Download Potential effect of the risk of ovarian cancer algorithm (ROCA) on the

IJC
International Journal of Cancer
Potential effect of the risk of ovarian cancer algorithm (ROCA)
on the mortality outcome of the Prostate, Lung, Colorectal and
Ovarian (PLCO) trial
Paul F. Pinsky1, Claire Zhu1, Steve J. Skates2, Amanda Black3, Edward Partridge4, Saundra S. Buys5 and Christine D. Berg1
1
Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD
Massachusetts General Hospital, Boston, MA
3
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
4
University of Alabama at Birmingham, Birmingham, AL
5
University of Utah, Salt Lake City, UT
2
Recently, the ovarian component of The Prostate, Lung,
Colorectal and Ovarian (PLCO) Cancer Screening Trial
reported its results, which showed no mortality benefit of annual screening with CA125 and transvaginal ultrasound
(TVU) versus usual care.1 In addition to a mortality relative
risk (RR) that was slightly, although not statistically significantly, elevated (RR ¼ 1.18), the majority (69%) of the screen
detected cancers presented in Stage III or IV.
Another large ovarian cancer screening trial is ongoing,
the UK Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS). UKCTOCS is a three-armed trial, with a usual
care arm, a TVU arm and a multimodal arm.2 The latter utilizes as the first-line screen the risk of ovarian cancer algorithm (ROCA), a statistical tool that considers current and
past CA125 values, as well as age, to assign an ovarian cancer
Key words: ovarian cancer, Prostate, Lung, Colorectal and Ovarian
(PLCO) cancer trial, risk of ovarian cancer algorithm (ROCA),
screening, mortality
DOI: 10.1002/ijc.27909
History: Received 1 Jun 2012; Accepted 10 Sep 2012; Online 15 Oct
2012
Correspondence to: Paul F. Pinsky, 6130 Executive Blvd., EPN
3064, Bethesda, MD, 20892, USA, Fax: þ301-480-0465,
E-mail: [email protected]
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Int. J. Cancer: 132, 2127–2133 (2013) V
risk probability, categorized as low, intermediate and elevated.2,3 The arm is denoted as multimodal because positive
(i.e., intermediate or elevated) ROCA results may trigger subsequent follow-up with TVU.
In contrast to the screened arm of PLCO, which utilized a
cut-off value of CA125 based on the current level only, the
multimodal arm of UKCTOCS, and specifically ROCA, takes
into account serial levels of CA125. The unfavorable stage
distribution in PLCO of screen-detected cancers, and the lack
of a mortality benefit, gives rise to the speculation that the
CA125 cutoff of 35 U/ml is too high and catches cancers too
late. A serial CA125 algorithm may be able to detect these
cancers sooner, but without engendering too high a false positive rate, by considering the CA125 trajectory over time. A
high false positive rate is problematic in ovarian cancer
screening due to the frequent use of oophorectomy, and attendant complications, following false positive screens.1,4
The purpose of this manuscript is to ascertain whether
the use of ROCA in the PLCO trial could have favorably
affected the trial’s outcome. Specifically, we utilize the
observed PLCO CA125 values to calculate a ROCA score at
each screening visit and then analyze how many women
would have had their tumor detected earlier (or later) using
ROCA than they did under the standard PLCO protocol
(CA125 Œ35 and/or positive TVU). Under a ‘‘best-case’’
Early Detection and Diagnosis
Recently, the Prostate, Lung, Colorectal and Ovarian (PLCO) Trial reported no mortality benefit for annual screening with CA125 and transvaginal ultrasound (TVU). Currently ongoing is the UK Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS), which utilizes the risk of ovarian cancer algorithm (ROCA), a statistical tool that considers current and past CA125
values to determine ovarian cancer risk. In contrast, PLCO used a single cutoff for CA125, based on current levels alone. We
investigated whether having had used ROCA in PLCO could have, under optimal assumptions, resulted in a significant
mortality benefit by applying ROCA to PLCO CA125 screening values. A best-case scenario assumed that all cancers showing a
positive screen result earlier with ROCA than under the PLCO protocol would have avoided mortality; under a stage-shift
scenario, such women were assigned survival equivalent to Stage I/II screen-detected cases. Updated PLCO data show 132
intervention arm ovarian cancer deaths versus 119 in usual care (relative risk, RR 5 1.11). Forty-three ovarian cancer cases,
25 fatal, would have been detected earlier with ROCA, with a median (minimum) advance time for fatal cases of 344 (147)
days. Best-case and stage-shift scenarios gave 25 and 19 deaths prevented with ROCA, for RRs of 0.90 (95% CI: 0.69–1.17)
and 0.95 (95% CI: 0.74–1.23), respectively. Having utilized ROCA in PLCO would not have led to a significant mortality benefit
of screening. However, ROCA could still show a significant effect in other screening trials, including UKCTOCS.
