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Screening for ovarian carcinoma: not quite there yet
Reflection and Reaction
Screening for ovarian carcinoma: not quite there yet See Articles page 327
308
Ovarian carcinoma is often called the silent killer because it is characterised by few or late symptoms and has the highest mortality rate of all malignant gynaecological tumours. Therefore, being able to identify a premalignant stage of ovarian carcinoma is the holy grail for the physicians who take care of patients with ovarian cancer. Unfortunately, borderline (ie, non-invasive malignant) ovarian tumours rarely precede invasive epithelial ovarian carcinoma. Furthermore, it has not yet been shown that diagnosing invasive ovarian carcinoma at a very early stage results in decreased mortality. In this issue of The Lancet Oncology, Menon and colleagues1 report on the sensitivity and specificity of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), the largest study of its kind to date. 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control), annual multimodal screening by serum CA125 assay and transvaginal ultrasound (MMS), and transvaginal ultrasound screening alone (USS) in a 2:1:1 ratio. The authors are to be congratulated for this huge study. However, to draw any conclusions about the effect of ovarian-cancer screening on mortality we need to be able to compare the mortality rates in the screening groups with the mortality rate in the control group, and these data are not yet available. 58 invasive ovarian/fallopian tube cancers were detected in the screening groups, of which 24 (14 MMS, 10 USS) were stage I. At over 40%, the percentage of screen-detected stage I invasive ovarian cancers is encouraging, since only about 28% of invasive cancers are detected at this early stage in most ovarian cancer series.2 However, 35·2 surgeries per invasive carcinoma detected had to be done in the USS group, compared with 2·9 per invasive cancer detected in the MMS group. From these preliminary results it might be speculated that MMS will be the preferred screening strategy, if the completed UKCTOCS study shows that it has had a significant effect on mortality when it is concluded in December, 2014. From a public-health perspective, the total cost of screening and the cost per year of life saved is very important. At this point in time, it is not
possible to calculate what the cost of MMS will be, because the risk-of-ovarian-cancer algorithm on which MMS is based is patented (Sept 1, 1998, US patent 5800347, and Feb 29, 2000, US patent 6030341), and has not been made publicly available. The price of the algorithm per year of life saved has been estimated at US$20 000–40 000.3 One should also note that high-quality gynaecological ultrasound is not globally available and, from the data presented by Menon and colleagues, USS seems to result in too many false-positive cases and unnecessary surgery. In the UKCTOCS study the decision to operate was made by clinicians acting on their clinical judgement. All clinicians received written information on the risks for malignancy associated with various previously published morphological classifications when applied to the International Ovarian Tumour Analysis (IOTA) study, as presented at the annual European Society of Gynaecological Oncology meeting in 2003. However, this abstract4 only reported on the risk of malignancy defined by the simple morphological classification originally proposed by Granberg and colleagues,5 and not on any subsequent second-stage test that included the use of models developed during the IOTA study to distinguish between malignant and benign tumours.6 In the UKCTOCS study, the clinicians were not given guidelines on when to intervene nor up to what level of risk conservative management was acceptable for the management of a probable benign mass. Previous screening studies have suggested that there is no benefit in removing screen-detected benign ovarian masses.7 Many unnecessary interventions in women with benign masses could have been prevented by clear instructions on conservative management and by implementing the best methods available to discriminate between benign and malignant masses. Several studies have confirmed the high sensitivity for malignancy and the high specificity of subjective assessment (or pattern recognition) achieved by experienced ultrasound examiners.8–10 Lastly, the reasons given by the authors for changing the cutoffs for intermediate and increased risk of ovarian cancer in the MMS group during the study remain obscure. This lack of clarity is worrying, since it could indicate a bias in favour of the MMS screening strategy. www.thelancet.com/oncology Vol 10 April 2009
Reflection and Reaction
Hopefully in the near future new molecular markers for early stage ovarian cancer will be discovered. Undoubtedly, the UKCTOCS trial serum bank of over 350 000 samples will be very valuable for this research. We feel that this research will be necessary, since data from the prevalence screen of the UKCTOCS trial and other screening trials have not yet convinced us that the time has come to screen for ovarian carcinoma in women without a familial history of ovarian and breast cancer.
