Attachment 7 Literature Review

Attachment 7
Literature Review

Literature Review
From:
Prorok PC, Andriole GL, Bresalier RS, et.al. Design of the Prostate, Lung, Colorectal and
Ovarian (PLCO) Cancer Screening Trial. Controlled Clinical Trials 21:273S-309S (2000).

Design of the PLCO Trial

275S

Ovarian (PLCO) Cancer Screening Trial is a 23-year randomized trial in which
37,000 men will be screened for prostate, lung, and colorectal cancers and 37,000
women will be screened for lung, colorectal, and ovarian cancers. Prostatespecific antigen (PSA) and digital rectal examination (DRE) (for prostate), chest
X-ray (for lung), 60-cm flexible sigmoidoscopy (for colorectal), and CA125 blood
test and transvaginal ultrasound (TVU) (for ovary) are being investigated as
screening modalities. An equal number of men and women will be followed
with routine medical care as controls. There will be a follow-up period of at
least 13 years from randomization for both intervention and control participants
to determine the effects of screening on cause-specific mortality.
This paper describes the design of this trial at the completion of protocol
development (just prior to the initiation of the pilot-phase recruitment) and
protocol modifications that have occurred since. Included are the specific rationale for each cancer site, overall design features, screening and follow-up
procedures, sample-size considerations, and data analysis plans. Recruitment
into the pilot phase began November 16, 1993, with main-phase recruitment
commencing September 30, 1994.
TRIAL RATIONALE

Prostate Cancer Screening
The DRE, the most common screening test for prostate cancer screening
prior to 1990, has never been completely evaluated. Observational studies have
examined sensitivity and case survival data, but without appropriate controls
and with no adjustment for lead-time and length biases [4, 5].
In 1984, Chodak and Schoenberg [6] reported on 811 patients from 50-80
years of age who underwent rectal examination and follow-up. Thirty-eight of
43 patients with a palpable abnormality in the prostate agreed to undergo
biopsy. The positive predictive value for prostate cancer was 29%. Forty-five
percent of the cases were stage B, 6% stage C, and 18% stage D. More recent
results from the same investigators revealed a 25% positive predictive value
with 68% of the detected tumors clinically localized [7]. Others also reported
a high proportion of localized disease when prostate cancer is detected by
routine rectal examination [8-11]. In contrast, Wajsman and Chu [12] among
others have reported that even with annual rectal examination, only 20% of
cases are localized at diagnosis. Thompson and Zeidman [13] reported that
25% of men presenting with metastatic disease had a normal prostate exam.
A summary of the data on DRE for detection of prostate cancer concluded
the following: sensitivity is 55-69%, specifiCity is 89-97%, positive predictive
value is 11-26%, and negative predictive value is 85--96% [14]. Further, the
rectal examination depends on the skill and experience of the examiner and
the presence of a cancer in the posterior prostate. However, DRE is inexpensive,
relatively noninvasive, nonmorbid, and can be taught to nonprofessional health
workers. What remains to be determined is whether routine annual screening
by rectal examination reduces prostate cancer mortality. A case-control study
involving 139 men with metastatic prostate cancer and matched controls found
the relative risk of metastatic prostate cancer to be 0.9 for men with one or
more rectal examinations compared with men with none. The 95% confidence

