mesothelioma cancer

Amid this chronicle of success was the knowledge that numerous, presumed
harmless viruses had been recovered from the primary monkey kidney cell cultures
used for the efficient growth of polio virus needed for mass vaccine production.
However, in 1961 Eddy and col¬leagues (2) conducted the first investigations
demonstrating the devel¬opment of tumors in 71% of newborn hamsters injected
with polio vaccine culture extracts. The tumors were identified as
mesotheliomas, ependymomas, osteogenic sarcomas, and lymphomas. Multiple other
investigators confirmed these initial findings (3–6). The oncogenic property of
the cell extract was later attributed to a double-stranded DNA virus designated
simian virus 40 (SV40), an indigenous pathogen in the African green monkey (7).
Diamandopoulos (3) provided com-pelling evidence of the role of the virus by
demonstrating that animals inoculated with anti-SV40 serum demonstrated no tumor
growth. Important independent studies by Koprowski et al (8) showed that, in
fact, cultured human cells underwent transformation with SV40, raising concerns
about the possible consequences of human exposure to this virus.

Simian virus 40 and the closely related human polyomaviruses BK and Jamestown
Canyon (JC) produce subclinical infection in immuno-

No immediate, unexpected short-term consequences to polio vaccina¬tion were
reported in a series of field trials involving live poliovirus. Specifically,
newborn and infant postvaccination studies were unre¬markable, and there were no
reports of adverse fetal outcomes follow¬ing immunization of pregnant women
(11). It appeared that exposure to SV40 might be innocuous to humans; however,
the tumorigenic effect of the virus in animal models was worrisome. Concerns
escalated with additional clinical studies in humans that demonstrated the
ability of the virus to replicate, generate subclinical infection, and spread
through oral and respiratory routes, suggesting that transmis¬sion from polio
vaccines to innumerable nonvaccinated, nonimmune human contacts may be possible
(12,13). Increasing questions spurred some early epidemiologic investigations to
more carefully examine this potential threat to public health.

In 1963 Fraumeni and colleagues (14) conducted a study to identify changes in
cancer mortality within 4 years of the initiation of the mass-immunization
program. Annual mortality rates among persons less than 25 years of age from
1950 to 1959 were examined. Using published data from the Office of Vital
Statistics, the trends over the decade in mortality due to leukemia, selected
sites of cancer (brain, kidney, and connective tissue) and all cancers combined
were examined. Only minor fluctuations were detected in the age-specific
mortality rates from all cancers combined among persons less than 25 years old
from 1955 to 1959; however, the leukemia mortality rates increased from 3.5 to
3.8 per 100,000 children ages 5 to 9, and from 2.2 to 2.5 per 100,000 in
children ages 10 to 14. No significant changes in mortality for brain, kidney,
or connective tissue tumors were noted. Given the very short latency period
since vaccination (<5 years), it was unlikely that differ¬ences in patterns of
mortality would occur.

In a second analysis these investigators included only children who were 6 to 8
years old in 1955, since it was this birth cohort that was eli-

gible for vaccination at the start of the program. In May and June of that year
only a small number of lots of vaccine were distributed to each state, and
specific records regarding the distribution and contam¬ination of those lots
were available. Accessing that data, Fraumeni et al classified the states
according to three levels of estimated per capita dose of contaminated vaccine.
A cohort analysis was conducted to compare cancer-specific mortality over the
10-year period. Cause-specific mortality data were available from death
certificates filed with National Vital Statistics Division of the U.S. Public
Health Service (USPHS); the population at risk was defined from age- and
state-specific census data available for 1950 and 1960. A comparison of cancer
mortality rates among states grouped according to the distri¬bution of SV40
contaminated vaccine showed no change in patterns. Rates of mortality were, in
fact, higher among states receiving contam¬inated vaccine as compared to those
not receiving contaminated vaccine; however, this increase was noted before as
well as after the introduction of the vaccination program. The investigators
concluded that there was no evidence to suggest an increase in cancer mortality
related to SV40-contaminated vaccine distribution. In addition, the authors
reported that an increase in leukemia rates among 6- to 8-year-olds receiving
vaccine free of SV40 in 1956 occurred, suggesting that the reported increase in
mortality rate due to leukemia among those less than 25 years of age was
independent of contaminated vaccine dis¬tribution. To check for the presence of
another leukemia-associated agent in the vaccine, vaccine samples were sent to
the Laboratory of Viral Oncology, National Cancer Institute, and used for
inoculation of mice. After 10 months of observation, no laboratory animals
displayed any problems. The authors admit that their negative results are not
sur¬prising. They point out that the SV40 exposure in previous animal studies
was of a far higher viral titer than that related to the vaccine; that the
laboratory animals were exposed as newborns, whereas in the initial vaccination
program only school-age children were exposed; and that there was very short
follow-up in this study. The investigators emphasized the desirability of
long-term studies with attention to those vaccinated in infancy. Continued
surveillance was recommended. In addition, it is important to note that this was
an ecologic study, i.e., no person-specific observations were included in the
analysis, thus no information is available regarding the vaccination status of
children who actually died of cancer.