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Effect of ROCA on PLCO trial
What’s new?
The Prostate, Lung, Colorectal and Ovarian (PLCO) trial found no mortality benefit for ovarian cancer screening using a single
cutoff value for the biomarker CA125. PLCO, however, did not incorporate the potential impact of ROCA (Risk of Ovarian
Cancer Algorithm), which evaluates serial CA125 values. Here, in a best-case scenario analysis, ROCA was found to have little
impact on mortality in the context of PLCO. The findings do not rule out possible benefits from ROCA in the ongoing UK
Collaborative Trial of Ovarian Cancer Screening.
scenario, any women dying of ovarian cancer who would
have had their cancer detected earlier with ROCA could be
considered ‘‘saved’’ under ROCA. If, under the best-case scenario, there was still no significant mortality reduction for
the screened arm, then having used ROCA in the PLCO trial
likely would not have resulted in a qualitatively different outcome. Note that we are not attempting here to simulate the
results of UKCTOCS, since that trial had a different protocol,
over and above the use of ROCA, than did PLCO. The
differences include different lengths of the screening and
post-screening periods and the use in UKCTOCS of a standardized diagnostic algorithm following a positive screen.2
Methods
Early Detection and Diagnosis
PLCO trial
The design of PLCO has been described in detail.5 Briefly, subjects aged 55–74 were randomized at 10 US centers into an
intervention or usual care arm between 1993 and 2001. Two
initial exclusion criteria—previous oophorectomy and current
tamoxifen use—were dropped in 1996 and 1999, respectively.
However, women who had undergone previous bilateral
oophorectomy were not screened for ovarian cancer (they were
screened for lung and colorectal cancer). The primary outcome
paper excluded them and they are similarly excluded here.
Other PLCO exclusion criteria included history of a PLCO
cancer and cancer treatment within the past year.
At study entry, participants completed a self-administered
baseline questionnaire, which inquired about demographics,
general risk factors and screening and medical history. Women
in the intervention arm received a CA125 blood test and TVU
at baseline, an annual TVU for three additional years, and an
annual CA125 for five additional years; women randomized
before April 1995, received only three additional years of CA125
testing. CA125 assays were performed centrally at the Immunogenetics Laboratory at the University of California at Los
Angeles; CA125 results > 35 U/mL were classified as abnormal.
TVU was conducted by trained examiners using a 5–7.5 MHz
transvaginal probe; ovary or cyst volume greater than 10 cubic
cm, any solid area or papillary projection extending into the cavity of a cyst of any size and any mixed (solid/cystic) component
within a cyst were considered positive results. Diagnostic followup was determined by participants’ primary care physicians.
Incident cancers, and deaths, were ascertained primarily
by means of a mailed Annual Study Update (ASU) questionnaire. Additionally, to obtain more complete mortality data,
ASU follow-up was supplemented by periodic linkage to the
National Death Index (NDI). Medical records pertaining to
diagnosed cancers were obtained by the screening centers
and certified tumor registrars abstracted data on stage, histology, grade and initial treatment. The underlying cause of
death was determined in a uniform and unbiased manner
from the death certificate and relevant medical records.5
The endpoint of the PLCO ovarian component was deaths
from ovarian, peritoneal and fallopian tube cancers through 13
years of follow-up from randomization; these are denoted here
for simplicity as ‘‘ovarian cancers.’’ As in the primary outcome
paper, ovarian cancers of low malignant potential (LMP) are
excluded. Included here are several more ovarian cancer cases,
and deaths, determined by updating the PLCO data set.
