[CANCER RESEARCH 49. 5736-5747. October 15. 1989)
Screening Prescription Drugs for Possible Carcinogenicity: Eleven to Fifteen Years
of Follow-up1
Joseph V. Selby,2 Gary D. Friedman, and Bruce H. Fireman
From the Division of Research, Kaiser Permanente Medical Care Program, Oakland, California 94611
ABSTRACT
Using computerized pharmacy records from 1969 to 1973 for a cohort
of 143,574 members of the Kaiser Permanente Medical Care Program,
we have been testing associations of 215 drugs or drug groups with
subsequent incidence of cancer at 56 sites. This paper presents findings
with follow-up through 1984. There were 227 statistically significant (P
< 0.05, two-tailed) associations: 170 positive, 57 negative. Some were
undoubtedly chance findings; others were likely due to confounding by
unmeasured covariables. However, several associations suggested hy
potheses for further studies and/or the need for continued observation.
Most notable among findings not previously reported were associations
of several antibiotics, both oral and topical, with lung cancer. These
associations could not be explained by indications for drug use or by
differences in smoking habits between users and nonusers, and suggest a
possible link between the occurrence of bacterial infections and risk for
cancer.
In general, our results continue to suggest that most medications used
during that period did not affect cancer incidence substantially. However,
for less frequently prescribed medications, our power to detect moderate
increases in cancer risk was quite low.
INTRODUCTION
Extended postmarketing surveillance is essential for detecting
possible carcinogenicity of medications. For chemicals that
promote growth of previously initiated cancer cells, the interval
between exposure and an increase in cancer incidence should
be relatively short. For those that initiate the process in normal
cells, more than 20 years may elapse before an effect on cancer
incidence is noted (1). Detection of such varied effects by
epidemiological means requires observation over a period of
two decades or more following initial exposure.
We have been following a cohort of 143,574 members of
KPMCP1 of Northern California for whom computerized in
formation on prescriptions was obtained during the years 19691973. Beginning with follow-up data through 1976, we have
conducted biennial screening analyses for incidence of cancer
at 54 specific sites and two combinations of sites in persons
exposed to each of 215 drugs or drug groups (see "Appendix
A" for a complete listing of cancer sites and drugs screened).
In previous reports we presented results of screening analyses
with follow-up through 1976 (2) and 1978 (3). This report
updates screening results through 1984.
This study was conceived as a hypothesis-generating investi
gation for detecting unsuspected drug-cancer associations.
Many of the statistically significant associations, both positive
and negative, will be due to chance, given the very large number
of associations considered. However, other associations will
suggest the need for more detailed studies with control for
Received 3/21/89; revised 7/18/89; accepted 7/21/89.
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.
1This work supported by National Cancer Institute Grant R37-CA-19939.
2To whom requests for reprints should be addressed, at the Division of
Research. Kaiser Permanente Medical Care Program. 3451 Piedmont Avenue.
Oakland. CA 94611.
' The abbreviations used are: KPMCP. Kaiser Permanente Medical Center
Care Program; SMR, standardized morbidity ratio: MHC. multiphasic health
checkup.
potential confounders. For many drugs, these represent the
only available data on carcinogenicity in humans. We therefore
consider it important to make this information available to
scientists interested in drug safety and carcinogenesis.
SUBJECTS AND METHODS
Descriptionof Data Sources
Between 1969 and 1973, all prescriptions filled at the outpatient
pharmacy for the San Francisco KPMCP facility were computer-stored.
This facility served an ethnically and economically diverse population,
numbering approximately 120,000 persons at any given time. A total
of 1,307,767 dispensings to 143,574 members were recorded. Mean
age at initial prescription was 31 years; 54% of the cohort was female.
Attrition from KPMCP membership in this cohort, including deaths,
has averaged approximately 4% per year since 1972 with higher attri
tion rates in the first few years of follow-up and among younger cohort
members. As of December 1984, 1,370,000 person-years of follow-up
had been accumulated and 68,695 persons (48% of the original cohort)
remained active KPMCP members.
Occurrence of cancer was ascertained from the California Resource
for Cancer Epidemiology, the tumor registry for the five counties of
the San Francisco Bay Area, and from KPMCP hospital discharge
abstracts. For each tumor identified, the patient's medical record is
reviewed by a trained medical record analyst to verify diagnosis date,
anatomic site and histológica! type. Through 1984, 6,809 incident
cancers have been verified in 6,382 cohort members.