In an attempt to more specifically examine the risk of cancer among individuals
known to have received contaminated vaccine as new-borns, Fraumeni et al (15)
conducted an analysis of 1077 newborns who were vaccinated between 1960 and 1962
at a single medical facility for the purposes of assessing the induction of
active immunity to polio with the Sabin vaccine in the presence of maternal
antibodies. Within a few days of birth 925 infants in five treatment groups
received atten¬uated oral polio vaccine; the sixth group was administered
intramus¬cular injections of inactivated poliovirus vaccine. Independent of the
study purpose, the vaccines administered to each group had differing titers of
SV40. Later in infancy, booster injections were given to all chil-

dren, which presumably also contained SV40. Beginning in 1964 Fraumeni et al
attempted to follow up this mostly black, highly mobile 1960 birth cohort. With
86% follow-up at 8 years, the investigators documented 11 deaths. This mortality
rate was similar to that expected in this population, and no difference in risk
of death among vaccine groups was observed. Of note, no deaths due to cancer
were recorded. The authors concluded that there was no effect on mortality noted
among newborns ingesting SV40 at a dose, which is carcinogenic in hamsters when
administered parenterally. This study used the Sabin vaccine, whereas reported
tumor growth in animals had been observed with administration of the Salk
vaccine. Follow-up was limited to 8 years, although surveillance of the study
sample was to be maintained.

Mortimer and coworkers (16) followed the original Fraumeni cohort of 1073
children born in the United States between 1960 and 1962 who received either
oral or inactivated vaccine within 3 days of birth. In 1977 to 1979 15 children
had died, but no deaths were due to cancer; one cancer death was expected. One
girl developed a salivary tumor of “low degree of malignancy.” No recurrence
occurred after surgical excision. With 87% follow-up for 19 years and the
occurrence of only one cancer, the study concluded no carcinogenic effect of
SV40 in humans. Given the difficulties of continuing follow-up, termination of
surveillance in this cohort was planned. However, due to the identifi¬cation of
SV40 DNA fragments in some tumors from other studies, this cohort follow-up was
reactivated. An update of mortality with more than 35 years of cohort follow-up
was reported in 2001 by Carroll-Pankhurst et al (17). Forty-four deaths were
identified and for 41 of these, death certificates were obtained. Four of the
deaths were due to cancer, two due to testicular tumors, and two to leukemia.
All four of the deceased subjects had received live, attenuated vaccine as
new-borns. The investigators noted that the increase in testicular cancer
[relative risk (RR) = 37.9; p = .002] was particularly interesting since SV40
antigens have been previously detected in seminal fluid (18). The occurrence of
death due to leukemia resulted in an RR of 2.62 (p = .16); it is notable that
hematologic malignancies developed in some of the original laboratory animals
injected with SV40. None of the other suspect cancers, i.e., brain, osteogenic
sarcoma, or mesotheliomas, were documented to have occurred in this cohort.
Given that death rates in this cohort were similar to those expected in similar
age, sex, and ethnic groups, there was no suggestion that mortality was
underreported. While the follow-up of these subjects exceeded 35 years’
duration, the number of expected malignancies for this small cohort was only
3.16, resulting in inadequate power. In fact, the results of this study
demon¬strate that a threefold increase in cancer risk among persons exposed to
SV40-contaminated vaccine as newborns is not incompatible with the reported
findings of this study.