Intervention arm cases were categorized by method of
detection as either screen detected, interval, post-screening or
never-screened. Screen detected cases were diagnosed within
a year of a positive screen, interval cases were non-screen
detected cases diagnosed within 3 years of a screen and postscreening cases were diagnosed more than 3 years from the
last screen; never-screened cases had no PLCO screens.
ROCA
The ROCA utilizes current and past CA125 values, as well as
age, to estimate absolute ovarian cancer risk.3 As used in
UKCTOCS, it categorizes women at each screen into three
risk categories: normal, intermediate and elevated risk.2 Initially in UKCTOCS, the cutoffs for these categories were set
at 1/1,818 for intermediate and 1/500 for elevated risk; during the trial these were modified to 1/3,500 and 1/1,000,
respectively, to try to attain the desired distribution of 85%
low, 13% intermediate and 2% elevated risk.2 In this analysis,
we used the modified cutoffs for our primary analysis. We
also examined the raw ROCA results for all PLCO screens to
derive cutoffs that gave the desired 85/13/2 percent distribution in PLCO women; for a sensitivity analysis, these derived
cutoffs were also evaluated. In UKCTOCS, prescribed diagnostic follow-up algorithms were employed for intermediate
and elevated risk ROCA scores; these involved further ROCA
tests and TVUs, followed by biopsy referral if warranted.
Analysis methods
Figure 1 shows a flowchart of the analysis scheme. First, for
each intervention arm woman with an ovarian cancer diagnosis and any PLCO screens, we examined CA125 levels at
each screening year (SY), as well as age, in order to compute
ROCA scores at each screen. The next step was to determine
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Int. J. Cancer: 132, 2127–2133 (2013) V
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Pinsky et al.
the earliest SY for which ROCA demonstrated a stable positive (i.e., intermediate or elevated risk) score, defined as a
positive that was not followed by a negative (i.e., low risk)
ROCA score at a later screen; this is denoted as the earliest
stable positive ROCA SY. In the absence of any stable positive ROCA score, there was no earliest stable positive ROCA
SY. The requirement that the positive not be followed by a
negative was to guard against a spurious (false) positive
ROCA score. For the final PLCO screen there was no subsequent exam for which to assess whether ROCA was subsequently negative; to guard against spurious positive ROCA
scores in this instance it was assumed that if the cancer was
diagnosed more than 3 years from the last PLCO screen (and
last ROCA score) that any positive ROCA scores were spurious and not stable positives. The rationale for using the 3
year cutoff comes from an analysis of the PLCO data. Specifically, we examined all subjects whose first positive ROCA
score was 3.0–4.9 years before ovarian cancer diagnosis and
who had at least one subsequent ROCA determination. Of these,
17/18 (94%) had a subsequent negative ROCA score. Additionally, the screening results for women with subsequent cancer
within 3.0–4.9 years were essentially identical to those for
women without cancer; median CA125, percent with ROCA
score intermediate or elevated and percent TVU positive were
11.0, 19.9% and 3.7% in the former compared to 10.0, 17.7%
and 3.5% in the latter. Note also that the design of UKCTOCS
specifies that the last scheduled screen is 3 years before the end
of follow-up, suggesting that screening with UKCTOCS modalC 2012 UICC
Int. J. Cancer: 132, 2127–2133 (2013) V
ities (including ROCA) is thought to have little potential impact
on cancers diagnosed after this time interval.
We defined a similar earliest stable positive SY for the combined PLCO modality of CA125/ TVU, determining the earliest
positive screen, if any, that was not followed by a negative
screen, and compared the two earliest stable positive SYs (PLCO
vs. ROCA). Women whose earliest stable positive SY with
ROCA occurred earlier than with PLCO screening (including
instances where there was no earliest stable positive SY under
PLCO) were defined as having earlier diagnosis under ROCA.
Figure 2 displays six scenarios of CA125/ TVU and ROCA outcomes over time to illustrate the process of determining whether
diagnosis would have occurred earlier under ROCA.
