Cancer Epidemiology Biomarkers & Prevention Vol. 9, 127-137, February 2000
© 2000 American Association for Cancer Research
Perspectives on Surrogate End Points in the Development of Drugs that Reduce the Risk of Cancer
Gary J. Kelloff1,
Caroline C. Sigman,
Karen M. Johnson,
Charles W. Boone,
Peter Greenwald,
James A. Crowell,
Ernest T. Hawk and
Linda A. Doody
Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [G. J. K., K. M. J., C. W. B., P. G., J. A. C., E. T. H.], and CCS Associates, Mountain View, California, 94043 [C. C. S., L. A. D.]
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Abstract
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This paper proposes a scientific basis and possible strategy for
applying surrogate end points in chemopreventive drug development. The
potential surrogate end points for cancer incidence described are both
phenotypic (at the tissue, cellular, and molecular levels) and
genotypic biomarkers. To establish chemopreventive efficacy in
randomized, placebo-controlled clinical trials, it is expected that in
most cases it will be critical to ensure that virtually all of the
biomarker lesions are prevented or that the lesions prevented are those
with the potential to progress. This would require that both the
phenotype and genotype of the target tissue in agent-treated subjects,
especially in any new or remaining precancers, are equivalent to or
show less progression than those of placebo-treated subjects. In the
National Cancer Institute chemoprevention program, histological
modulation of a precancer (intraepithelial neoplasia) has thus far been
the primary phenotypic surrogate end point in chemoprevention trials.
Additionally, we give high priority to biomarkers measuring specific
and general genotypic changes correlating to the carcinogenesis
progression model for the targeted cancer (e.g.,
progressive genomic instability as measured by loss of heterozygosity
or amplification at a specific microsatellite loci). Other potential
surrogate end points that may occur earlier in carcinogenesis are being
analyzed in these precancers and in nearby normal appearing tissues.
These biomarkers include proliferation and differentiation indices,
specific gene and general chromosome damage, cell growth regulatory
molecules, and biochemical activities (e.g., enzyme
inhibition). Serum biomarkers also may be monitored
(e.g., prostate-specific antigen) because of their
accessibility. Potentially chemopreventive drug effects of the test
agent also may be measured (e.g., tissue and serum
estrogen levels in studies of steroid aromatase inhibitors). These
initial studies are expected to expand the list of validated surrogate
end points for future use. Continued discussion and research among the
National Cancer Institute, the Food and Drug Administration, industry,
and academia are needed to ensure that surrogate end point-based
chemoprevention indications are feasible.
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Introduction
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Surrogate end point biomarkers are an important aspect of the
chemopreventive drug development process (e.g., Refs.
1, 2, 3, 4, 5, 6, 7
). This paper provides our present understanding of
the value of these end points in chemopreventive drug development,
along with a scientific basis and strategy for their present and future
application. Cancer chemoprevention shares the interest and need for
surrogate end points in drug development with other chronic diseases of
aging (e.g., cardiovascular disease) and life-threatening
diseases (e.g., AIDS). Particularly, the use of blood lipid
lowering as a surrogate end point for cardiovascular disease provides a
model for and insight into the issues that might surround the use of
surrogates for cancer incidence in chemoprevention studies.
Cancer chemoprevention can be defined as treatment of carcinogenesis,
i.e., its prevention, inhibition, or reversal
(e.g., Ref. 5
). In most epithelial tissues,
accumulating mutations (i.e., genetic progression) and loss
of cellular control functions are observed as the phenotype changes
from normal histology to early
IEN2
(2)
then to increasingly severe IEN, superficial cancers,
and finally invasive disease. There are likely to be situations in
which the process is relatively aggressive (e.g., in the
presence of a DNA repair-deficient genotype or viral transformant such
as the human papilloma virus), but generally, these changes appear to
occur over a long time period (Fig. 1
). For example, in the breast, it is estimated that progression from
atypical hyperplasia through DCIS to adenocarcinoma may require 30
years or more (8
, 9)
. Colorectal adenomas may form over a
period as long as 5–20 years, and progression from adenoma to
colorectal carcinoma may require another 5–15 years (10
, 11)
. PIN may develop over 
20 years (12)
. The
development from PIN to early latent cancer may take 
10 years,
and clinically significant carcinoma may not occur until 3–15 years
later (12)
.
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Fig. 1. Multiyear progression from initiation and early precancerous lesions to
invasive disease in major cancer target organs: prostate (Ref.
12
), breast (Refs. 8
and 9
),
lung (Ref. 72
), lung (smokers; Refs. 73
and
74
), colon (Refs. 10
and 11
),
bladder (Ref. 75
), cervix (Ref. 76
),
esophagus (Refs. 77
78
79
80
81
82
), and liver (Ref.
83
).