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P.C. Prorok et al.
interval was 0.5-1.7, suggesting that screening by routine DRE appears to
have little effect in detecting and treating prostate cancer before it becomes
metastatic [15].
Prostatic imaging by ultrasound, computerized tomography, and magnetic
resonance imaging have also been suggested for prostate cancer screening.
Each modality has relative advantages and disadvantages. Transrectal ultrasound has received the most attention [8, 16-22]. In a summary, Waterhouse
and Resnick [23] reported that the sensitivity and specificity of ultrasound are
too low for the procedure to be a valuable screening tool. Sensitivity ranged
from 71-92% for prostate cancer and 60-85% for subclinical disease. Specificity
ranged from 41-79%, and positive predictive values in the 30% range have
been reported. The sensitivity and positive predictive value of ultrasound may
be better than those of DRE when each is used as a single test. However, the
relatively low specificity along with the invasiveness and cost of the procedure
preclude routine screening for prostate cancer by transrectal ultrasound.
Serum PSA has been examined in several observational settings, both for
initial diagnosis of disease and as a tool to detect recurrence after initial therapy
[8, 20, 24-27]. Parameter estimates for this test include sensitivity near 70%
and positive predictive values of 17-28%, although these estimates of predictive
value are strongly dependent upon the disease prevalence in the populations
studied [28]. The potential value of PSA lies in its simplicity, objectivity, reproducibility, lack of invasiveness, and lower cost relative to ultrasound. The test
has increased the detection rate of early stage cancers, many of which may be
curable by local therapy [9, 29, 30]. However, the test must be carefully evaluated because false positives in the form of benign prostatic lesions are common,
requiring biopsies and added expense, and PSA testing cannot distinguish
between latent or biologically irrelevant versus aggressive tumors.
The use of serial tests to assess the rate of change of PSA has been evaluated
as a method to improve the specificity of the test [31]. The combination of PSA
and ultrasound has been used to determine PSA density indexed to prostate
size [32-34]. In one study, volume-adjusted PSA identified a population at
higher risk of carcinoma [35], but another study of intermediate levels of PSA
found no advantage to volume-adjusted PSA levels for screening [36]. Ratios
of free to complexed PSA can amplify the differences in PSA levels for individuals with prostate cancer versus prostatic hyperplasia [37, 38]. No statistical
advantage has been established for using the ratio of free to total PSA compared
to total PSA alone in a screened population [39]; however, the free to total PSA
ratio did improve specificity in other studies [40].
In a study by Cooner et al. [41] to resolve questions surrounding the relative
merits of the three tests, all subjects had a rectal examination, PSA determination
(Hybritech assay), and a 7-mHz ultrasound examination. Most of the participants with positive results on ultrasound plus a few other individuals were
biopsied. The pertinent findings of this study and a similar study by Lee et al.
[20] are given in Table 1. Both studies demonstrate that the rate of cancer
among subjects with positive results on ultrasonography in whom the rectal and
PSA exams are normal is extremely low. Hence, ultrasound was not included as
one of the screening tests in this trial.
Careful evaluation of prostate cancer screening is mandatory because the
natural history of the disease is variable and appropriate treatment is not clearly

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Design of the PLCO Trial
Table I

Effect of Rectal and Prostate-Specific Antigen Examinations on
Cancer Rate in Patients with Abnormal Rectal Ultrasound
Cooner Study
Lee Study
Biopsies
Cancer
Rate
Biopsies
Cancer
Rate

Rectal
Rectal
Rectal
Rectal

PSA
PSA
PSA
PSA

+,
+,
-,
-,

+
+
-

235
166
134
177

151
23
41
12

0.64
0.14
0.31
0.07

89
23
92
44

63
6
31
2

0.71
0.26
0.34
0.05

PSA = prostate-specificantigen.

defined [28, 42, 43]. The ~cidence of prostate cancer found at autopsy steadily
increases for each decade after age 50, and most of these lesions are clinically
latent. Some progress has been made in predicting the biologic behavior of
these tumors, but despite improved understanding of the relationship among
histologic grade, tumor volume, and biologic behavior, it is difficult to determine appropriate therapy for any given tumor [44]. A meta-analysis indicated
that patients with low-grade prostate cancer can experience long-term survival
with deferred therapy [45]. Decision analyses produce indeterminate results
because of uncertainty regarding treatment efficacy and metastatic rates for
prostate cancer [46-48]. On the other hand, a review of 60,000 cases of prostate
cancer diagnosed between 1983 and 1992 showed that men with poorly or
moderately differentiated cancer had improved survival if treated rather than
followed [49].
Screening and treatment of a large population of males could entail substantial risks and morbidity, which include urinary incontinence, urethral strictures,
sexual impotence, rectal injury, and a small probability of treatment-related
mortality [44, 50]. Given these circumstances, careful evaluation of prostate
cancer screening is needed. Currently, there is insufficient evidence with which
to decide the efficacy or effectiveness of screening asymptomatic men [44, 47].
In addition to the PLCO trial, randomized trials are underway in other countries
to address these issues [51, 52].