In a review by Shah and Nathanson (19) published in 1976, the authors add to the
evidence related to the carcinogenic effect of SV40 by summarizing an
unpublished presentation by Hammond (20) in 1966, who reported on 700,000
subjects, ages 32 to 91, who participated in an American Cancer Society study in
which they were questioned

about their history of polio vaccination. In the next 2.5 years 24,000 of these
individuals were documented as dead (1962–64). About 25% of the group reported
having received one or more doses of vaccine, and these subjects were compared
to those who reportedly had received no vaccine. No difference in incidence or
type of cancer was detected. Shah and Nathanson question the sensitivity of this
investigation given the age of the sample. However, they conclude, “The large
numbers do provide a fair degree of assurance that SV40 injections into adults
produces no major untoward effect within 5–10 years.” Related to the question of
cancer risk associated with administration of SV40-contaminated vaccine, it
would be unlikely to expect that a car¬cinogenic effect would be clinically
apparent within such a short follow-up. In addition, the rate of polio
vaccination among older persons, i.e., those at greatest risk of the occurrence
of cancer or death, was likely to be low. Therefore, the detection of a
difference in these rates associated with vaccination would be unexpected.

Heinonen and colleagues (21) conducted a study to examine the risk of malignancy
among offspring of women immunized against poliomyelitis and influenza or
experiencing viral infections during pregnancy. These data were drawn from a
prospective, collaborative study of etiologic factors in neurologic and sensory
disorders in infancy and childhood. There were 58,807 eligible pregnancies
included in the original study sample drawn from 12 U.S. hospitals from 1959 to
1965. After exclusion criteria for this study were considered, 50,897 pregnant
women remained in the sample. During the prenatal period, monthly assessments of
immunizations, medications, viral infections, and x-ray exposure were made.
After delivery, infants were examined three times in the first year of life.
Cancer incidence was available during the first year; only mortality and autopsy
information was available in years 2 through 4. Prior to their fourth birthday,
24 children developed malig¬nancy; eight were diagnosed with neural tumors,
eight developed leukemia, six had renal tumors, one infant had a granulosa cell
tumor, and one infant had a hepatoblastoma. In 14 of the 24 malignancies (seven
of eight neural tumors), the mothers had received the polio vaccine (7.6 versus
3.1 per 10,000; p < .05), yielding an RR of 2.4. The difference in rates of
neural tumors among infants whose mothers were vaccinated as compared to those
whose mothers did not receive the polio vaccine during pregnancy was
statistically significant (p = .01). Risk of cancer appeared to be higher when
vaccination occurred in the early months of pregnancy. No malignancies were
documented among the 3056 infants whose mothers received oral polio vaccine
during pregnancy. Race, birth order, mean maternal age, frequency of mater¬nal
exposure to abdominal or pelvic radiation, and drug exposures were similar
between the two groups. These data suggest that injec¬tions of killed polio
vaccine in pregnant mothers were associated with malignancies and tumors of
neural origin, in particular, in offspring born between 1959 and 1966. This
study provides no information regarding vaccination of children after birth. The
authors correctly emphasized that the reported findings may have occurred by
chance or may have been due to confounding. While the authors concluded

Although the U.S. immunization program had the greatest scope, many other
countries had launched polio vaccination programs; several of these were
initiated using U.S.-produced, i.e., contaminated, vaccine. Between 1958 and
1967, Innis (22) studied 816 Australian hospitalized children with malignancy
and the same number of hospital controls matched for age and gender. Although
the rates of other routine child¬hood immunizations were similar between the two
groups, a signifi¬cantly greater number of cases over 1 year of age (n = 618;
87.5%) than controls (n = 569; 80.6%) had been vaccinated for poliomyelitis,
sug¬gesting an association between malignancy and polio vaccine admin¬istration
(odds ratio = 1.69, p < .001). The investigator raised questions regarding the
comparability of the controls to the cases, given that there was a higher
proportion of city dwellers among the controls (but this should bias in favor of
the cases). The authors suggest continued sur¬veillance based on these positive
findings; however, no additional find¬ings have appeared in the literature.