We hypothesized two scenarios for women with earlier diagnosis under ROCA. First, we evaluated a ‘‘best-case’’ scenario, where all subjects who died of ovarian cancer and who
would have had their diagnosis moved up, i.e., earlier, with
ROCA were presumed to have survived. Subjects not dying
who had their diagnosis moved back (i.e., later) due to
ROCA were presumed not to be affected in terms of ovarian
cancer mortality, nor were subjects dying of ovarian cancer
whose diagnosis was not moved up under ROCA. We also
examined a more realistic scenario, which was less optimistic
but still assumed a large benefit from earlier detection with
ROCA. Under this ‘‘stage-shift’’ scenario, women with diagnosis moved up under ROCA were assumed to have the
same ovarian cancer specific survival as PLCO screendetected Stage I/II cases and a total follow-up time in PLCO
Early Detection and Diagnosis
Figure 1. Flowchart of analysis scheme.
Early Detection and Diagnosis
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Effect of ROCA on PLCO trial
Figure 2. Determining first stable positive SY and advance in diagnosis with ROCA. Scenarios of CA125/TVU and ROCA results are
presented, with first stable positive SY in brackets. In panel (1), first stable positive SY with ROCA precedes first stable positive SY with
CA125/TVU (PLCO screening), so diagnosis is advanced with ROCA. In panel (2), CA125/TVU is never positive, whereas ROCA is, so again
diagnosis is advanced. In panel (3), CA125/TVU is positive and ROCA never is, so diagnosis is delayed with ROCA. In panels (4, 5), first
stable positive SY with CA125/TVU equals first stable positive SY with ROCA (4) or neither is ever positive (5), resulting in no change in
diagnosis time; note in panel (4), the initial positive ROCA is not stable since it is followed by negative ROCA. Finally, in panel (6),
diagnosis is more than 3 years after the last screen, so by assumption this is not a stable positive ROCA score (diagnosis not advanced).
CA125/TVU results are N (negative), P(Positive) or ND(not done); ROCA results are L(low risk), I (intermediate risk) and E (elevated risk).
The * indicates observed diagnosis time.
equal to the trial average (11.4 years); 10 year survival for
these cases (n ¼ 23) was 64%. Prevented deaths were then
calculated as N(1 - D) where N is the number with diagnosis
moved up and D is the expected proportion of these dying of
ovarian cancer during the trial based on the Stage I/II survival curves. Cases diagnosed later, or never, with ROCA
were still, as with the best-case scenario, not counted against
ROCA, since there was no evidence that the PLCO screening
regimen affected mortality.
In order to estimate the amount of time that diagnosis
would have been advanced in those women with earlier stable
positive screens under ROCA, we assumed that such women
would have had ovarian cancer diagnosis 74 days after the first
stable positive ROCA screen, where 74 days was the median
time from first positive screen to diagnosis in PLCO.
As noted above, cases diagnosed more than three years
from the last screen had little chance to be affected by
screening with either CA125 (single cutoff or ROCA) or TVU.
In PLCO, the a priori primary endpoint was all deaths from
ovarian cancer, regardless of when the disease was diagnosed.
Therefore, deaths from cancers diagnosed in this time period,
generally eight or more years from study entry, are essentially
‘‘noise’’ and only serve to attenuate both the magnitude and
statistical significance of the mortality RR estimate. In the
screening trial literature, this phenomenon is known as the
‘‘dilution’’ effect.6 To take into account the dilution effect, we
also estimated mortality RRs, under both the best-case and
stage-shift scenarios, after subtracting out those deaths, in each
arm, that arose from cancers diagnosed more than 3 years after
the end of scheduled screening. This corresponds to the start
of study year 8 for subjects enrolled from April 1995 on (about
85%) and the start of study year 6 for those enrolled before
April 1995, who only had four annual screens instead of six.
Results
Table 1 summarizes the ovarian cancer cases by arm in the
trial. Among the analysis set of 34,253 intervention and
34,304 control arm women with at least one ovary at
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Int. J. Cancer: 132, 2127–2133 (2013) V
baseline, there were 243 and 218 ovarian cancers, respectively. About 4/5 of the cases were primary tumors of the
ovary, 3/4 were Stage III or IV and 80–85% were either cystadenocarcinoma or adenocarcinoma not otherwise specified.
