**7. Trials in ovarian cancer screening**

Ultrasound and serum CA125 testing are two main modalities that have been used in ovarian cancer screening. Ultrasound alone has been used in some of the studies. In some other studies, multimodal screening with a combination of serum CA125 and ultrasound have been used. Following are some of the larger trials in the general population.

#### **7.1. The University of Kentucky Ovarian Cancer Screening (UKOCS) trial**

leading to a cascade of trial therapies and investigations until a diagnosis is reached. Hence, there may be a time lapse from initial presentation to actual diagnosis of ovarian cancer. The National Institute for Health and Care Excellence (NICE) in the UK advises primary care physicians to conduct preliminary testing if a woman reports persistent or frequent symptoms of abdominal distension, early satiety and/or appetite loss, pelvic/abdominal pain or increased urinary urgency and/or frequency [35]. This has been followed-up by a nationwide campaign,

In an effort to trigger early detection in patients presenting non-specifically, Goff et al. developed a symptom index (SI) [36]. The presence of any one of six symptoms was considered a positive result, including bloating, increased abdominal size, pelvic or abdominal pain, difficulty eating and/or early satiety. In the detection of ovarian cancer, the specificity of the SI was higher in women over 50 (90%) when compared to women under 50 (86.7%) years of age [37]. The SI also had a better sensitivity for advanced stage disease (79.5%) when compared to early stage disease (56.7%). Similar data was noted in a further study, when considering the SI as an isolated screening tool [38]. Acceptability of symptombased screening was assessed in a subsequent prospective study. Encouragingly, of the 1261 women involved, symptom-based screening yielded a mean acceptability score of 4.8/5 and 4.7/5 for TVS and CA125 utilisation, respectively [36]. A multivariate approach involving SI, CA125 and HE4 biomarkers has also been studied for suitability [38]. Use of all three variates combined yielded an overall sensitivity of 83.8% and specificity of 98.5%. The authors concluded that these combined tests could be beneficial as first-line screening tool to aid

Despite these results, the question still remains as to whether detection using a symptombased approach increases survival rates. Overall, there has been conflicting data regarding the correlation between symptom onset, referral and diagnostic delays, stage at presentation and overall survival rates in ovarian cancer patients. Several studies have demonstrated no such association [39]. Moreover, a recent Australian study discovered no correlation between time of symptom onset and FIGO stage III and IV disease, and concluded that longer time to diagnosis does not affect survival in women, even with advanced stage ovarian cancer [40]. A large qualitative study noted no difference between duration of symptom onset or time to diagnosis amongst patients with early to more advanced disease. Interestingly, women with advanced disease were more likely to report disregarding their symptoms [41]. Overall, current evidence suggests that the most successful direction of symptom-based detection of ovarian cancer is with a multivariate approach, but further research is required to ascertain

Ultrasound and serum CA125 testing are two main modalities that have been used in ovarian cancer screening. Ultrasound alone has been used in some of the studies. In some other studies, multimodal screening with a combination of serum CA125 and ultrasound have been

used. Following are some of the larger trials in the general population.

encouraging patients to present if any of the aforementioned symptoms occur.

selection for second-line imaging.

220 Ovarian Cancer - From Pathogenesis to Treatment

**7. Trials in ovarian cancer screening**

its applicability.

This trial was set up in 1987 to assess the efficacy of annual transvaginal ultrasonography (TVS) to detect ovarian cancer in asymptomatic women. All asymptomatic women: (1) 50 years or older and (2) 25 years or older with a family history of ovarian cancer in a first- or seconddegree relative were eligible to participate in the trial. The control group for this study consisted of those women diagnosed with epithelial ovarian cancer entered in the University of Kentucky Tumor registry or statewide Kentucky Cancer registry between 1995 and 2001, who had not participated in screening [42].