Lung Cancer Screening
Evaluations of chest X-ray and sputum cytology, the most common screening
tests for lung cancer, were first reported nearly 30 years ago. The early studies
include the Philadelphia Pulmonary Neoplasm Research Project [53], a nonrandomized, uncontrolled study begun in 1951; the Veterans Administration study
[54], a nonrandomized, uncontrolled study performed from 1958 to 1961; the
South London Lung Cancer Study [55], a nonrandomized, uncontrolled study
done in 1955 to 1963; the North London Cancer Study [56, 57], a randomized
study with industrial firms randomized between screening and no screening
done in the early 1960s; and the Kaiser Foundation Health Plan multiphasic
screening trial [58, 59], a controlled trial with annual chest X-ray, spirometry,
and medical questionnaire as part of the multiphasic screening begun in 1964.
None of these studies demonstrated a significant impact of screening on lung
cancer mortality. The South London study, for example, showed an increase

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P.C. Prorok et al.
in the survival of screen-detected cases compared with other cases found in
the same geographical region, but without adjustment for self-selection bias,
lead-time bias, overdiagnosis bias, or length bias [60, 61]. These studies typically
were small, and for most, follow-up was short, so that any small to moderate
size effect or any long-term effect was not likely to be demonstrated.
More recent studies include a randomized trial in Czechoslovakia [62, 63],
a case-control study in the former German Democratic Republic [64], and a
case-control study in Japan [65]. As with some earlier studies, the randomized
groups in the Czechoslovakian study were screened with cytology and X-ray
at two frequencies, semiannual versus every 3 years, so that there was no
unscreened control group. There was no difference in mortality between the
two groups. The German case-control study evaluated chest X-rays originally
used for control of tuberculosis. The Japanese case-control study considered
X-ray histories among deceased lung cancer cases and matched controls. In
contrast to the German study, the odds ratio of dying from lung cancer for
those screened within 12 months versus those not screened was 0.72, suggesting
some benefit from the screening.
Three other randomized controlled trials have been conducted. One trial,
the Mayo Lung Project, was initiated in 1971 for males 45 years or older who
were heavy smokers [66-68]. Participants free of lung cancer on initial screening
were randomized either to a group offered screening with sputum cytology
and chest X-ray every 4 months or to a group not offered screening but advised
to seek it annually. In the studies at the Johns Hopkins University Hospital
[69-72] and at Memorial-Sloan Kettering Cancer Center [73, 74], intervention
and control groups were offered annual chest X-ray, while the intervention
group was also offered sputum cytology every 4 months. In the Mayo Clinic
study, cases found in the screened arm were diagnosed in earlier stages than
those in the control arm. However, there was no significant reduction in lung
cancer mortality between the screened group and the control group in any of
these trials.
Therefore, at this point there is no solid evidence that screening for lung
cancer can reduce lung cancer mortality. Sputum cytology has not been shown
to be effective as an adjunct to annual chest X-ray. There is evidence that
screening with chest X-ray plus sputum cytology does improve stage at diagnosis and case survival rate relative to cases diagnosed through usual care, but
despite this there was no reduction in lung cancer mortality. However, modeling using data from these trials suggests that there may have been as much as
an 18% mortality reduction in these trials [75-77].
The Mayo study is the only one of the three which is pertinent to studying
annual X-ray in the present trial because the use of screening X-rays differed
in the two arms. However, several reservations can be noted about the Mayo
study finding. First, the study was designed to detect a 50% reduction in lung
cancer mortality and was too small to demonstrate a lesser but important
reduction of 10-15%. Second, at the time the study was terminated there were
still 40 excess cases of lung cancer in the screened group. Whether these cases
represent overdiagnosis or a screening benefit that would only be seen with
longer follow-up is not known. Third, about 50% of the men in the control
group received an annual chest X-ray [68]. Thus, the level of contamination
may have been sufficient to obscure any small to moderate benefit. Finally,