2
3
4
5
6
7
Ignace Vergote*, Frédéric Amant, Lieveke Ameye, Dirk Timmerman
8
Department of Gynaecology and Obstetrics (IV, FA, DT) and Department of Electrical Engineering (LA), Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium [email protected]
9
The authors declared no conflicts of interest.
10
1
Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 2009; 10: 327–40.
Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006; 95 (suppl 1): S161–92. Skates SJ, Menon U, MacDonald N, et al. Calculation of the risk of ovarian cancer from serial CA125 values for preclinical detection in postmenopauzal women. J Clin Oncol 2003; 21: 206s–10s. Timmerman D, De Smet F, De Brabanter J, et al. News on ultrasonographic techniques for pelvic malignancies. Int J Gynecol Cancer 2003; 13 (suppl 1): 120–121. Granberg S, Wikland M, Jansson I. Macroscopic characterization of ovarian tumors and the relation to the histological diagnosis: criteria to be used for ultrasound evaluation. Gynecol Oncol 1989; 35: 139–44. Timmerman D, Testa AC, Bourne T, et al. Logistic regression model to distinguish between the benign and malignant adnexal mass before surgery: a multicenter study by the International Ovarian Tumor Analysis Group. J Clin Oncol 2005; 23: 8794–801. Crayford TJ, Campbell S, Bourne TH, Rawson HJ, Collins WP. Benign ovarian cysts and ovarian cancer: a cohort study with implications for screening. Lancet 2000; 355: 1060–63. Timmerman D, Schwärzler P, Collins WP, et al. Subjective assessment of adnexal masses using ultrasonography – an analysis of interobserver variability and experience. Ultrasound Obstet Gynecol 1999; 13: 11–16. Valentin L, Hagen B, Tingulstad S, Eik-Nes S. Comparison of ‘pattern recognition’ and logistic regression models for discrimination between benign and malignant pelvic masses. A prospective cross-validation. Ultrasound Obstet Gynecol 2001; 18: 357–65. Van Calster B, Timmerman D, Bourne T, et al. Discrimination between benign and malignant adnexal masses by specialist ultrasound examination versus serum CA-125. J Natl Cancer Inst 2007; 99: 1706–14.
Resources needed to complete a phase III oncology study have increased substantially over the last decade. One way to reduce costs is to shorten the time needed for randomised trials to show a clinically significant benefit. Surrogate endpoints for overall survival might help to achieve this goal. Overall survival is a clearly defined endpoint that is not affected by investigator definitions of failure, compliance of patients with long-term follow-up, clinical or radiographic assessment, complexities of identifying cause of death, or physician bias. This endpoint is the gold standard for assessment of efficacy of clinical interventions in patients with cancer in phase III trials. Regulatory authorities rely on overall survival when evaluating the efficacy of new treatments compared with standard care. However, overall survival requires large sample sizes and a long time for data maturation to show an effect, and it therefore has high associated costs. Many investigations have searched for valid surrogate endpoints for overall survival. For example, in an analysis of 18 randomised trials in patients treated with adjuvant chemotherapy for colorectal cancer, there was www.thelancet.com/oncology Vol 10 April 2009
a strong association between disease-free and overall survival. Moreover, a benefit in disease-free survival was associated with improved overall survival in 92% of analyses.1 In advanced colorectal cancer, therefore, disease-free survival is an appropriate surrogate endpoint and is accepted by regulatory authorities that approve drugs.1 Both colorectal cancer and head and neck cancer are treated with the intention of curing the disease and can be cured with definitive locoregional therapy. Hence, the potential of disease-free survival as an endpoint in head and neck cancer is clear. In this issue of The Lancet Oncology, Michiels and colleagues2 investigated locoregional control and event-free survival as potential surrogates for overall survival in locally advanced head and neck cancer with meta-analyses of individual patients’ data from 116 randomised trials. The authors analysed data from four meta-analyses included in the meta-analysis of chemotherapy in head and neck cancer study (MACH-NC) and the meta-analysis of radiotherapy in carcinomas of head and neck (MARCH)m with a total of 22 744 patients. Event-free survival was defined
Getty Images
Surrogate endpoints in head and neck cancer
See Articles page 341
309
Screening for ovarian carcinoma: not quite there yet See Articles page 327
308