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The prolonged time course of carcinogenesis provides an opportunity for
chemoprevention—to intervene when the mutations are fewer, even before
tissue level phenotypic changes are evident. However, the long latency
also presents significant challenges for the clinical phase of
chemopreventive drug development. In this paper, we discuss a potential
chemopreventive drug development strategy that addresses one major
challenge—the long delays that could be expected, even in the presence
of IEN, if modulation of a cancer end point were required to
demonstrate efficacy as part of the usual process for drug approval
(2, 3, 4, 5, 6)
. As suggested by the data presented above, cancers
generally develop over decades, and IEN (e.g., PIN,
colorectal adenomas) may also progress slowly (5–20 years). Typically,
cancer incidence reduction trials have planned durations of 5–10
years, with anticipated accrual in the tens of thousands. We believe
that the strategy we describe could allow demonstration of
chemopreventive efficacy in most cancer targets in 
3 years with
several hundred, not tens of thousands, subjects and is possible
because of increasing knowledge of the genetic, histopathological, and
molecular basis of carcinogenesis. This strategy involves identifying,
validating, and using phenotypic biomarkers (at the tissue, cellular,
and molecular levels) and genotypic biomarkers as surrogate end points
for cancer incidence.
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Biomarkers of Carcinogenesis
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IEN, such as colorectal adenomas, PIN, and CIN, are primary
examples of tissue level phenotypic biomarkers that, because they are
on the causal pathway to and are direct precursors of cancer, are
generally considered suitable for following carcinogenesis (2
, 3)
. Cellular biomarkers, such as nuclear and nucleolar
morphology, mitotic index, and DNA ploidy, are also being evaluated in
on-going studies; they may be useful in characterizing the progression
of IEN (2
, 5)
. Other possibly useful genotypic biomarkers
include LOH and gene amplification, either at specific gene loci
(e.g., those for tumor suppressors such as p53 or tumor
growth accelerators such as c-erbB2) or at panels of
microsatellite loci where mutations indicate increasing genomic
instability (13)
. Both phenotypic and genotypic changes
during carcinogenesis may also be manifested by molecular biomarkers
(3)
. For example, excess proliferation might be seen in
increased levels of cellular antigens, such as PCNA or Ki-67/MIB-1 or
overexpression of growth factors, such as epidermal growth factor,
TGF
, and insulin-like growth factor I; reduced propensity to undergo
apoptosis may be detected by increased expression of bcl-2.
Aberrant differentiation may result in changes in G-actin,
cytokeratins, and blood group antigens. Other molecular biomarkers may
reflect general changes in cell growth control. These include TGFß,
cyclins, p53, and other tumor suppressors, as well as mutations and
overexpression of oncogenes associated with carcinogenesis, such as
ras and the transcription factors myc,
fos, and jun. Tissue- and drug-related biomarkers
may also be useful. Examples of tissue-related biomarkers are the
expression of estrogen receptors in breast and PSA in prostate.
Drug-related biomarkers associated with chemopreventive activity
include inhibition of ODC by 2-difluoromethylornithine and inhibition
of prostaglandin biosynthesis by nonsteroidal anti-inflammatory drugs.
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Rationale for Using Biomarkers of Carcinogenesis as Surrogate End
Points—Importance of Developing Molecular Progression Models
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A key concept supporting the use of these biomarkers is that
carcinogenesis is progressive. Progression has been mapped in target
tissues by the appearance of specific molecular and more general
genotypic damage associated with increasingly severe dysplastic
phenotypes (e.g., Ref. 13
and other studies
cited below). In many cases early, critical steps include inactivation
of tumor suppressor genes, such as APC or the breast cancer (BRCA)
gene and activation of oncogenes such as ras.
Carcinogenesis may take multiple paths and be multifocal; not all
cancers in a given tissue nor all cells in a given cancer may
ultimately contain the same lesions. Progression may also be influenced
by factors specific to the host tissue’s environment, such as the
action of hormones produced in stroma around the developing epithelial
tumor and changes in tissue structure (e.g., Refs.
14, 15, 16
). Further, carcinogenesis may not necessarily be
driven by the order in which the changes appear; the disorganization
caused by and exacerbating the accumulation of multiple effects may be
more important. This disorganization is an obvious manifestation of
carcinogenesis. Progression models that reflect increasing
disorganization have been developed by Vogelstein, Sidransky, and their
colleagues, the seminal work being that by Fearon and Vogelstein
(17)
in the colon. These researchers have also described
carcinogenesis in the brain (18)
, bladder [Refs.
19, 20, 21, 22
; see also Simoneau and Jones (23)
],
and in the head and neck (13)
. Lam, Gazdar, and their
colleagues (24
, 25)
have described early analyses
of chromosomal loss correlating to grade of dysplasia and the
appearance of non-small cell lung cancer. Also, Larson et
al. (26)
described accumulating chromosomal loss at
defined loci in CIN. It is these genotypic and corresponding tissue and
cellular histological lesions or biomarkers, when they are sufficiently
stable to allow screening during carcinogenesis, that we think have the
highest potential to serve as surrogate end points. Specific
carcinogenesis-associated molecular lesions identified thus far,
although important, may not be the most informative among those that
will be discovered as research continues. Thus, at present, because
most cancer does not appear to occur unless it is preceded by an
abnormal histological precancer phenotype, a focus on this
abnormal phenotype, which integrates the relevant genetic and molecular
changes, and, as described below, direct measurement of the
accompanying genotypic changes, appears to us to provide the best
opportunity for validating surrogate end points.