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Design of the PLCO Trial

Table 2 Power to Detect Various Screening Effects in Previous Studies of
Chest X-Ray Screening for Lung Cancer (Based on Actual Deaths
Observed)
Mortality Reduction (%)
Study
Philadelphia
VA
South London
North London
Kaiser
Czechoslovakia
Mayo

10

20

30

40

50

0.14
0.16
0.14
0.16
0.12
0.16
0.21

0.32
0.38
0.31
0.39
0.27
0.39
0.54

0.59
0.69
0.57
0.70
0.50
0.71
0.88

0.85
0.92
0.83
0.93
0.76
0.93
0.99

0.98
0.99
0.97
0.995
0.94
0.996
0.999

when prevalence cases were detected at the first screen, they were followed
separately and were not part of the randomized comparison. Hence, any effect
of X-ray on reducing lung cancer mortality among these cases could not have
been determined. It can also be argued that therapeutic advances may render
early detection more effective today than at the time of the Mayo trial.
The concern about insufficient size of previous studies of chest X-ray screening is illustrated in Table 2. The uncertainty in interpretation of results from
completed studies has led to differences of opinion regarding the value of
the annual chest X-ray. Whether a small but important benefit exists can be
demonstrated only by a properly designed randomized trial.

Colorectal Cancer Screening
DRE, sigmoidoscopy, and fecal occult blood testing have each been suggested
for colorectal cancer screening. However, only the fecal occult blood test has
been proven to be beneficial.
Several uncontrolled studies suggesting that the fecal occult blood test leads
to early detection have been reported [78-80] as have two case-control studies
of the effect of occult blood testing on colorectal cancer mortality. In one study,
the screening histories of fatal colorectal cancer cases and matched controls
were compared, resulting in an odds ratio of 0.69 for exposure to at least one
occult blood test over a 5-year period. The wide confidence interval (0.52-0.91)
suggested a benefit from the screening but also the need for further data [81].
In the second study, cases were less likely to have ever been screened than
controls. The odds ratio was 0.7 with a 95% confidence interval of 0.5-1.0,
consistent with a screening benefit [82].
Five prospective, controlled studies of fecal occult blood testing have also
been conducted. The Strang Clinic of New York undertook a nonrandomized
study involving some 12,000 screenees and 7000 controls designed to test the
effect of combining the stool guaiac test with annual sigmoidoscopy. Individuals were allocated to the study arms by calendar periods. A reduction in
colorectal cancer mortality of borderline significance was reported [83].
A randomized trial of the stool guaiac test began in 1974 at the University
of Minnesota, where nearly 47,000 persons ages 50-80 were randomized into
three groups: a control group, an annually screened group, and a biennially