Olin and Giesecke (23) examined cancer incidence rates in Sweden where
vaccination of preschool and school-age children began in 1957 using
U.S.-produced vaccine. Approximately 70% of children born between 1946 and 1949
and 59% of those born between 1950 and 1953 were vaccinated with potentially
contaminated vaccine. Age-adjusted incidence rates of cancer were reported for
5-year intervals from 1960 through 1990. Although age-standardized incidence
rates among boys had increased for brain cancers, but not ependymomas, and
mesothe-liomas, no association with polio vaccination in children ages 4 to 11
was detected.

Using the National Cancer Registry of the German Democratic Republic, Geissler
(24) conducted a large study with significantly longer follow-up than those
previously described. The author com¬pared cancer rates among the 885,783
children born between 1959 and 1961, 86% of whom received presumably
contaminated Sabin live vaccine beginning in 1960, and 891,321 persons born
between 1962 and 1964, most of whom were inoculated with vaccine free of SV40.
With 22 years of follow-up, these researchers reported a cancer incidence of
28.7/10,000 among those receiving contaminated vaccine as compared to
30.1/10,000 among those receiving SV40-free vaccine. These inves-

With new molecular technologies, the early 1990s brought a growing body of
laboratory studies reporting the detection of SV40 DNA in mesotheliomas as well
as other types of tumors. Although not all studies supported the association
between SV40 and cancer, mounting evidence stimulated additional epidemiologic
investigations. With the passage of 40 years since the polio vaccination program
was initiated in the United States, and the maturation of a population-based
cancer registry in the United States, the time was ripe to reassess the
available data using an epidemiologic approach.

The Surveillance, Epidemiology, and End Results (SEER) Program provides
population-based, tumor-specific data on all histologically proven cancers
occurring in selected geographic sites in the United States. The sample includes
approximately 12% of the entire U.S. pop¬ulation and reflects the general
characteristics of U.S. residents. All reportable diagnoses of invasive cancer
occurring each year since 1973 among residents of the coverage area are included
in this database. The consistency, scope, and quality of the SEER system provide
an excel¬lent tool for comparing cancer incidence in the United States from
1973. Overinclusion of some minorities and exclusion of many geographic areas,
however, may affect type-specific cancer rates depending on the genetic,
personal, and environmental risk factors specific to each type.

Strickler and colleagues (25) conducted an ecologic study to examine trends in
cancer incidence and mortality related to distribution of the polio vaccine in
the United States. These investigators accessed inci¬dence data from SEER and
the Connecticut Cancer Registry as well as U.S. mortality rates. Strickler et al
compared age-specific incidence rates of ependymoma, osteogenic sarcoma, and
mesothelioma in two birth cohorts likely to have received contaminated vaccine
and an unexposed birth cohort. Persons born in 1947 through 1952 composed the
cohort of persons likely to have been exposed to SV40-containing polio vaccine
as children, while a second cohort born between 1956 and 1962 was considered
likely to be exposed during infancy. The un-exposed group was defined as persons
born in 1964 through 1969. Poisson regression was employed to assess whether the
age-specific incidence rates varied according to birth cohort. These
investigators reported no statistically significant increase in cancer incidence
rates among children likely to have received SV40-contaminated polio vaccine
more than 35 years ago. There was also no association reported between brain
cancer mortality and polio vaccination. The authors, therefore, concluded,
“After millions of Americans were parenterally exposed as infants or children,
the absence of a discernible effect in our

study adds to the evidence that no relation exists between exposure to
SV40-contaminated vaccine and the development of cancer.”

As shown in Table 18.1, the SEER database only completely captures tumors
occurring during ages 26 to 41 years, 17 to 31 years, and 9 to 24 years in the
childhood-exposed, infant-exposed, and unexposed cohorts, respectively, as
defined in the study by Strickler et al (25). In fact, for the critical
comparison of the childhood-exposed and unex-posed cohorts, there is literally
not one year of age in which both cohorts are completely represented in the SEER
data. The accuracy of statistical conclusions drawn from mathematical models
generated from data in which the age distribution of subjects within comparison
groups is not overlapping is of serious concern, particularly when the three
cancers of interest are highly correlated with age. The data upon which
Strickler and colleagues’ analysis is based provides inadequate power, and the
statistical techniques employed may not represent an optimal assessment of risk
in these populations. Hypothesis testing should be conducted only in situations
in which the study design allows for comparisons of two comparable samples in
which bias is minimized and power is adequate to appropriately answer the
scien¬tific question.