Table 1. Ovarian cancer cases in PLCO
Intervention
(N ¼ 39,105)
Control
(N ¼ 39,111)
Analysis data set (at least one
ovary at randomization )
34,253
34,304
Ovarian cancers1
243
218
Cancer Site
N (%)
N (%)
Ovary
195 (80)
183 (84)
Peritoneum
30 (12)
21 (10)
Fallopian Tube
18 (7)
14 (6)
I, II
51 (21)
40 (18)
III
132 (54)
105 (48)
IV
50 (21)
61 (28)
Unknown
10 (4)
12 (6)
Serous
131 (54)
121 (56)
Mucinous
7 (3)
3 (1)
Endometroid
19 (8)
8 (4)
Clear cell
6 (3)
7 (3)
Not specified/other
73 (30)
79 (36)
Deaths from ovarian cancer
132
119
TNM stage
Histology
1
Includes ovarian, peritoneal and fallopian tube cancers; excludes
cancers of low-malignant potential (LMP).
Table 2 shows the number of cases and deaths by method
of detection. A total of 25% (n ¼ 60) of intervention arm
cases were screen detected by CA125 (with or without TVU
positivity), 5% screen detected by TVU only and 33% postscreening. The distribution of the deaths by method of detection was generally similar to that of the cases. Among screen
detected cases, ovarian cancer-specific survival varied significantly (p ¼ 0.01, log-rank test) by method of detection, with
CA125 positive-TVU negative women having the lowest 5
year survival (41.9%) and CA125 negative-TVU positive
(‘‘TVU-only’’) women having the highest (84.6%). Survival
for the post-screening (5-year survival 30%) and neverscreened (5-year survival 27%) cases were lowest of all the
groups. The TVU-only cases had a much greater proportion
of cancers being Stages I–II (77%) than all of the other
groups (11–36%).
Table 3 summarizes the estimated changes in diagnosis
time by method of detection category. Among CA125 screen
detected cases, ROCA moved up (earlier) the diagnosis in 13
of 40 (33%) fatal cases and 6 of 20 (30%) non-fatal cases. None
of the TVU-only cases had diagnosis moved earlier. Of interval
cases within one year, 10 of 19 fatal and 5 of 9 non-fatal cases
were moved earlier; the corresponding figures were 2 of 18
(fatal) and 6 of 18 (non fatal) for 1–3 year interval cancers. With
respect to diagnoses delayed under ROCA, two were delayed for
CA125 screen detected cases and 8 for TVU-only screen
detected cases. Of the 25 (13þ10þ2) fatal cases with diagnosis
moved earlier with ROCA, the median interval between original
and modified diagnosis date was 344 days, with an inter-quartile
range of 247–542 and a minimum of 147 days. Of the cases
detected later (or never) with ROCA, 8 of 10 were Stage I/ II
(including 7 of 8 TVU-only detected cases).
Table 2. Ovarian cancers, deaths and survival by method of detection
No. (%)
No. (%)
ovarian cancer
Mode of detection
cases
deaths
Intervention arm
Five year
survival rate
(95% CI)
% of cases
Stage I–II/III/IV
243 (100)
132 (100)
51.2 (44–58)
28/51/19
Screen-detected
CA125þ/TVU
27 (11)
20 (15)
41.9 (25–64)
15/74/11
CA125þ/TVU N.D.
12 (5)
7 (5)
46.3 (22–80)
36/64/0
CA125þ/TVU þ
21 (9)
13 (10)
66.7 (53–89)
24/52/14
CA125-/TVU þ
13 (5)
4 (3)
84.6 (79–98)
77/15/7
Interval, within 1 year
of last screen
28 (12)
19 (14)
57.1 (41–77)
11/68/21
Interval, 1–3 years
from last screen
36 (15)
18 (14)
48.6 (32–68)
24/44/32
Never Screened
28 (12)
17 (13)
33.1 (14–52)
24/64/12
Post-screening (> 3 years
from last screen)
78 (32)
34 (26)
24.7 (7–43)
15/54/31
Control arm
218 (100)
119 (100)
34.9 (27–43)
19/51/30
Ovarian cancers and deaths ascertained through 13 years of follow-up from randomization.
N.D. indicates Not Done.
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Int. J. Cancer: 132, 2127–2133 (2013) V
Early Detection and Diagnosis
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Effect of ROCA on PLCO trial
Table 3. Potential changes in diagnosis time with ROCA
Earlier
Later detection
detection
with ROCA
All cases
with ROCA
Mode of detection
Fatal/non–
fatal cases
Fatal/non–
fatal cases
Table 4. Potential modified relative risks for ovarian cancer death
RR (95% CI)
Intervention Control
for intervention
Analysis
arm deaths arm deaths vs. control
Fatal/non–
fatal cases
Screen–detected
CA125þ/TVU
20/7
7/3
0/0
CA125þ/TVU N.D.