Incident cancers are not detected for persons after they leave the
Health Plan. We have been concerned that risk estimates could be
biased if cancer risk differs between persons remaining in the Health
Plan and those who leave. Since the last report, we examined this
possibility in two ways. We ascertained mortality through 1980 for all
cohort members using the California Automated Mortality System (6).
In all, 9,771 deaths were confirmed, 4,408 due to cancer. Selected drugcancer screenings were conducted on this mortality data and findings
were generally quite similar to those from our incidence data. We also
compared our incident cancer cases through 1982 in a 10% sample of
the cohort with those detected by the California Resource for Cancer
Epidemiology (7). Our surveillance missed 15% of cancers, largely
those that occurred in cohort members who had left KPMCP but
remained in the area. The distribution of missing cancers appeared
comparable to that of those we detected. Because the gains in sensitivity
from adding the overlooked cancers were relatively small (7) and costs
of identifying these cases very high, we have not pursued this additional
case ascertainment for our routine screening analyses.
Identification and Reporting of "Significant" Associations. Details of
our screening analysis methods have been described previously (2-4).
Briefly, the number of new cases of each cancer observed in users of a
drug is compared to the number expected. Expected numbers are
obtained by calculating standard incidence density rates for each cancer
in the entire cohort (by sex and 10-year age interval) and applying these
rates to the age- and sex-specific distribution of follow-up for users of
each drug. For the standard rates, follow-up begins at issuance of any
prescription and continues until diagnosis of the cancer, termination
from the Health Plan, or the end of 1984, whichever occurs first.
Follow-up for a specific drug begins at first prescription of that drug.
A SMR (observed/expected) is calculated to assess the strength of each
drug-cancer association. The departure of the observed from expected
number of cases is then tested for statistical significance assuming that
the observed number follows a Poisson distribution.
The choice of method for reporting findings from these screening
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SCREENING DRUGS FOR CARC1NOGENICITY
analyses is difficult. Presenting results of all 12,040 tests is not practical.
Listing a portion of the results in rank order by P value or SMR may
unduly favor the commonly used drugs and more frequently occurring
cancers (P value ranking) or the less commonly prescribed drugs and
rarer cancers (SMR ranking). A Bayesian approach is unappealing
because little prior information is available for most associations and
the primary' purpose of these analyses is to detect previously unsus
pected relationships.
In our opinion, no alternative offers a clear advantage over the
method we have used previously, which was to present all associations
with P values below 0.05, two tailed. However, as follow-up has contin
ued, the number of associations with P values below this cutoff has
increased to 227, 170 of which were positive. Because of this very large
number of "significant" associations and the preponderance of positive
associations, this report will focus on those positive associations signif
icant at P < 0.01, two-tailed. A list of positive associations with P
values between 0.05 and 0.01 is presented in "Appendix B." We
continue to report the smaller number of negative associations signifi
cant at P < 0.05, two-tailed. As in our previous reports, positive
associations based on only one case are not included.
Control for Possible Confounding of Associations. Many of the ob
served drug-cancer associations are likely the result of confouding.
Cancer-causing behaviors, in particular cigarette smoking, are related
to use of a variety of medications in this cohort (8). In other instances,
the indication for drug use may itself be associated with an increased
cancer risk (e.g., bronchodilators prescribed for chronic obstructive
pulmonary disease leads to an apparent association of these drugs with
lung cancer). A drug may even be prescribed for early symptoms of an
as-yet-undiagnosed cancer. Neither smoking status nor alcohol con
sumption is available for the entire cohort. However, this information
is available for a subset of 56,228 cohort members who also took at
least one MHC (5) at a KPMCP facility between 1964 and 1973. MHC
data have been used to explore possibilities of confounding by smoking
in the association of antibiotics with lung cancer and the inverse
association of bronchodilators with uterine cancer (see below). A second
computerized database containing records of all outpatient diagnoses
at the San Francisco facility for the same years covered by the pharmacy
data was used to establish presumptive indications for drug prescription
in the investigation of the antibiotic-lung cancer and vitamin E-all
cancer associations (see below).
All significant associations are reexamined after removing the 1 year
and 2 years of observation immediately following the first recorded
prescription for the drug to eliminate associations due to drug use for
early symptoms of cancer. Associations are reported in this paper only
if statistical significance persisted (P < 0.05) in the 2-year lag analysis,
or alternatively, if the SMR was not reduced with lag analysis by more
than one-third of its original deviation from 1.0.