A total of 37,293 women were screened over a period of 24 years between 1987 and 2011 with TVS. Women with an abnormal ultrasound at screening underwent repeat ultrasound in 4–6 weeks. If this scan was also abnormal, then further characterisation of the ovarian mass was performed with tumour indexing, colour Doppler and serum CA125 levels. Women underwent surgery if the second screen was also abnormal. However, if this screen was normal, then the scan was repeated in 6 months. As a result of screening, 47 invasive epithelial ovarian cancers and 15 epithelial ovarian tumours of low malignant potential were detected. An improved survival rate was noted in the screened group when compared to controls. The 5-year survival rate for all women with invasive epithelial ovarian cancer detected by screening as well as interval cancers was 74.8 ± 6.6% compared with 53.7 ± 2.3% for unscreened women with ovarian cancer from the same institution who had undergone treatment using the same protocol (p < 0.001) [43].

#### **7.2. The Shizuoka Cohort Study of Ovarian Cancer Screening (SCSOCS) trial**

A total of 82,487 asymptomatic postmenopausal women were enrolled into this study between 1985 and 1999 across 212 hospitals in Shizouka, Japan. They were randomised into an intervention group (n = 41,688) or a control group (n = 40,799) and were followed up for a mean period of 9.2 years. The women in the intervention group were screened with a pelvic ultrasound scan (USS) and a serum CA 125 test. If the USS was normal and if the CA125 was <35 U/ml, then they returned to yearly follow-up. If the scan suggested malignant disease and/or if the CA 125 was elevated, then the women were referred for surgery. However, if the scan was abnormal but suggestive of benign disease, it was repeated every 3–6 months. Also, if the CA125 was above a certain threshold with a normal scan, the women had a repeat scan in 6 months. There was no statistical difference between the number of ovarian cancers detected in the screening arm when compared to the control arm (27 vs. 32). However, there were a higher proportion of stage 1 ovarian cancers in the screened group when compared to the control group (63% vs. 38%) [44].

#### **7.3. The Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Randomised Controlled Trial**

A total of 78,216 postmenopausal women aged 55–74 years were enrolled into this trial across 10 centres in the US. They were randomised to either annual screening (n = 39,105) or usual medical care (n = 39,111). Main outcome measure was mortality from ovarian/tubal/primary peritoneal cancers. The women in the screening arm had annual transvaginal ultrasound scan and CA125 (using a 35 kU/L cut-off) for 3 years and CA125 alone for a further 2 years. Women with an abnormal screening result were managed by their physicians. The follow-up period was 13 years in total. A total of 212 women were diagnosed with ovarian cancer in the screening arm when compared to 176 in the no screening (usual care) arm. In the screening arm, there were 118 deaths when compared to 100 deaths in the usual care arm as a result of ovarian cancer (mortality RR, 1.18; 95% CI, 0.82–1.71). This trial concluded that screening with CA125 and transvaginal ultrasound did not reduce mortality from ovarian cancer [45].

compared with the flat-profile model of known controls [47]. The ROCA calculates and updates the risk based on the most recent CA125 level. The risk is categorised as elevated, intermediate and normal. Women with an elevated risk are referred for an ultrasound, intermediate risk for repeat CA125 within a few months and normal risk for an annual CA125 test

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Between 2001 and 2005, 202,638 women were randomly assigned to a control arm (n = 101,359) and an intervention arm (n = 101,279). The intervention arm was further subdivided into a multimodal screening (MMS) arm with annual CA125 screening (interpreted using the ROC algorithm) followed by ultrasound as a second-line test (n = 50,640) or annual screening with ultrasound (USS) alone (n = 50,639). Randomisation into the control arm and the two-intervention arm was carried out in a 2:1:1 ratio. The main aim of the trial was to determine the impact of

Women in the MMS arm had their serum CA125 tested at recruitment and their risk was interpreted using the ROC algorithm. They went on to have (1) ultrasound scan if their risk was elevated or (2) repeat CA125 in 12 weeks if their risk was intermediate and (3) annual CA125

Women in the USS arm had transvaginal ultrasound at recruitment. They had repeat scans if the initial scan was abnormal. Women with persistent abnormalities were referred for clinical evaluation and had surgery if indicated. This trial was conducted across 13 centres in the UK.