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Phenotypic and Genotypic Surrogate End Points to Establish
Chemopreventive Efficacy
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We presently view IEN, the embodiment of the abnormal cancer
phenotype, as a promising surrogate end point for clinical
chemoprevention studies in epithelial tissues (2,
3
, 27)
.
Although shorter than the period for developing cancer, the latency for
IEN progression can also be lengthy compared with the practical time
frame for a chemopreventive intervention study. Importantly, the number
of precancers may far exceed the number of cancers that subsequently
develop in the target tissue, and behavioral (e.g., smoking
history), environmental (e.g., hormonal status), and
coexisting disease (e.g., immune system competence) factors
may influence progression in individual subjects. IEN that will
progress also may have particular characteristics predisposing them to
develop into cancers. For example, the potential of colorectal adenomas
to progress to cancer correlates to histological growth pattern, size,
and severity of dysplasia (28, 29, 30)
. Two to five percent of
tubular, 22% of tubulo-villus, and 20–55% of villus adenomas
progress. Risk of malignancy is negligible for adenomas 1 cm in
diameter and increases at larger diameters. Of the 70% of adenomatous
polyps that are mildly dysplastic, no more than 5% progress to
cancers; whereas, a much higher fraction (up to 55%) of the 10% of
adenomas that are severely dysplastic become cancerous. In one study,
one-third of severely dysplastic adenomas contained invasive carcinoma
(see Ref. 28
), and severe dysplasia is found most commonly
in larger adenomas with villous histology. Therefore, to establish
chemopreventive efficacy, we expect that it will be critical to ensure
that virtually all of the precancer lesions are prevented or that the
lesions prevented are those with the potential to progress.
For these reasons, drug-induced prevention or regression of IEN
determined histologically will not often be sufficient to determine
chemopreventive efficacy. The evaluation should usually also consider
the specific and general genotypic effects comprising the progression
models for carcinogenesis and may also look at molecular pathology. As
described in detail below, we believe determining that a reduced
incidence of new precancers is chemoprevention requires that the
genotype of the target tissue in agent-treated subjects, especially in
any new precancers, is equivalent to or shows less genetic progression
than that of placebo-treated subjects. Similarly, in studies with
regression of existing precancers as the end point, where regression is
incomplete, we feel that the remaining lesions in the agent-treated
subjects should have genotypes equivalent to or showing less
progression than placebo control subjects.
A critical issue to the application and validation of these surrogate
end points is developing standardized, appropriate, and quantitative
techniques for sampling the target tissues. Improved diagnostic tools
such as gene-chip analyses, the confocal microscope, digital
mammography, the lung-imaging fluorescence endoscope for visualizing
bronchial tissue, and the magnifying endoscope for colorectal
monitoring will be critical to assuring the adequate visualization and
monitoring of precancerous tissue.
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Cohorts for Surrogate Endpoint Chemoprevention Studies
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Another important concept is the definition of high-risk tissue,
particularly as applied to patients with previous cancers or
precancers. Generally, these patients show an increased risk for
developing new primary lesions in tissue that is histologically related
to tissue from which the original lesion arose. Slaughter
(31)
coined the term "field cancerization" to describe
the early evidence of carcinogenesis found in normal appearing mucosa
of patients with previous head and neck cancers. In fact, the lifetime
risk for a second primary tumor of the aerodigestive tract following a
squamous cell cancer of the head or neck has been estimated at 20–40%
(32)
. Many studies, particularly those carried out by
Hong, Lippman, Hittelman, and their colleagues
(32, 33, 34)
, have confirmed this phenomenon. For
example, Hittelman (33)
delineated the use of chromosome
in situ hybridization to detect carcinogenesis-associated
genotypic changes (3 copies of a single chromosome) in normal and
precancerous tissue nearby head and neck cancers. The tissues were
histologically and otherwise phenotypically distinct from cancers;
hence, the genotypic changes did not likely result from random sampling
errors. In these studies, the degree of genetic change detected
correlated to histological progression of the lesion toward cancer.
Very importantly, 8 of 15 patients (53%) having premalignant
lesions of the oral cavity containing high levels of genetic damage
(3.5% of cells with three or more copies of chromosome 9)
subsequently developed aerodigestive tract cancer compared with none
among patients with lower levels. Similar results were found by
Hittelman and his colleagues (33)
at chromosome 9 in lung
tissue from previous smokers and at chromosome 17 from breast tissue
(35)
, and by Segers et al. (36)
at
chromosome 1 from cervical tissue from patients with various grades of
CIN. Although none of these studies tracked the development of specific
lesions into cancers, they all confirmed that carcinogenesis could be
detected by genotypic changes in high-risk tissue.