Fisher and colleagues (26) also examined trends in overall cancer incidence and
the occurrence of the specific tumors linked to SV40 from 1973 to 1993 using the
data from SEER. Increases in age-adjusted inci¬dence rates across the 20 years
were observed for all sites combined (11.5%) even after exclusion of breast and
prostate cancers, which have increased in part due to significant increases in
screening. The incidence also increased over time for ependymomas/choroids
plexus tumors (25%), other brain tumors (23%), other bone tumors (22.9%), and
mesotheliomas (90%). Rates of osteosarcoma over the 20 years remained relatively
stable with an increase of only 2.4%. A multitude of host and environmental
factors may account for these increases, as well as period-specific changes in
cancer diagnosis, disease classifica¬tion, and cancer reporting policies.

Although the incidence rates of ependymoma/choroids plexus tumors, osteogenic
sarcoma, other bone tumors, and mesotheliomas appear higher among the exposed
group, the numbers of cases are very small, resulting in extremely limited power
to detect a difference in rates if such a difference does exist. Also of
importance, a persistent problem inherent in the use of birth cohorts for cancer
epidemiologic studies is the period effect of improved reporting of cancer
events, increased screening, and more sensitive diagnosis. In this study the
period effect may artificially inflate the incidence rates in the unex-posed
cohort, thereby biasing the risk ratio toward unity. Table 18.3 pre¬sents an
adjusted relative risk for each tumor type, which accounts for the 13% increase
in overall cancer rates in this specific age group over the 20-year period.
These adjusted rates suggest that the risk of ependy-moma, osteogenic sarcoma,
and mesothelioma in the cohort potentially exposed to contaminated vaccine may
be increased as much as 37%, 26%, and 220%, respectively. Similarly, any
confirmed increases in inci¬dence within the exposed cohort may be due to
innumerable factors other than SV40. Therefore, based on this analysis no
definitive con¬clusions can be drawn. The descriptive data suggest that while
the attributable risk of SV40 is not likely to be large, further investigation
of this association is warranted. In particular, the increase in mesothe-lioma,
although based on extremely small numbers, warrants careful investigation using
methods that ensure adequate power to detect an association if, in fact, one
truly exists.

Most recently, a report examining the trends in U.S. pleural mesothe-lioma
incidence rates following SV40 contamination of early vaccines was released
(27). The most well-established risk factor for mesothe-lioma is asbestos
exposure; however, in 20% to 50% of cases of the disease asbestos exposure is
not documented, particularly among females. This is a particularly interesting
analysis because the authors attempt to carefully examine pleural mesothelioma
incidence trends among adults in various age groups in relation to the
probability of their exposure to potentially contaminated vaccine between 1955
and 1961. These investigators provide estimates of likely exposure by age group
from data drawn from the national household sample surveys that were conducted
annually by the Bureau of the Census. As part of

these surveys, participation in the nationwide inoculation program was
monitored. Since survey data were not available for individuals older than 59
years, the rates for the 60- to 70-year age group were estimated based on the
trend in lower age groups. These estimates of inoculation rates have not been
previously published and provide a good frame¬work for study of this difficult
question. This study reports that the rates of mesothelioma have increased on
average 3.25% (95% CI = 2.41, 4.09) per year from 1975 through 1997 in males
and, similarly, an increase of 2.99% (95% CI = 1.92, 4.08) among females. The
authors point out that mesothelioma overall is a rare cancer and that the public
health impact of such increases is small. This increase, however, is
dis¬appointing given that asbestos exposure has clearly been known for many
years to be a significant factor in the development of mesothe-lioma, and much
has been done to decrease this exposure. It is possi¬ble that it is too early to
see decreasing trends in this disease, but one would anticipate that rates
should be decreasing in the very near future. Price (28) points out that there
was significant growth in the use of asbestos in the 1930s, and peaked in 1950
where it remained until 1970 when it declined precipitously. Workers born after
1929 have experienced fewer years of exposure at peak asbestos consumption
levels. In addition, for those born after 1929, the Occupational Safety and
Health Administration reduced its permissible exposure limit four times since
1971, and the Environmental Protection Agency (EPA) restricted use of asbestos
in building construction and imposed work practices for building demolitions. In
fact, the potential for asbestos exposure is relatively low compared to
historical worker exposures.