Analysis of the prevalence screen results revealed that the MMS strategy was superior to ultrasound alone for detection of ovarian cancer (sensitivity of 89.4% and specificity of 99.8% for multimodal screening group compared to sensitivity of 84.9% and specificity of 98.2% for

During the follow-up period, a total of 1282 women were diagnosed with ovarian cancer (median follow-up—11.1 years). A total of 652 women in the screening arm were diagnosed with ovarian cancer, which included 338 women in the MMS group and 314 women in the USS group when compared to 630 in the no screening group. A total of 148 women in the MMS group, 154 women in the USS group (n = 302) and 347 women in the no screening died from ovarian cancer. There was no significant reduction in mortality from ovarian cancer demonstrated in the primary analysis. However, after exclusion of the prevalent cases, further analysis of the mortality data revealed a significant reduction in mortality in the MMS group when compared to the no screening group. An overall average reduction in mortality of 20% was observed in the MMS group, with a reduction of 8% in years 0–7 and 28% in years 7–14. However, the authors concluded that further follow-up was required to ascertain the benefits of screening [51].

Screening studies in the high-risk population also adopted the following two strategies: (1) annual screening with transvaginal ultrasound and CA125 and (2) multimodal screening with 3–4

*7.4.2. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)*

[48]. The ROCA has been used in subsequent screening trials.

screening on mortality from ovarian cancer [49].

screening if the risk was low.

ultrasound only group) [50].

**7.5. Screening in the high-risk population**

#### **7.4. Ovarian Cancer Screening Trials in the UK**

In 1993, Jacobs et al. screened 22,000 asymptomatic postmenopausal women with serum CA125 using a cut-off value of 30 kU/L. A transvaginal ultrasound was performed if the CA125 level was ≥30 kU/L. Women were referred for a gynaecological opinion if the ovarian volume was ≥ 8.8 ml. Out of the 41 women who had a positive screening result, 11 had ovarian cancer. Of the 21,959 women with a negative screening result, eight subsequently developed ovarian cancer. This protocol achieved a specificity of 99.9% and a positive predictive value of 26.8% and an apparent sensitivity of 78.6% and 57.9% at the first year and second year of follow-up, respectively [23].

Jacobs et al. then conducted a randomised controlled trial to assess the feasibility of a multimodal approach using serum CA125 level and transvaginal ultrasound to screen for ovarian cancer [46]. A total of 21,935 postmenopausal women aged ≥45 years were randomised to either a screening group (n = 10,958) or a control group (n = 10,977). In the screening group, women were offered three annual screens using serum CA125 level as the first screening test. If the CA125 level was ≥30 kU/L, a transvaginal ultrasound scan was performed as a second test. If the ovarian volume was ≥8.8 ml on ultrasound, the women were referred for a gynaecological opinion. Twenty-nine women with a positive screening test had surgical intervention out of which six were found to have ovarian cancer and the remaining 23 had a false positive result. Therefore, the positive predictive value of screening was 20.7%. During the 8 year follow-up period, 10 more women in the screening group developed ovarian cancer bringing the total to 16 in the screened group. In the control group, 20 women were diagnosed with ovarian cancer. The median survival was better in the screening group when compared to the control group—72.9 months versus 41.8 months (p = 0.0112). There were nine deaths from ovarian cancer in the screened group when compared to 18 in the control group, which was not statistically significant (relative risk 2.0, 95% CI, 0.78–5.13; p = 0.083).

#### *7.4.1. Risk of Ovarian Cancer Algorithm (ROCA)*

The two UK studies discussed earlier used a cut-off value of CA125 of 30 kU/L for screening. Analysis of the serial serum CA125 data in women who subsequently developed ovarian cancer revealed a significant rise in the CA125 level after a 'change point'. In the unaffected women, however, the CA125 maintained a flat profile, fluctuating around the individual's baseline levels. The ROCA takes into account an individual woman's age, serial CA125 profile and estimates her risk of developing ovarian cancer based on known cases of ovarian cancer compared with the flat-profile model of known controls [47]. The ROCA calculates and updates the risk based on the most recent CA125 level. The risk is categorised as elevated, intermediate and normal. Women with an elevated risk are referred for an ultrasound, intermediate risk for repeat CA125 within a few months and normal risk for an annual CA125 test [48]. The ROCA has been used in subsequent screening trials.