The implication for clinical chemoprevention studies is that patients
with previous cancers or precancers provide cohorts who are at high
risk for new primary cancers and will benefit from chemoprevention,
allowing smaller trials to be designed in which premalignant changes
(surrogate end points) can be followed both phenotypically and
genotypical. One criterion we use for selecting these cohorts is
expectation of a high incidence of the cancer or precancer, or
observable progression of the precancer, under study within a
reasonable time period. For Phase II and III studies using surrogate
end points, we anticipate durations 3 years (in some situations, such
as preventing second primary cancers, as few as 3 years may even be a
feasible duration for detecting a reduction in cancer incidence). The
high incidence of new lesions in head and neck cancer patients was
cited above. Superficial bladder cancer patients are appropriate
subjects for chemoprevention studies because the recurrence rate is
50% within 6–12 months (37)
and 60–75% within 2–5
years (38
, 39)
. Similar high rates of recurrence or new
lesions apply to colorectal adenomas (e.g., Ref.
40
). Studies in these settings would appear to be
particularly promising for the validation of surrogate end points,
which may then be suitable for application in cohorts without previous
precancers/cancers.
Germ-line mutations and other genetic and molecular evidence of
susceptibility may also be used to define high-risk cohorts. For
example, subjects with FAP, which is identified by loss of the APC
tumor suppressor gene, develop hundreds to thousands of colorectal
adenomas (41)
. Fabian and colleagues (42)
have described high-risk breast cancer subjects suitable for
chemoprevention studies based on the presence of early biomarkers of
carcinogenesis, including atypical hyperplasia, aneuploidy, and
overexpression of p53 and EGFR, as well as the potential use of these
biomarkers as surrogate end points for breast cancer prevention trials.
Patients scheduled for surgical treatment of precancer or early cancer
provide cohorts for obtaining early evidence of efficacy. Agents are
administered to these patients during the several-week time period
after diagnostic biopsy and before more definitive surgery so that
modulation of biomarkers in the precancer/cancerous, and, if possible,
normal appearing tissue in the target organ can be assessed. The
National Cancer Institute is now using such protocols in Phase I/early
Phase II studies in breast and prostate cancer (2
, 3)
.
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Modulation of Surrogate End Points that Provides Evidence for
Chemoprevention
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Important issues in using surrogate end points in chemoprevention
studies are determining when a less-than-complete phenotypic response
of a precancerous lesion constitutes prevention and the role of
genotypic biomarkers in evaluating this result. A related, subtle
efficacy issue is distinguishing chemoprevention from regression of
existing disease. We believe that establishing chemopreventive efficacy
solely on the basis of phenotypic regression would in most cases
require near complete regression of existing lesions. Similarly,
phenotypic chemoprevention would in most cases only be demonstrated
rigorously by near complete inhibition of new lesions. With less than
this level of efficacy, it is possible that the remaining lesions are
those that will continue to progress to cancer.
However, if a posttreatment lesional genotype showed decreased
incidence of cancer-related changes (either in specific genes or in
more general measures of genomic instability) compared with the
baseline, we feel that a significantly less than near complete
regression could be considered prevention. Also, less than complete
inhibition of phenotypic progression could establish chemopreventive
efficacy if no lesions in the active intervention group exhibited a
genotype that had progressed beyond those of the baseline lesions or
placebo controls. This outcome would be further supported if the
genotype of normal appearing tissue in the target also was stable or
showed reduced cancer-related changes compared with the baseline. These
concepts are summarized by the four hypothetical examples in Table 1
. Each represents the results of using a potential chemopreventive agent
to treat patients with precancer or with previous precancer or cancer.
It is assumed that the phenotypic inhibition or regression observed is
statistically significant and that previous studies have determined
important cancer-related genotypic changes for this target.
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Table 1 Evaluation of chemopreventive efficacy: phenotype vs.genotype ( from baseline, treatment group vs.
placebo controls)a
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Cases 1 and 2 are based on prevention of colorectal adenomas as the
primary end point. In both examples, patients receive baseline
colonoscopies during which all visible adenomas are counted, measured,
and removed. Biopsy samples are taken from polyps and normal appearing
tissue for biomarker analysis. Patients are then randomized to
treatment with a chemopreventive agent or placebo. After treatment, the
patients again receive colonoscopies. Any new polyps are counted,
measured, and excised, and, as at the baseline, biopsy samples are
taken from both the polyps and normal appearing mucosa. In all
patients, samples are taken from the same area of the colorectum at the
baseline and posttreatment, and the biopsy sampling pattern is
representative of the total tissue and is the same at both time points.
In both cases, significantly fewer polyps (e.g., 50% lower
incidence) are found in the treatment group than in the placebo group.