Ovarian carcinoma is often called the silent killer because it is characterised by few or late symptoms and has the highest mortality rate of all malignant gynaecological tumours. Therefore, being able to identify a premalignant stage of ovarian carcinoma is the holy grail for the physicians who take care of patients with ovarian cancer. Unfortunately, borderline (ie, non-invasive malignant) ovarian tumours rarely precede invasive epithelial ovarian carcinoma. Furthermore, it has not yet been shown that diagnosing invasive ovarian carcinoma at a very early stage results in decreased mortality. In this issue of The Lancet Oncology, Menon and colleagues1 report on the sensitivity and specificity of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), the largest study of its kind to date. 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control), annual multimodal screening by serum CA125 assay and transvaginal ultrasound (MMS), and transvaginal ultrasound screening alone (USS) in a 2:1:1 ratio. The authors are to be congratulated for this huge study. However, to draw any conclusions about the effect of ovarian-cancer screening on mortality we need to be able to compare the mortality rates in the screening groups with the mortality rate in the control group, and these data are not yet available. 58 invasive ovarian/fallopian tube cancers were detected in the screening groups, of which 24 (14 MMS, 10 USS) were stage I. At over 40%, the percentage of screen-detected stage I invasive ovarian cancers is encouraging, since only about 28% of invasive cancers are detected at this early stage in most ovarian cancer series.2 However, 35·2 surgeries per invasive carcinoma detected had to be done in the USS group, compared with 2·9 per invasive cancer detected in the MMS group. From these preliminary results it might be speculated that MMS will be the preferred screening strategy, if the completed UKCTOCS study shows that it has had a significant effect on mortality when it is concluded in December, 2014. From a public-health perspective, the total cost of screening and the cost per year of life saved is very important. At this point in time, it is not
possible to calculate what the cost of MMS will be, because the risk-of-ovarian-cancer algorithm on which MMS is based is patented (Sept 1, 1998, US patent 5800347, and Feb 29, 2000, US patent 6030341), and has not been made publicly available. The price of the algorithm per year of life saved has been estimated at US$20 000–40 000.3 One should also note that high-quality gynaecological ultrasound is not globally available and, from the data presented by Menon and colleagues, USS seems to result in too many false-positive cases and unnecessary surgery. In the UKCTOCS study the decision to operate was made by clinicians acting on their clinical judgement. All clinicians received written information on the risks for malignancy associated with various previously published morphological classifications when applied to the International Ovarian Tumour Analysis (IOTA) study, as presented at the annual European Society of Gynaecological Oncology meeting in 2003. However, this abstract4 only reported on the risk of malignancy defined by the simple morphological classification originally proposed by Granberg and colleagues,5 and not on any subsequent second-stage test that included the use of models developed during the IOTA study to distinguish between malignant and benign tumours.6 In the UKCTOCS study, the clinicians were not given guidelines on when to intervene nor up to what level of risk conservative management was acceptable for the management of a probable benign mass. Previous screening studies have suggested that there is no benefit in removing screen-detected benign ovarian masses.7 Many unnecessary interventions in women with benign masses could have been prevented by clear instructions on conservative management and by implementing the best methods available to discriminate between benign and malignant masses. Several studies have confirmed the high sensitivity for malignancy and the high specificity of subjective assessment (or pattern recognition) achieved by experienced ultrasound examiners.8–10 Lastly, the reasons given by the authors for changing the cutoffs for intermediate and increased risk of ovarian cancer in the MMS group during the study remain obscure. This lack of clarity is worrying, since it could indicate a bias in favour of the MMS screening strategy. www.thelancet.com/oncology Vol 10 April 2009
Reflection and Reaction
Hopefully in the near future new molecular markers for early stage ovarian cancer will be discovered. Undoubtedly, the UKCTOCS trial serum bank of over 350 000 samples will be very valuable for this research. We feel that this research will be necessary, since data from the prevalence screen of the UKCTOCS trial and other screening trials have not yet convinced us that the time has come to screen for ovarian carcinoma in women without a familial history of ovarian and breast cancer.