### *7.4.2. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)*

peritoneal cancers. The women in the screening arm had annual transvaginal ultrasound scan and CA125 (using a 35 kU/L cut-off) for 3 years and CA125 alone for a further 2 years. Women with an abnormal screening result were managed by their physicians. The follow-up period was 13 years in total. A total of 212 women were diagnosed with ovarian cancer in the screening arm when compared to 176 in the no screening (usual care) arm. In the screening arm, there were 118 deaths when compared to 100 deaths in the usual care arm as a result of ovarian cancer (mortality RR, 1.18; 95% CI, 0.82–1.71). This trial concluded that screening with CA125 and transvaginal ultrasound did not reduce mortality from ovarian cancer [45].

In 1993, Jacobs et al. screened 22,000 asymptomatic postmenopausal women with serum CA125 using a cut-off value of 30 kU/L. A transvaginal ultrasound was performed if the CA125 level was ≥30 kU/L. Women were referred for a gynaecological opinion if the ovarian volume was ≥ 8.8 ml. Out of the 41 women who had a positive screening result, 11 had ovarian cancer. Of the 21,959 women with a negative screening result, eight subsequently developed ovarian cancer. This protocol achieved a specificity of 99.9% and a positive predictive value of 26.8% and an apparent sensitivity of 78.6% and 57.9% at the first year and second year of

Jacobs et al. then conducted a randomised controlled trial to assess the feasibility of a multimodal approach using serum CA125 level and transvaginal ultrasound to screen for ovarian cancer [46]. A total of 21,935 postmenopausal women aged ≥45 years were randomised to either a screening group (n = 10,958) or a control group (n = 10,977). In the screening group, women were offered three annual screens using serum CA125 level as the first screening test. If the CA125 level was ≥30 kU/L, a transvaginal ultrasound scan was performed as a second test. If the ovarian volume was ≥8.8 ml on ultrasound, the women were referred for a gynaecological opinion. Twenty-nine women with a positive screening test had surgical intervention out of which six were found to have ovarian cancer and the remaining 23 had a false positive result. Therefore, the positive predictive value of screening was 20.7%. During the 8 year follow-up period, 10 more women in the screening group developed ovarian cancer bringing the total to 16 in the screened group. In the control group, 20 women were diagnosed with ovarian cancer. The median survival was better in the screening group when compared to the control group—72.9 months versus 41.8 months (p = 0.0112). There were nine deaths from ovarian cancer in the screened group when compared to 18 in the control group, which was

The two UK studies discussed earlier used a cut-off value of CA125 of 30 kU/L for screening. Analysis of the serial serum CA125 data in women who subsequently developed ovarian cancer revealed a significant rise in the CA125 level after a 'change point'. In the unaffected women, however, the CA125 maintained a flat profile, fluctuating around the individual's baseline levels. The ROCA takes into account an individual woman's age, serial CA125 profile and estimates her risk of developing ovarian cancer based on known cases of ovarian cancer

not statistically significant (relative risk 2.0, 95% CI, 0.78–5.13; p = 0.083).

*7.4.1. Risk of Ovarian Cancer Algorithm (ROCA)*

**7.4. Ovarian Cancer Screening Trials in the UK**

222 Ovarian Cancer - From Pathogenesis to Treatment

follow-up, respectively [23].

Between 2001 and 2005, 202,638 women were randomly assigned to a control arm (n = 101,359) and an intervention arm (n = 101,279). The intervention arm was further subdivided into a multimodal screening (MMS) arm with annual CA125 screening (interpreted using the ROC algorithm) followed by ultrasound as a second-line test (n = 50,640) or annual screening with ultrasound (USS) alone (n = 50,639). Randomisation into the control arm and the two-intervention arm was carried out in a 2:1:1 ratio. The main aim of the trial was to determine the impact of screening on mortality from ovarian cancer [49].