7/5
4/2
0/1
CA125þ/TVU þ
13/8
2/1
1/0
CA125–/TVU þ
4/9
0/0
2/6
Interval, within 1 year
of last screen
19|9
10/5
0/0
Interval, 1–3 years
from last screen
18|18
2/6
0/0
Unaffected by ROCA1
51|55
0/0
0/0
Total
132|111
25/17
3/7
1
Early Detection and Diagnosis
Never screened and post-screening cases.
N.D. indicates Not Done.
The above results were obtained using the UKCTOCS cutoffs
for ROCA of 1/3,500 and 1/1,000. Over all screening rounds,
these cutoffs gave proportions of 82.3%, 14.3% and 3.4% of the
screened population in the low, intermediate and elevated risk
categories, respectively. To achieve the desired breakdown of
85%, 13% and 2% in the PLCO screening population, the
derived cutoffs were 0.00032 (1/3,125) and 0.00159 (1/629). We
re-ran the above analyses using these cutoffs and the results
were similar. There were four fewer women with earlier detection with ROCA using the modified cutoffs as compared to the
original cutoffs, with one of these a fatal case. In addition, there
were three additional cases with later (or never) detection with
ROCA using the derived cutoffs, all in non-fatal cases.
Table 4 gives revised mortality RR estimates based on the
best-case and other scenarios under ROCA. The observed
RR, based on 119 control and 132 intervention arm deaths
from ovarian cancer was 1.11 (95% CI 0.87–1.42). Under the
best-case scenario there were 25 fewer intervention arm
deaths, giving an RR of 0.90 (95% CI 0.69–1.17). The stageshift scenario showed 18.8 expected fewer intervention arm
deaths and an RR ¼ 0.95 (95% CI: 0.74–1.23). With 24 prevented deaths using the derived cutoffs (and best-case scenario), the RR was 0.91 (95% CI: 0.70–1.18). For the analysis
accounting for dilution, the RRs were 0.84 (95% CI: 0.62–
1.15) and 0.91 (95% CI: 0.67–1.23) for the best-case and
stage-shift scenarios, respectively, with 34 intervention and
32 control arm deaths excluded due to diagnosis more than 3
years after the end of scheduled screening.
Discussion
This exercise in retrospectively applying the ROCA algorithm
to intervention arm subjects in PLCO shows that, under the
best-case scenario, having had used ROCA as the screening
modality in PLCO would not have produced a statistically
Original
132
119
1.11 (0.87–1.42)
Best-case
107
119
0.90 (0.69–1.17)
Stage-shift
113.2
119
0.95 (0.74–1.23)
Original, dilution
analysis1
98
87
1.13 (0.85–1.50)
Best-case, dilution
analysis1
73
87
0.84 (0.62–1.15)
Stage-shift, dilution
analysis1
79.2
87
0.91 (0.67–1.23)
1
Deaths from cancers diagnosed more than 3 years after last
scheduled screen excluded.
significant, or clinically substantial, mortality effect in the
trial, with best-case and stage-shift RR estimates of 0.90 (95%
CI: 0.69–1.17) and 0.95 (95% CI: 0.74–1.23), respectively. A
limitation to this analysis, however, is the relatively small
number of ovarian cancer deaths and the resulting lack of
precision of our best-case (and the PLCO) mortality RR estimates, as evidenced by the rather wide 95% confidence limits.
Therefore, chance may be playing some role in our findings.
More specifically, the observed modest excess of deaths in
the intervention (n ¼ 132) compared to the control arm (n
¼ 119) clearly makes it more difficult to achieve a substantial
and/or statistically significant mortality reduction with
ROCA, even under the best-case scenario. Although it is possible that this small excess represents a true elevated mortality risk with screening, most would probably agree that it is
likely purely due to chance, in the face of a null or slightly
favorable true mortality benefit for PLCO screening.
Accounting for a probable dilution effect in PLCO, i.e., for
deaths arising from cancers diagnosed at a time when screening was unlikely to affect them, led to a modest reduction in
the mortality RRs, to 0.84 and 0.91 for the best-case and
stage-shift scenarios, respectively, which still failed to reach
statistical significance.