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P.C. Prorok et al.
screened group. The preponderance of test slides were rehydrated. Recent
results provided the first definitive evidence that annual testing for occult blood
in the stool can reduce the death rate from colorectal cancer. The 13-year
cumulative mortality from colorectal cancer was reduced by 33% (mortality
ratio 0.67 with 95% confidence interval 0.50-0.87) [84].
A controlled trial in Nottingham, United Kingdom randomized approximately 76,000 individuals to each of two arms using lists of family practitioners.
Fecal occult blood testing every 2 years using nonrehydrated slides was offered
to the screened arm for three to six rounds of screening. A 15% reduction in
colorectal cancer mortality was reported after a median follow-up time of 7.8
years [85].
Two additional randomized trials of occult blood screening were initiated
more recently. A trial in Sweden targeted individuals in the narrow age range
of 60-64 years [86]. A Danish trial randomized about 31,000 individuals ages
45-75 into two arms. Participants in the screened arm were offered nonrehydrated fecal occult blood tests every 2 years for five rounds over a 10-year
period [87, 88]. This trial demonstrated an 18% reduction in colorectal cancer
mortality [89].
In summary, testing for occult blood in the stool as a colorectal cancer
screening maneuver has been studied in several trials, and a mortality reduction
has been demonstrated. The focus of the PLCO trial is therefore flexible sigmoidoscopy.
DRE and rigid sigmoidoscopy were both part of the multiphasic screening
program carried out by the Kaiser-Permanente Foundation, and some considered the results of this study to be evidence of the effectiveness of these tests
[90]. Approximately 5000 individuals were allocated to a study group urged
to receive an annual multiphasic checkup, and a comparable number served
as controls. After 11 years, the screened group experienced a colorectal cancer
death rate of 1.0 per 1000 participants entered compared to a rate of 3.3 per
1000 in the control group [58, 59]. The observed decrease in colorectal cancer
mortality in this study could be a real effect resulting from screening. However,
this conclusion has been questioned for several reasons [91]. Some cancers
were detected in an investigation of anemia resulting from the multiphasic
examination as well as by the two tests. Further, in a reanalysis the investigators
found that rates of sigrnoidoscopy were low in both groups (control: 25%;
screened: 30%), that there was only a slight excess of exposure to sigmoidoscopy
in the study group compared to the control group, and that there was not an
appreciable difference in removal of colorectal polyps between groups. They
concluded that this study should not be used as evidence either for or against
sigmoidoscopy screening [92]. DRE made a minor contribution. In addition, a
case-control study found no statistically significant mortality reduction from
distal rectal cancer using DRE [93].
Two additional observational cohort studies of sigmoidoscopy have been
reported. One involved 21,000 participants in Minnesota who underwent an
annual physical examination that included sigmoidoscopy [94, 95]. Polyps
discovered during screening were removed, and the number of sigmoid cancers
ultimately found was only 15% of the number expected. All of the 13 cancers
found were localized, and none of the patients had died as of 1979. The second
study followed 26,000 men and women in New York [96]. In 50 cancer patients

Design of the PLCO Trial

281S

identified by screening and followed over 15 years, the 5-year survival rate
was reported to be 90%. The interpretation that screening was of benefit in
these two studies can be questioned on several grounds. Both studies are likely
to be affected by self-selection bias of participants and by exclusion of certain
individuals from the follow-up process. In the New York study, seven people
with a history of symptoms and eight with previously diagnosed lesions were
excluded, thereby lowering the observed incidence and mortality rates. In the
Minnesota study, cases found at the initial examination were excluded from
the observed incidence, and only individuals without gastrointestinal symptoms were allowed to participate. Thus, the data cannot be validly compared
with the general population [91]. In addition, the reported survival data from
both studies are affected by lead-time and length biases, but no adjustment for
these biases was attempted.
Flexible sigmoidoscopy has been shown to be more acceptable to screenees
than rigid endoscopy, and the test appears to be very sensitive and highly
specific for cancer [97, 98]. The test can discover a high proportion of polyps,
and evidence suggests that removal of adenomas decreases the risk of colorectal
cancer [99]. The need to address the impact of flexible sigmoidoscopy screening
on colorectal cancer mortality has been discussed by several investigators [97,
100, 101]. Encouraging reports of the potential impact of this test come from
two case-control studies and from the modeling work of Eddy et al. [102, 103],
which suggests a potential mortality reduction of 25--40%. Both case-control
studies were conducted in prepaid health plans and used colorectal cancer
deaths as cases, with matched controls. Exposure to sigmoidoscopy in cases
and controls was compared [104, 105]. Rigid sigmoidoscopy was used in one
study, while a majority of the screening was by flexible sigmoidoscopy in the
other study. Both studies suggested a strong effect of sigmoidoscopy in reducing
colorectal cancer mortality, with unadjusted odds ratios of 0.30 and 0.21. The
modeling conclusions and the case-control studies are subject to the assumptions and biases in the methodologies, so that conclusive results will only be
obtained from a randomized trial.