Women in the MMS arm had their serum CA125 tested at recruitment and their risk was interpreted using the ROC algorithm. They went on to have (1) ultrasound scan if their risk was elevated or (2) repeat CA125 in 12 weeks if their risk was intermediate and (3) annual CA125 screening if the risk was low.

Women in the USS arm had transvaginal ultrasound at recruitment. They had repeat scans if the initial scan was abnormal. Women with persistent abnormalities were referred for clinical evaluation and had surgery if indicated. This trial was conducted across 13 centres in the UK.

Analysis of the prevalence screen results revealed that the MMS strategy was superior to ultrasound alone for detection of ovarian cancer (sensitivity of 89.4% and specificity of 99.8% for multimodal screening group compared to sensitivity of 84.9% and specificity of 98.2% for ultrasound only group) [50].

During the follow-up period, a total of 1282 women were diagnosed with ovarian cancer (median follow-up—11.1 years). A total of 652 women in the screening arm were diagnosed with ovarian cancer, which included 338 women in the MMS group and 314 women in the USS group when compared to 630 in the no screening group. A total of 148 women in the MMS group, 154 women in the USS group (n = 302) and 347 women in the no screening died from ovarian cancer. There was no significant reduction in mortality from ovarian cancer demonstrated in the primary analysis. However, after exclusion of the prevalent cases, further analysis of the mortality data revealed a significant reduction in mortality in the MMS group when compared to the no screening group. An overall average reduction in mortality of 20% was observed in the MMS group, with a reduction of 8% in years 0–7 and 28% in years 7–14. However, the authors concluded that further follow-up was required to ascertain the benefits of screening [51].

#### **7.5. Screening in the high-risk population**

Screening studies in the high-risk population also adopted the following two strategies: (1) annual screening with transvaginal ultrasound and CA125 and (2) multimodal screening with 3–4 monthly measurement of serum CA125 as the first and transvaginal ultrasound as the secondline test based on the CA125 levels.

ROCA estimated risk [54]. If the risk was normal, TVS was performed annually and if it was

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There were 13 screen-detected and 6 occult (diagnosed following risk reducing salpingooophorectomy) primary ovarian/fallopian tube cancers in women who had been screened in the preceding year. Five out of the 13 screen-detected cancers and five out of the six occult cancers were stage I–II. Of these 19 women, 18 underwent optimal cyto-reductive surgery, with zero residual disease. This protocol had a high sensitivity of 94.7%, high negative predictive value of 100% and a positive predictive value of 10.8% for the detection of ovarian/ fallopian tube cancers within 1 year of screening. The conclusion from Phase II was that ROCA-based screening could be an option for high-risk women who declined risk-reducing surgery. However, there was no conclusive evidence to suggest an impact on survival.

The Cancer Genetics Network (CGN) ROCA study in Australia and the Gynecologic Oncology Group (GOG) study-GOG-0199 in the US used the same protocol to screen women at increased risk of developing ovarian/fallopian tube cancer [55]. All women received an annual transvaginal scan and CA125 testing every 3 months. The ROCA was used to estimate the risk and

A total of 3692 women were screened in the two studies combined. There were four prevalent cancers and six incident cancers detected as a result of screening. Nine additional cancers were detected following risk reducing surgery. Three out of the six incident cases were detected at CA125 levels <35 U/ml using ROCA. The specificity for referral for ultrasound was 92% and the positive predictive value was 4.6%. This study concluded that three monthly CA125 testing with result interpretation using ROCA had a high specificity in the detection of early stage ovarian cancer with half of the incident cancers being diagnosed at CA125 levels <35 U/ml. There was a high rate of complete cytoreduction following surgery for the incident cancers diagnosed during the study period. The authors concluded that this screening regime with three monthly CA125 measurements performed better than 6–12 monthly screening using an absolute CA125 cut-off of 35 U/ml; however, larger studies were required given the small number of incident cases.