However, the genotypic status of colorectal polyps and tissue in the
treatment groups compared with the placebo groups and with the baseline
differ in the two cases. LOH at markers on chromosomes 5q
[affecting the APC and the mutated in colorectal carcinogenesis (MCC)
genes], 17p (p53 gene), and 18q [deleted in
colorectal carcinoma (DCC) gene], along with ras mutations,
have been shown to increase with progression of colorectal dysplasia
(43)
. In case 1, the percentages of LOH at 5q, 17p,and 18q and of ras mutations are comparable
in the treatment and control groups; also, posttreatment percentages
are comparable to the baseline. Because the relevant genotypic
biomarkers did not show progression, we feel that this study would
provide evidence of chemopreventive efficacy. In case 2, the
percentages of allelic loss at 5q, 17p, and 18q
are significantly higher in polyps from the treatment group than from
the placebo group. These data suggest that the treatment may only have
inhibited less severe dysplasia, which would be less likely to develop
into carcinoma. We would not consider this result a convincing
demonstration of chemopreventive efficacy.
Cases 3 and 4 are based on the genetic progression model for head and
neck cancer described by Sidransky and colleagues (13)
,
showing the correlation of LOH frequencies at ten specific
microsatellite loci and increasing numbers of affected loci to severity
of dysplasia. In both studies, a chemopreventive agent or placebo is
administered to patients with dysplastic lesions in the oral cavity.
These lesions are measured at the baseline and are biopsied along with
normal appearing adjacent tissue. Biopsies of both the dysplastic
lesions and normal appearing tissue are also taken at the end of
treatment. The same rigorous attention to adequate and representative
sampling described for the colorectal adenoma studies is applied to
these assessments. At the end of both studies, significant regression
of the dysplastic lesions is observed. Fewer lesions remain in the
treatment group than in the control group; lesions in the treatment
group are also significantly smaller. LOH at the ten important loci is
analyzed in cells from the lesions and nearby, normal appearing tissue.
In case 3, LOH frequency distribution is similar in the dysplasia from
the treated and control groups. Also, LOH frequency distributions in
normal appearing mucosa are comparable in all groups. Hence, assuming
that the ten loci analyzed are informative biomarkers, no genetic
changes are seen that would suggest that the lesions in the treated
patients are likely to progress faster than those in controls. We
expect that such a result provides supporting evidence that the reduced
incidence of dysplasia is a true chemopreventive effect. Case 4 is the
same hypothetical study with negative results. In this case the
phenotypic regression is misleading. Although the number of lesions is
fewer, the average frequency of LOH is significantly higher in lesions
from the treated patients than the controls, indicating that the
lesions in the treated patients are likely to progress more quickly
than those in the controls and that the chemopreventive intervention is
only preventing lesions less likely to progress. It should be noted
that the reliability of such genotypic assessments would be determined
by knowledge of the important genetic lesions.
Remarkable advances in genome sequencing and functional genomics and
proteomics are being made that will soon produce genetic progression
models that are increasingly more comprehensive and informative; these
capabilities have been reviewed by Brown and Botstein
(44)
. Besides the research to develop genetic progression
models described above, the sequencing and functional analysis efforts
of the Cancer Genome Anatomy Project are a major contribution to this
knowledge. We envision two types of genotypic analyses that, after
extensive sampling, methods, and statistical standardization, could be
used as end points for chemoprevention studies. The first is monitoring
prespecified sets of genetic lesions that are strongly associated with
neoplastic progression and is analogous to and an extension of the LOH
analysis cited in the hypothetical colorectal and oral cavity examples.
Many academic researchers and commercial sources are now designing and
producing gene chips (e.g., cDNA microarrays) that can be
used to measure specific cancer-related genotypic changes. The second
type of method is also based on microarray analysis, but is a more
generalized comparison of gene expression in posttreatment and baseline
lesions. One such method, cluster analysis of genome-wide expression
patterns has been described by Eisen et al.
(45)
.
