. J Clin Oncol 2011; 29: 2253–58. Kobayashi H, Yamada Y, Sado T, et al. A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer 2008; 18: 414–20. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA 2011; 305: 2295–303. Pinsky PF, Zhu C, Skates SJ, et al. Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial. Int J Cancer 2013; 132: 2127–33. Zhu CS, Pinsky PF, Cramer DW, et al. A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer. Cancer Prev Res (Phila) 2011; 4: 375–83.
www.thelancet.com Published online December 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01236-2