Thus, screening studies in high-risk women have demonstrated that annual screening with CA125 using a cut-off value and TVS is likely to miss the cancers that develop during the interval period. More frequent testing with CA125 with result interpretation using the ROCA helps to estimate an individual's risk based on their baseline CA125 level, aiding detection of ovarian cancer at an early stage or advanced cancer with low volume disease that can be optimally cytoreduced surgically. However, there is still paucity of evidence with regards to a mortality benefit from screening. Therefore, screening cannot be recommended as an alternative to risk reducing surgery, which remains the definitive preventative strategy in high-risk women.

Ovarian cancer is a heterogeneous group of cancers, which includes both epithelial and nonepithelial neoplasms. Within the epithelial cancers, there are both slow growing Type 1 cancers

abnormal, then TVS was performed within 2 months.

*7.5.2. Cancer Genetics Network and Gynecologic Oncology Group study*

an interval TVS was performed for an abnormal ROCA result.

**7.6. Future of ovarian cancer screening**

In a Dutch multicentre observational study, 880 BRCA1 or BRCA2 carriers who had annual screening with CA125 and transvaginal scan were followed-up between 1993 and 2005. There were 10 incident cancers diagnosed. Five out of these ten cancers were in women who had previously had a normal screening within the last 3–10 months preceding the diagnosis. Eight out of the ten incident cancers were stage III–IV. In this study, despite annual screening, a large majority of the cancers were interval cancers that were diagnosed at an advanced stage. This study concluded that annual screening with TVS and CA125 neither helped in early diagnosis nor reduced mortality in high-risk women from ovarian cancer [52].

In the UK, Stirling et al. conducted a study involving 1110 high-risk women who were screened in three cancer genetic centres with annual CA125 and transvaginal ultrasound, between 1991 and 2004 [53]. Thirteen ovarian cancers were detected (including one borderline tumour). Three of these were detected during the first screen and seven during annual follow-up. The remaining three were interval cancers out of which one was an incidental finding following prophylactic surgery 2 months after a normal screen and the remaining two presented with symptoms, 4 and 12 months after a normal screening, respectively. This study also concluded that annual screening with CA125 and TVS was not effective in early diagnosis of ovarian cancer to have an impact on prognosis. In addition, the false positive rate was high in premenopausal women leading to unnecessary surgical intervention.

#### *7.5.1. United Kingdom Familial Ovarian Cancer Screening Study (UK FOCSS)*

Between 2002 and 2008, 3563 high-risk women (≥10% estimated lifetime risk) aged 35 years or above were recruited into this multicentred study across 37 centres in the UK. The trial had two phases—1 and 2.

In Phase 1, women underwent screening with annual transvaginal ultrasound scan and serum CA125 measurement. For CA125, a cut-off of 35 IU/ml for premenopausal women and 30 IU/ ml for postmenopausal women was used.

A total of 27 primary ovarian/fallopian tube/peritoneal cancers were diagnosed during the course of screening and a further 10 cancers developed after 365 days following the last screen (median 539 days, range, 382–1369) in Phase 1 of the study. Nine of the primary ovarian/fallopian tube cancers were diagnosed during the prevalent screen and 13 were incident, screendetected cancers. The positive predictive value was 25.5% (95% CI, 14.3–40.0) and negative predictive value was 99.9% (95% CI, 99.8–100) for the incident screen. Of the 13 incident cancers, only four were stage I or II. There was a delay in surgical intervention in the prevalent and screen-detected cancers (median—79 days). This study concluded that annual screening was not adequate in high-risk women for early detection of ovarian/fallopian tube cancer.

Following from the results of Phase I, women underwent more frequent screening with CA125 testing in Phase 2 (2007–2012) of the study. Serum CA125 levels were measured every 4 months, and the risk of developing ovarian cancer was estimated using the Risk of Ovarian Cancer algorithm (ROCA). Ultrasound was used as a second-line screen depending on the ROCA estimated risk [54]. If the risk was normal, TVS was performed annually and if it was abnormal, then TVS was performed within 2 months.