Strickler and colleagues (27) point out that while mesothelioma inci¬dence rates
in age groups most heavily exposed to SV40-contaminated polio vaccine remained
stable or decreased from 1975 through 1997, increases in mesothelioma occurred
in the older age groups that had only a small likelihood of receiving
contaminated vaccine. These age group trends are likely to reflect the potential
high exposure to asbestos, which peaked in 1950 when these individuals would
have been in the midst of occupational exposure. One may ask, however, if there
is no effect of SV40 on mesothelioma rates, then why have the rates among the
younger cohorts not dropped more dramatically; perhaps these rates should have
decreased by approximately 70% given the authors, estimate of a 60% to 80%
disease rate attributable to asbestos. Interestingly, although numbers are small
and imprecise, no decreases are noted in younger women, 45 to 65 years of age,
in whom the issue of asbestos exposure is likely to be moot. Given the lack of
actual descriptive data, including number of cases analyzed by age and gender in
this study, it is difficult to interpret. One consideration is very important:
given the relatively low prevalence of mesothelioma in men age >85 in the United
States, even an extremely large increase in the relative risk of mesothelioma
due to SV40 exposure would result in only a small absolute change in rate of
disease. The change in incidence of 3.5/100,000 in 1974 (from Fig. 2B) to that
of 14/100,000 in 1996–1999 represents a fourfold increase in risk among men over
the age of 85. Based on Table 18.1, Strickler et al estimate that a man who is
85 in

1996, and thus would have been 50 years of age in 1961, had more than a 25%
chance of being exposed to SV40 vaccine. Therefore, for every 100,000 men over
the age of 85 in 1996 we can expect that 25,000 of them were exposed. If all
10/100,000 additional cases of mesothelioma occurring in 1996 are attributable
to SV40 exposure, the incidence among SV40-exposed males would be 40/100,000,
representing a greater than 10-fold increase in risk. Given that the data as
presented in this study are potentially consistent with this magnitude of risk
attributable to SV40, this study provides evidence that may be con¬sidered to
support the possibility of an important carcinogenic effect associated with
SV40, as has been suggested by laboratory findings to date.

In a report released by the Institute of Medicine in October 2002, it was
concluded that emerging biologic evidence suggests that SV40 expo¬sure could
lead to cancer in humans under natural conditions (29). “The principal lines of
evidence are based on in vitro and animal studies that demonstrate that SV40
acts in ways consistent with tumorigenesis and that DNA sequences consistent
with SV40 have been detected in several types of human tumors.” The institute
emphasized, however, that the detection of SV40 in tumors does not, by itself,
demonstrate a causal relationship. Simian virus 40 could merely be a passenger
virus. The institute emphasized that, to date, the epidemiologic investigations
were sufficiently flawed such that the evidence was inadequate to draw
conclusions regarding the role of SV40 in the development of human cancer.

Future epidemiologic investigations of the association between SV40 and
malignancy will require access to cancer incidence data from larger, age-matched
samples in order to achieve adequate power for drawing conclusions. Analytic
approaches, either case-control or cohort designs, require feasible methods of
exposure classification in order to overcome the inherent limitations of the
ecologic designs that have been used to date. Recall bias, inaccessibility of
medical records, inadequate personal health documentation, lack of information
regard¬ing viral contamination of vaccine lots, and limited ease of antibody
testing are just some of the obstacles to be overcome in the conduct of these
studies. Studies specific to mesothelioma are greatly disadvan-taged due to the
rarity of the tumors and the resulting imprecision of risk estimates. In
addition, the fact that the disease is extremely rare before the age of 60
suggests that it remains too early to assess the ultimate impact of SV40
exposure on this disease entity.

Although the public health impact of a role of SV40 in the develop¬ment of
mesothelioma would be relatively small, a similar association in more common
cancers such as non-Hodgkin’s lymphoma would represent a significant risk to
public health. Regardless of incidence, however, the greatest progress in the
field of research on SV40 and malignancy has occurred with mesothelioma; studies
examining the

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