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Precedents for Surrogate Endpoints in Development of Drugs for
Disease Prevention—Lipid Lowering Drugs in Prevention of
Cardiovascular Disease
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To date, the best characterized surrogate end points in drug
development have been for AIDS (46
, 47)
and cardiovascular
drugs (reviewed in Refs. 48
and 49
). Because
of the long time required for disease development, the multiple paths
by which the disease progresses, and the chronic administration of
preventive drugs, the course of cardiovascular disease closely
parallels carcinogenesis. In the cardiovascular setting, a prominent
surrogate end point is cholesterol level, which is a validated
predictor of CHD (50)
. Modulation of cholesterol levels
has been used to gain marketing approval for 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors such as lovastatin (51
, 52)
, simvastatin, pravastatin (53
, 54)
, and
gemfibrozil (55)
. 3-Hydroxy-3-methylglutaryl coenzyme A
reductase catalyzes a critical step in cholesterol biosynthesis, the
formation of mevalonate. Gould et al. (56)
have
carried out a meta-analysis of 35 randomized clinical trials that
essentially summarizes the evidence supporting cholesterol lowering as
a surrogate end point for CHD. The trials reviewed (all primary or
secondary intervention studies of >2 years’ duration) include single
drug studies such as the Helsinki Heart Study of gemfibrozil
(55)
, as well as diet (57
, 58)
, surgical
(59)
, and multifactorial interventions (60
, 61)
. The results show that cholesterol lowering is correlated to
CHD, non-CHD, and overall mortality. Specifically, it was found that
for every 10% lowering of cholesterol, CHD mortality was reduced by
13% (P < 0.002) and total mortality by 10%
(P < 0.03), whereas no effect was found on non-CHD
mortality. A caveat applies here as to all studies with
biomarkers—the relationship between lower CHD and lower cholesterol is
the result of averaging individual responses. There are many
individuals for whom the correlation is not seen. In other words, when
the parameter evaluated is one of several in the multifactorial disease
process, other variables along with secondary or indirect processes
contributing to the disease (in the case of heart disease, examples are
smoking history and diabetes mellitus) or protecting the subject may
confound interpretation. Also, the proportion of disease attributable
to a specific biomarker may vary according to this variety of
intervening variables characteristic of any particular population.
The research on cholesterol lowering and other surrogate end points for
cardiovascular disease provides a model for studies needed to validate
surrogate end points—both in the relationship of the surrogate end
point to the ultimate disease and in its ability to predict activity of
a given drug on that disease. Table 2
shows data that validates cholesterol lowering as a surrogate end point
for CHD; analogous data might be applied to a surrogate for cancer
incidence. For example, it has been well-established that the presence
of colorectal adenomas increases the risk for colorectal cancer
(29
, 40)
. It has been estimated that 2–5% of all
colorectal adenomas progress to adenocarcinomas if not removed or
treated (the rate increases with size and severity of dysplasia; up to
22% of tubule-villus colorectal adenomas progress; Refs.
10
, 11
, and 29
). These data
alone or combined with results of studies showing cancer risk reduction
on polyp removal could possibly be used to validate adenomas as a
surrogate end point for cancer incidence and demonstrate that a drug
that prevents polyps has cancer chemopreventive efficacy. As will be
discussed below, the cardiovascular and AIDS drugs also demonstrate
problems associated with drug evaluations based on surrogate end
points.
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Table 2 Validation of surrogate end points (relationship of surrogate end point
to disease, effect of drug intervention on surrogate end point, effect
of drug intervention on disease): cholesterol lowering and CHD
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Issues in Using Surrogate End Points
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There are several philosophical and practical issues that arise in
applying surrogate end points to the evaluation of drug efficacy and,
specifically, chemopreventive efficacy. Temple (49
, 62)
previously addressed many of these issues in the context of
cardiovascular drug development.
Impact of Surrogate End Point Modulation on Cancer
Incidence/Mortality.
One issue is the degree of clinical benefit that should be derived from
efficacy against the surrogate end point (48
, 63
, 64)
. As
described by Blue and Colburn (63)
, surrogate end points
fall onto a continuum from showing no particular clinical benefit but
only correlation to the target disease end point (e.g., drug
effect markers), through demonstrating a clinical benefit that is not a
direct effect on the target disease (e.g.,
immunostimulation), to demonstrating a clinical benefit that is
directly related to the target disease (e.g., inhibiting
colorectal adenomas). Initially, the criteria we describe for selecting
surrogate end points support drugs with a clinical benefit directly
related to cancer incidence prevention. However, as more data are
developed on the role of general genotypic and specific molecular
changes in carcinogenesis and with careful correlative studies, the
effects on surrogate end points with antecedent impact on clinical
outcome may also support chemopreventive drug efficacy.
Quality of Life.
Chemopreventive drugs may ultimately be given to asymptomatic
populations for years or decades. Therefore, minimal toxicity is
essential. Determining standards in terms of allowable type and
frequency of side effects and impact on quality of life will be
critical issues as chemopreventive drugs are introduced.
Adverse Effects May Not Be Observed in Short-Term Surrogate End
Point Studies.
It is also possible that life-threatening toxicities compromising the
long term use of drug would not be detected within the time frame of
surrogate end point-based efficacy trials. In the meta-analysis of
cholesterol-lowering interventions cited above, the investigators found
that despite their cholesterol-lowering efficacy, fibrates such as
gemfibrozil were associated with increased non-CHD mortality by 30%
(P < 0.01) and total mortality by 17%
(P < 0.01) on long-term administration
(56)
. A different but dramatic example of unanticipated
late toxicity is provided by the results of the Cardiac Arrhythmia
Suppression Trial (48)
. This randomized,
placebo-controlled trial of three type 1C antiarrhythmics was designed
to evaluate mortality reduction in patients experiencing 10 VPBs/h and
few or no symptoms following a recent myocardial infarction. Entry in
the trial required that the patients respond to antiarrhythmic therapy
as measured by at least a 70% reduction in VPBs as a surrogate for
arrhythmia. This trial was stopped when it was found that drug
treatment was associated with increased mortality or cardiac arrest
despite lowering VPBs (65
, 66)
.