There were 13 screen-detected and 6 occult (diagnosed following risk reducing salpingooophorectomy) primary ovarian/fallopian tube cancers in women who had been screened in the preceding year. Five out of the 13 screen-detected cancers and five out of the six occult cancers were stage I–II. Of these 19 women, 18 underwent optimal cyto-reductive surgery, with zero residual disease. This protocol had a high sensitivity of 94.7%, high negative predictive value of 100% and a positive predictive value of 10.8% for the detection of ovarian/ fallopian tube cancers within 1 year of screening. The conclusion from Phase II was that ROCA-based screening could be an option for high-risk women who declined risk-reducing surgery. However, there was no conclusive evidence to suggest an impact on survival.

#### *7.5.2. Cancer Genetics Network and Gynecologic Oncology Group study*

monthly measurement of serum CA125 as the first and transvaginal ultrasound as the second-

In a Dutch multicentre observational study, 880 BRCA1 or BRCA2 carriers who had annual screening with CA125 and transvaginal scan were followed-up between 1993 and 2005. There were 10 incident cancers diagnosed. Five out of these ten cancers were in women who had previously had a normal screening within the last 3–10 months preceding the diagnosis. Eight out of the ten incident cancers were stage III–IV. In this study, despite annual screening, a large majority of the cancers were interval cancers that were diagnosed at an advanced stage. This study concluded that annual screening with TVS and CA125 neither helped in early

In the UK, Stirling et al. conducted a study involving 1110 high-risk women who were screened in three cancer genetic centres with annual CA125 and transvaginal ultrasound, between 1991 and 2004 [53]. Thirteen ovarian cancers were detected (including one borderline tumour). Three of these were detected during the first screen and seven during annual follow-up. The remaining three were interval cancers out of which one was an incidental finding following prophylactic surgery 2 months after a normal screen and the remaining two presented with symptoms, 4 and 12 months after a normal screening, respectively. This study also concluded that annual screening with CA125 and TVS was not effective in early diagnosis of ovarian cancer to have an impact on prognosis. In addition, the false positive rate was high in pre-

Between 2002 and 2008, 3563 high-risk women (≥10% estimated lifetime risk) aged 35 years or above were recruited into this multicentred study across 37 centres in the UK. The trial had

In Phase 1, women underwent screening with annual transvaginal ultrasound scan and serum CA125 measurement. For CA125, a cut-off of 35 IU/ml for premenopausal women and 30 IU/

A total of 27 primary ovarian/fallopian tube/peritoneal cancers were diagnosed during the course of screening and a further 10 cancers developed after 365 days following the last screen (median 539 days, range, 382–1369) in Phase 1 of the study. Nine of the primary ovarian/fallopian tube cancers were diagnosed during the prevalent screen and 13 were incident, screendetected cancers. The positive predictive value was 25.5% (95% CI, 14.3–40.0) and negative predictive value was 99.9% (95% CI, 99.8–100) for the incident screen. Of the 13 incident cancers, only four were stage I or II. There was a delay in surgical intervention in the prevalent and screen-detected cancers (median—79 days). This study concluded that annual screening was not adequate in high-risk women for early detection of ovarian/fallopian tube cancer.

Following from the results of Phase I, women underwent more frequent screening with CA125 testing in Phase 2 (2007–2012) of the study. Serum CA125 levels were measured every 4 months, and the risk of developing ovarian cancer was estimated using the Risk of Ovarian Cancer algorithm (ROCA). Ultrasound was used as a second-line screen depending on the

diagnosis nor reduced mortality in high-risk women from ovarian cancer [52].

menopausal women leading to unnecessary surgical intervention.

*7.5.1. United Kingdom Familial Ovarian Cancer Screening Study (UK FOCSS)*

line test based on the CA125 levels.

224 Ovarian Cancer - From Pathogenesis to Treatment

two phases—1 and 2.

ml for postmenopausal women was used.

The Cancer Genetics Network (CGN) ROCA study in Australia and the Gynecologic Oncology Group (GOG) study-GOG-0199 in the US used the same protocol to screen women at increased risk of developing ovarian/fallopian tube cancer [55]. All women received an annual transvaginal scan and CA125 testing every 3 months. The ROCA was used to estimate the risk and an interval TVS was performed for an abnormal ROCA result.