2
3
4
5
6
7
Ignace Vergote*, Frédéric Amant, Lieveke Ameye, Dirk Timmerman
8
Department of Gynaecology and Obstetrics (IV, FA, DT) and Department of Electrical Engineering (LA), Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium [email protected]
9
The authors declared no conflicts of interest.
10
1
Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 2009; 10: 327–40.
Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006; 95 (suppl 1): S161–92. Skates SJ, Menon U, MacDonald N, et al. Calculation of the risk of ovarian cancer from serial CA125 values for preclinical detection in postmenopauzal women. J Clin Oncol 2003; 21: 206s–10s. Timmerman D, De Smet F, De Brabanter J, et al. News on ultrasonographic techniques for pelvic malignancies. Int J Gynecol Cancer 2003; 13 (suppl 1): 120–121. Granberg S, Wikland M, Jansson I. Macroscopic characterization of ovarian tumors and the relation to the histological diagnosis: criteria to be used for ultrasound evaluation. Gynecol Oncol 1989; 35: 139–44. Timmerman D, Testa AC, Bourne T, et al. Logistic regression model to distinguish between the benign and malignant adnexal mass before surgery: a multicenter study by the International Ovarian Tumor Analysis Group. J Clin Oncol 2005; 23: 8794–801. Crayford TJ, Campbell S, Bourne TH, Rawson HJ, Collins WP. Benign ovarian cysts and ovarian cancer: a cohort study with implications for screening. Lancet 2000; 355: 1060–63. Timmerman D, Schwärzler P, Collins WP, et al. Subjective assessment of adnexal masses using ultrasonography – an analysis of interobserver variability and experience. Ultrasound Obstet Gynecol 1999; 13: 11–16. Valentin L, Hagen B, Tingulstad S, Eik-Nes S. Comparison of ‘pattern recognition’ and logistic regression models for discrimination between benign and malignant pelvic masses. A prospective cross-validation. Ultrasound Obstet Gynecol 2001; 18: 357–65. Van Calster B, Timmerman D, Bourne T, et al. Discrimination between benign and malignant adnexal masses by specialist ultrasound examination versus serum CA-125. J Natl Cancer Inst 2007; 99: 1706–14.
Resources needed to complete a phase III oncology study have increased substantially over the last decade. One way to reduce costs is to shorten the time needed for randomised trials to show a clinically significant benefit. Surrogate endpoints for overall survival might help to achieve this goal. Overall survival is a clearly defined endpoint that is not affected by investigator definitions of failure, compliance of patients with long-term follow-up, clinical or radiographic assessment, complexities of identifying cause of death, or physician bias. This endpoint is the gold standard for assessment of efficacy of clinical interventions in patients with cancer in phase III trials. Regulatory authorities rely on overall survival when evaluating the efficacy of new treatments compared with standard care. However, overall survival requires large sample sizes and a long time for data maturation to show an effect, and it therefore has high associated costs. Many investigations have searched for valid surrogate endpoints for overall survival. For example, in an analysis of 18 randomised trials in patients treated with adjuvant chemotherapy for colorectal cancer, there was www.thelancet.com/oncology Vol 10 April 2009
a strong association between disease-free and overall survival. Moreover, a benefit in disease-free survival was associated with improved overall survival in 92% of analyses.1 In advanced colorectal cancer, therefore, disease-free survival is an appropriate surrogate endpoint and is accepted by regulatory authorities that approve drugs.1 Both colorectal cancer and head and neck cancer are treated with the intention of curing the disease and can be cured with definitive locoregional therapy. Hence, the potential of disease-free survival as an endpoint in head and neck cancer is clear. In this issue of The Lancet Oncology, Michiels and colleagues2 investigated locoregional control and event-free survival as potential surrogates for overall survival in locally advanced head and neck cancer with meta-analyses of individual patients’ data from 116 randomised trials. The authors analysed data from four meta-analyses included in the meta-analysis of chemotherapy in head and neck cancer study (MACH-NC) and the meta-analysis of radiotherapy in carcinomas of head and neck (MARCH)m with a total of 22 744 patients. Event-free survival was defined
Getty Images
Surrogate endpoints in head and neck cancer
See Articles page 341
309