|
Potential Surrogate End Points at Major Cancer Target Organs
|
|---|
We have previously described our criteria for selecting surrogate
end points for clinical chemoprevention studies (see Table 3
and Ref. 3
). There are now >40 clinical studies sponsored
by our National Cancer Institute, Division of Cancer Prevention
chemoprevention program, which are in progress and involve the
evaluation of potential surrogate end points. These are primarily Phase
II trials in 10 major cancer target sites (prostate, breast, colon,
lung, head and neck, bladder, cervix, esophagus, skin, and liver).
Table 4
surveys the cohorts and surrogate end points presently under evaluation
in these studies. Usually, the primary end point is a histological
modulation of a precancer. This modulation may be evaluated by both
classical pathological techniques and by morphometry and cytophotometry
using computer-assisted image analysis.
View this table:
[in this window]
[in a new window]
|
Table 4 Potential surrogate end points at major cancer target sites being
evaluated in Phase II/III studies sponsored or funded by the National
Cancer Institute, Division of Cancer
Preventiona
|
|
Additionally, we give high priority to biomarkers measuring specific
and general genotypic changes correlating to the carcinogenesis
progression model for the targeted cancer. Progressive genomic
instability as measured by LOH or amplification at specific
microsatellite loci was used by Sidransky and colleagues (Ref.
13
; see also references to other aspects of this study
elsewhere in this paper) to characterize head and neck carcinogenesis.
These biomarkers are potential surrogate end points in head and neck
and may also prove useful in other tissues where microsatellite
instability is a predominant feature of carcinogenesis—for example, in
hereditary non-polyposis colorectal cancer-associated and some sporadic
colorectal cancers (67
, 68)
. For all of the biomarkers, we
feel that it is highly desirable to measure modulation quantitatively
as the difference () between the biomarker value at the end of the
treatment and the baseline. The change in the surrogate end point
measures on chemopreventive treatment should also be compared with that
seen in appropriate controls. Thus, we also believe that baseline
biopsies or other tissue measurements are essential.
Although the precancer histological phenotype with the accompanying
genotypic changes determined to be relevant in the genetic progression
models serves as our primary focus for initially proving
chemopreventive efficacy, other potential surrogate end points that may
occur earlier in carcinogenesis are being analyzed in these precancers
and in nearby normal appearing tissues. These biomarkers include
proliferation and differentiation indices, specific gene and general
chromosome damage, cell growth regulatory molecules, and biochemical
activities (e.g., enzyme inhibition). Although these
biomarker studies focus on characterizing effects in the cancer target
tissue, serum biomarkers may also be monitored (e.g., PSA)
because of their accessibility. In some cases, biomarkers specifically
related to the postulated chemopreventive drug effect of the test agent
are measured. Although such biomarkers do not necessarily demonstrate a
chemopreventive effect, they are useful in determining that a
biologically active dose of the agent was present and in evaluating the
chemopreventive mechanisms that are operating. For example, in studies
with the ODC inhibitor 2-difluoromethylornithine, tissue and serum
polyamine levels are determined, and in studies with steroid aromatase
inhibitors, tissue and serum estrogen levels are analyzed. These
initial studies with drug effect biomarkers may expand the list of
validated surrogate end points for future use.
A potential set of criteria for establishing chemoprevention in terms
of the histological phenotypic and genotypic changes observed was
described above. In Table 5
, this description is extended to define the specific phenotypic and
genotypic results from chemoprevention trials in the major cancer
targets that we would consider definitive evidence of efficacy. Those
results, which would not likely be considered sufficient to be
definitive, but would provide significant supporting evidence, are also
described. In the future, it is likely that many biomarkers that are
now being investigated will be demonstrated to be predictive of cancer
incidence in clinical, or in the nearer term, in animal studies. The
potential role of such data are also cited in Table 5
. Note that the
focus in these tables is optimal results. In some cases, the trial
designs adequate to provide such results have not yet been fully
defined.
|
Clinical Benefit Based on Surrogate End Points (Not Cancer
Prevention)
|
|---|
There are several situations in which the treatment of
precancerous lesions would appear to provide clinical benefit,
notwithstanding the potential for cancer prevention. These benefits
include reduced morbidity, enhanced quality of life, delayed surgery,
and increased intervals for surveillance requiring invasive procedures.
Prevention of Precancers in Subjects at High Risk Associated with
Genetic Predisposition (e.g., Prevention of Colorectal
Adenomas in Patients with FAP).