A total of 3692 women were screened in the two studies combined. There were four prevalent cancers and six incident cancers detected as a result of screening. Nine additional cancers were detected following risk reducing surgery. Three out of the six incident cases were detected at CA125 levels <35 U/ml using ROCA. The specificity for referral for ultrasound was 92% and the positive predictive value was 4.6%. This study concluded that three monthly CA125 testing with result interpretation using ROCA had a high specificity in the detection of early stage ovarian cancer with half of the incident cancers being diagnosed at CA125 levels <35 U/ml. There was a high rate of complete cytoreduction following surgery for the incident cancers diagnosed during the study period. The authors concluded that this screening regime with three monthly CA125 measurements performed better than 6–12 monthly screening using an absolute CA125 cut-off of 35 U/ml; however, larger studies were required given the small number of incident cases.

Thus, screening studies in high-risk women have demonstrated that annual screening with CA125 using a cut-off value and TVS is likely to miss the cancers that develop during the interval period. More frequent testing with CA125 with result interpretation using the ROCA helps to estimate an individual's risk based on their baseline CA125 level, aiding detection of ovarian cancer at an early stage or advanced cancer with low volume disease that can be optimally cytoreduced surgically. However, there is still paucity of evidence with regards to a mortality benefit from screening. Therefore, screening cannot be recommended as an alternative to risk reducing surgery, which remains the definitive preventative strategy in high-risk women.

#### **7.6. Future of ovarian cancer screening**

Ovarian cancer is a heterogeneous group of cancers, which includes both epithelial and nonepithelial neoplasms. Within the epithelial cancers, there are both slow growing Type 1 cancers that include mucinous, low-grade endometrioid, low-grade serous, clear cell and transitional cell carcinomas; and, the more aggressive, fast multiplying Type 2 cancers, which include highgrade serous carcinomas (HGSC), high-grade endometrioid, undifferentiated and carcinosarcomas [56]. Given their indolent nature, Type 1 tumours tend to be confined to the ovary at diagnosis, are easily detectable on ultrasound at an early stage and carry a better prognosis. Type 2 tumours, however, metastasise early in the natural history of the disease, are diagnosed at a late stage and carry a poor prognosis as a result. Traditional approach to screening using TVS and serum CA125 has not been effective in detecting these Type 2 cancers at an early stage. Detailed pathological examination of the fallopian tube from high-risk women who have undergone prophylactic salpingo-oophorectomy has revealed pre-cancer precursor lesions (serous tubal intraepithelial carcinoma or STIC) thereby, suggesting that a good majority of HGSC originate in the tube rather than in the ovary [3]. Majority of the incidental HGSCs in the low-risk population have also been shown to arise from STICs [57]. STIC lesions exhibit mutation in the TP53 gene which is likely to signal the early stages of carcinogenesis. Exfoliative cytology from the fimbrial end of the tube to detect these precursor lesions [58] and novel assays to detect TP53 mutations in circulating DNA are being explored [59, 60]. Angiogenesis is present early in the development of cancer. The use of microbubbles that are small enough to pass through capillaries is being explored to detect micro-vascularity in ovarian tumours on ultrasound [61].

[3] Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, et al. The distal fallopian tube: A new model for pelvic serous carcinogenesis. Current Opinion in

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[5] Timmerman D, Valentin L, Bourne TH, Collins WP, Verrelst H, Vergote I. Terms, definitions and measurements to describe the sonographic features of adnexal tumors: A consensus opinion from the International Ovarian Tumor Analysis (IOTA) group.

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A better understanding of tumourigenesis is opening up new avenues in ovarian cancer screening. Studies have shown that the target lesion is not always the ovary in 'ovarian cancer' and that STIC is the pre-malignant lesion in a good majority of HGSCs which include primary ovarian/fallopian tube/peritoneal cancers. The focus of future screening strategies will be used to detect low volume early disease either from the primary site of origin using exfoliative cytology or novel imaging modalities, or, in circulation using sensitive assays to detect low levels of tumour DNA and tumour markers.