Ovarian Cancer Screening
Traditionally, the pelvic examination has been relied on to detect ovarian
cancer, but it is insensitive to early disease and small tumors [106]. Thus, most
ovarian cancers present as late-stage disease. Two new technologies may be
useful as screening tools: CA125 and TVU.
CA125 is an antigenic determinant on a high molecular weight glycoprotein
recognized by a monoclonal antibody (OC 125) using an ovarian cell line as
an immunogen. The test is performed on peripheral blood. In mostly small
(50-150 patients) preoperative studies of women with ovarian masses, serum
CA125 levels were elevated (typically above 35 U / m L ) in 68-100% of cases
averaged over all stages and in 40-50% of stage I disease. Serum CA125 may
also be elevated with pregnancy, endometriosis, menstruation, benign ovarian
tumors, and with breast, colon, pancreatic, lung, gastric, and liver cancers [107].
CA125 was reported to have high specificity in postmenopausal women in
two prospective trials. Among 1010 postmenopausal women undergoing both
pelvic examination and CA125, the only malignancy diagnosed was detected

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P.C. Prorok et al.
by CA125 [107]. The specificity was 94.3%. In a study in Sweden among 5550
w o m e n over 40 years of age, nine cancers were detected, six of the nine by
CA125 [108]. Specificity was 98.5% using a threshold of 35 U / m L in w o m e n
50 years of age and older. The sensitivity of CA125 was estimated in two nested
case-control studies using sera available from two serum banks [109, 110]. The
sensitivity for a level of at least 35 U / m L ranged from 20-57% for cases occurring within the first 3 years of follow-up. These two studies also reported
a specificity of 95%.
These preoperative and prospective studies together suggest early detection
potential for CA125. However, no studies have been conducted to measure
sensitivity and specificity in a large screened population, and no randomized
trials have been initiated to assess the impact of screening with CA125 on
ovarian cancer mortality.
TVU has been proposed for ovarian cancer screening [111], but experience
with this modality is limited. In a series of 1017 tumors, 0.3% of ovarian
tumors unilocular on ultrasound were malignant, while 8% of those that were
multilocular and 39% of those that were solid were malignant [106]. Higgins
et al. and Van Nagell et al. [111, 112] have been using TVU for screening w o m e n
over the age of 40 since 1987. Using 8 cm 3 as the upper limit of normal ovarian
volume, 31 abnormal ultrasonograms (in 1000 women) were obtained; 24 of
these w o m e n u n d e r w e n t laparotomy. TVU identified all three of the cancers detected.
Estimates of yield and false positivity of ultrasound are available from several
studies of w o m e n offered periodic screening. In a cohort of 801 w o m e n ages
40-70 w h o had one or more risk factors for ovarian cancer, 163 had an abnormal
abdominal ultrasound. Surgery was performed in 30 cases, and one borderline
ovarian tumor was found [113]. In another study of abdominal ultrasound,
5479 asyrnptomatic w o m e n u n d e r w e n t periodic screening. Of 326 participants
w h o had a positive test and went on to surgery, five w o m e n were diagnosed
with stage IA or IB ovarian cancer, and four were diagnosed with metastatic
ovarian cancer [114]. TVU was also used in a study of 3220 asymptomatic,
postmenopausal women. An abnormal exam led to exploratory laparotomy in
44 women. Three primary ovarian carcinomas were found, two with stage IA
cancer [115]. Finally, both transvaginal and transabdominal ultrasound were
used to screen 1601 w o m e n with a first- or second-degree relative w h o had
ovarian cancer. There were 61 positive tests, leading to six ovarian cancers, five
stage I. There were five additional cancers, three ovarian and two peritoneal,
reported 2-44 months after the last test [116].
The available evidence is not sufficient to determine if the sensitivity and
specificity of any single ovarian cancer screening test is adequate for routine
application. The modalities m a y be complementary w h e n used together. The
cost of a test such as TVU, as well as the risks and costs associated with surgical
evaluation of any positive test result, are potential impediments to general
screening. Prospective screening trials to evaluate these modalities are required.

DESIGN FEATURES
Objectives and Global Design
The PLCO trial is designed to determine, in screenees ages 55-74 at entry,
whether:

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