FAP is characterized by germ-line mutations in the APC tumor suppressor
gene. Usually starting when they are teenagers, patients with FAP
develop hundreds of colorectal adenomatous polyps. If untreated, FAP
patients will almost certainly develop colorectal cancer by age 50
(69)
; they are also at risk for developing other lesions,
particularly duodenal polyps and cancers. Once adenomas begin to
appear, these patients are monitored by periodic colonoscopy (at
6-month intervals), removal of existing polyps, and cancer
screening. When the polyp burden becomes unmanageable, most patients
have partial or total colectomies. Thereafter, they continue to be
monitored. Agents that prevent or slow the progression of the adenomas
could benefit these patients by delaying the need for colectomy and
increasing the intervals between surveillance colonoscopies and cancer
screenings.
Prevention of Precancers for Which Organ Removal or Other Major
Surgery with High Morbidity Is Standard of Care (e.g.,
Barrett’s Esophagus, Superficial Bladder Cancers).
Present treatment for Barrett’s esophagus, a precursor of esophageal
cancer, may involve partial or total esophagectomy (70)
.
Because of the high rate of their recurrence and potential for
progression, treatment for superficial bladder cancers includes
periodic surveillance (every 3 months) and removal of new lesions and
may include cystectomy (71)
. In both diseases, treatment
has profound detrimental effects on quality of life. Both are examples
of situations in which preventive agents could provide a clinical
benefit by reducing the need for these surgeries.
Prevention of Precancers in Patients at Risk for Recurrence
(e.g., Sporadic Colorectal Adenomas).
New adenomas occur within 1–3 years after resection in 30% of
patients with sporadic colorectal adenomas or cancers
(30)
. These patients are screened routinely at 1–5 year
intervals, receiving colonoscopies with removal of new lesions.
Preventive treatment could potentially provide a benefit by increasing
the screening interval, thereby decreasing associated morbidity and
lowering health care costs.
|
Potential Application of Surrogate Endpoints in Gaining Marketing
Approval for Chemopreventive Drugs
|
|---|
This paper focuses on what we believe are the critical scientific
aspects of developing surrogate end points to characterize cancer
chemopreventive efficacy. We anticipate that the material presented
will serve as a basis for designing clinical development strategies to
gain marketing approval for chemopreventive drugs. As we’ve discussed
here and previously (1
, 2
, 5
, 6)
, the multipath,
multifocal nature of carcinogenesis, as well as the very small
percentage of early lesions that progress to cancers and the long time
required for cancers to develop, suggests that, initially, the most
successful strategies will use well-defined precancers (IEN) as the
surrogate end points for cancer incidence. Despite their close temporal
and histological association with cancers, only a relatively small
percentage of IEN will progress. Therefore, the determination of
chemopreventive efficacy will rely on the assurance that the lesions
most likely to progress are inhibited (e.g., the genotype of
any posttreatment lesions is equivalent to or indicative of less
progression than baseline lesions). The phenotypic changes seen in IEN
during short-term studies are likely to be subtle; therefore,
quantitative measurements such as computer-assisted image analysis are
desirable; similarly, the evaluation of genotypic changes requires
sensitive, quantitative analysis of gene expression such as that
afforded by the various DNA microarray techniques. We also recognize
that standardization is critical, including determining adequate
sampling, handling of nonrelated biopsy effects, and timing of
biomarker assessment relative to normal biological cycles
(e.g., timing for measurement of breast cell proliferation
during the menstrual cycle). The gold standard for validating surrogate
end points is comparison with cancer incidence reduction. The resources
(e.g., time and number of subjects) required to successfully
complete such validation are enormous. We believe that continued
discussion and research on alternative strategies among the National
Cancer Institute, the Food and Drug Administration, industry, and
academia are needed to ensure that surrogate end point-based
chemoprevention indications are feasible. Demonstration of clinical
benefit on preventing IEN (as described above for FAP, sporadic
colorectal adenomas, superficial bladder cancers, and Barrett’s
esophagus) is one possible strategy. A second approach would follow the
accelerated approval pathway for gaining marketing approval as defined
in 21 Code of Federal Regulations 314.500. This
mechanism allows early marketing approval based on scientifically
strongly supported surrogate end points for disease incidence in the
setting of life-threatening disease such as cancer.
|
Footnotes
|
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom requests for reprints should be
addressed, at the National Cancer Institute, Division of Cancer
Prevention, EPN 201, MSC 7322, 9000 Rockville Pike,
Bethesda, MD 20892-7322 
2 The abbreviations used are: IEN, intraepithelial
neoplasia; APC, adenomatous polyposis coli; CHD, coronary heart
disease; CIN, cervical IEN; DCIS, ductal carcinoma in
situ; EGFR, epidermal growth factor receptor; FAP, familial
adenomatous polyposis; LOH, loss of heterozygosity; ODC, ornithine
decarboxylase; PCNA, proliferating cell nuclear antigen; PIN, prostatic
IEN; PSA, prostate-specific antigen; TGF, transforming growth factor;
VPB, ventricular premature beat.
Received 6/ 3/99;
revised 10/18/99;
accepted 11/ 1/99.
|
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Abstract
Introduction