Another limitation of this analysis is that we assumed that
follow-up of positive ROCA screens was the same as that for
positive PLCO screens, and utilized the median interval in
PLCO from first positive screen to diagnosis (74 days) as the
time from first positive ROCA screen to diagnosis. However,
as mentioned above, the targets with ROCA are 13% of
women classified as intermediate and 2% classified as elevated risk; this total 15% rate of referral is substantially
greater than the 5% rate observed in PLCO. A major problem in PLCO was the high rate of oophorectomy among positive screens without evidence of cancer. Therefore, for
ROCA to be practical, the oophorectomy rate in intermediate
risk women, over 99% of whom will not have ovarian cancer,
must be very low. In UKCTOCS this rate is kept low by the
diagnostic follow-up algorithm for intermediate risk, which
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Pinsky et al.
statistically significantly better survival (5 year survival 84%)
than those detected solely by CA125. It is not clear whether
this high level of survival in the TVU-only detected cancers
resulted from early detection and intervention or whether
these tumors are intrinsically of low risk. If the former is the
case, then including TVU with ROCA would be critical, since
ROCA only detected 7 of these 13 TVU-only tumors. Stratton et al., though, showed that larger ovarian tumors, which
are more likely to be detected by TVU, had better survival
than smaller tumors in a cohort of unscreened patients, suggesting that the latter possibility, that these are intrinsically
lower risk, may at least partially explain the difference.8
In PLCO, under 25% of CA125 detected tumors were Stage
I/II and survival for these cancers was poor, both of which suggest that CA125 with the cutoff of 35 U/ml is detecting ovarian
cancer too late. Whether ROCA can be effective in reducing
ovarian cancer mortality will depend on whether the algorithm
can detect changes in CA125 levels reflective of ovarian cancer
progression early enough while still maintaining a reasonable
referral rate; additionally, the corresponding work-up process
must result in a relatively rapid diagnosis of cancers while limiting the number of ‘‘unnecessary’’ oophorectomies.
In conclusion, having utilized ROCA in PLCO would not
likely have led to a statistically significant or substantial mortality benefit of screening in that study. This result does not imply
that utilizing ROCA in another setting, and specifically in the
UKCTOCS trial, would give a similarly null result. The results of
that trial, expected in 2014/2015, are eagerly awaited.9
Acknowledgements
Dr. Skates is a co-inventor of ROCA (patent no. 5800347).
References
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Early Detection and Diagnosis
mandates a repeat ROCA at 3 months followed by either
another repeat ROCA at 3 months, for an intermediate ROCA
score, or TVU for an elevated ROCA score.2 In part due to this
algorithm, in the baseline screening round in UKCTOCS the
median interval from initial screen to diagnosis for women
with an intermediate initial ROCA result (n ¼ 9) was 274 days;
median time was 75 days for women (n ¼ 42) with an elevated
initial ROCA result.2 Thus women with intermediate ROCA
risk will likely be followed up less aggressively than were
women with a positive screen in PLCO. Of the 42 PLCO cases
detected earlier with ROCA, 24 (57%) had an intermediate
ROCA score, including 12 of 25 (48%) fatal cases. Thus our
calculated median advance interval of 344 days for the above
25 fatal cases is likely an overestimate of the true median
advance interval had ROCA screening taken place in PLCO
with the UKCTOCS follow-up algorithm employed.
The survival patterns presented here stratified by mode of
detection were intriguing and may shed light on the potential
benefit of screening. Interval cases in PLCO had similar survival (5 year survival 49–57%) as cases screen detected with
CA125 alone (42–46%) and significantly (p ¼ 0.04) better survival than post-screening cases (30%). In general, due to
length-biased sampling, which selects out on average the faster
growing tumors as interval cases, interval cases tend to have
worse survival than both screen detected cancers and cancers
diagnosed in the absence of screening (post-screening cases
here).7 Thus, it is puzzling why this particular pattern was
observed in PLCO. Better observed survival in screen detected
cancers, of course, does not itself imply a mortality benefit of
screening, due to lead time and over-diagnosis bias.
However, among screen detected cancers, those detected
with TVU alone (and negative CA125) had substantially and