RESULTS
Table 1 is an alphabetical listing of drugs with at least one
significant (/>< 0.01) positive association in follow-up through
1984. For each drug, all significant associations are shown
together with findings for all cancers combined. Using a similar
Table 1 Drugs with at least one significant (P < 0.01) positive association, follow-up through 1984
To be included in this table, the significance must persist in the 2-year lag analysis (P < 0.05). or the decrease in SMR (toward 1 0) must be less than one-third of
the original difference from 1.0.
DrugAmpicillinAntacidsAspirin
of
type
users6,7063,05421.15816,072Cancer
siteLungAll
or
casesObserved48168122291761388153750Expected27.3158.73.0201.1141.85.2848.028.3741.5S
of
year
when0.0519841980198419761984
P<
cancerEsophagusAll
cancerLungMouth
codeineBelladonnaNo.
with
floorAll
cancerStomachAll
cancerNumber
Bronchodilators. systemic
5,329
Lung
All cancer
68
247
32.7
218.4
2.08
1.13
<0.002
1976
883
Larynx
All cancer
3
18
0.2
24.0
12.06
0.75
<0.01
1978
372
Nose, ear
All cancer
2
26
0.1
26.7
24.10
0.98
<0.01
1978
Dicyclomine
2,115
Thyroid
All cancer
6
71
1.4
68.5
4.23
1.04
<0.01
1976
Digitalis group
2,466
Lung
All cancer
56
261
34.0
211.5
1.65
1.23
<0.002
<0.002
1976
954
Brain
All cancer
7
61
0.9
52.6
8.18
1.16
<0.002
1976
13.941
Lung
Myeloma
All cancer
86
14
454
59.5
5.1
425.8
1.44
2.72
1.07
<0.002
<0.002
1984
1980
Estrogens
5,965
Uterus
All cancer
117
575
58.0
519.1
2.02
1.11
<0.002
<0.05
1976
1978
Folie acid
248
2
2
30
0.1
0.0
11.5
26.01
46.45
2.60
<0.01
<0.002
<0.002
1980
1982
1978
2
50
233
0.1
25.4
164.5
19.80
1.97
1.42
<0.01
<0.002
<0.002
1976
1976
1978
Cyproheptadine
Dexchlorpheniramine
Diphcnylhydantoin
Erythromycin
Furosemide
maléate
2,302
Oropharynx
Hypophrynx
All cancer
Pharynx, unspecified
Lung
All cancer
Continues
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SCREENING
DRUGS FOR CARCINOGENICITY
Table 1—Continued
casesObserved324219420744413119344332512551621225296814883124Expected0.319.70.12
of
of
type
year
users1,1483532491.88115,2081,6732,1563,6438,6822,850Cancer
siteHodgkinsAll
or
Value<0.01«cO.Ol<0.01<0.01<0.01<0.01<0.01<0.002<
when 0.05198419781980197619821978197
P <
Drug-,
hexachlorideMagaldrateMethyprylonMultivitaminsOral
Benzene
cancerUnspecified
leukemiaAll
cancerLymphosarcomaAll
cancerEsophagusMouth
floorMouth
unspecifiedHypopharynxAll
cancerCervix
contraceptivesPentazocinePentobarbitalPhenylbutazonePolymyxin-neomycin
uteriAll
cancerPharynx
unspecifiedLungAll
cancerLungThyroidAll
cancerRectumAll
cancerBreastAll
(topical)Progestérones
cancerEndocrineAll
& progestagensNo.
cancerNumber
Propantheline
1,600
All cancer
121
90.8
1.33
<0.01
1984
Secobarbital
2,884
Small intestine
All cancer
4
236
0.7
209.7
6.02
1.13
<0.01
1984
1980
3
26
0.3
19.9
11.54
1.30
<0.01
1978
2
155
0.1
127.4
20.54
1.22
<0.01
<0.05
1976
1976
Senna
355
Thyroid
All cancer
Spironolactone
1,475
Pharynx unspecified
All cancer
Sulfathiazole-sulfacetamide-sulfabenzamide-urea
(topical)
1,229
All cancer
64
36.8
1.74
<0.002
1982
Lung
All cancer
212
980
163.9
924.0
1.29
1.06
<0.002
1982
0.3
11.00
1.05
<0.01
1978
Tetracycline
Trihexyphenidyl
22,810
hydrochloride
177
Kidney, urinary
All cancer
3
16
15.3
°SMR, standardized morbidity ratio, or observed cases divided by expected cases.
format, the 57 significant (P < 0.05) negative associations are
presented in Table 2. Because we have conducted three biennial
analyses since the last publication, the follow-up year in which
the association first became statistically significant (at P< 0.05)
is also shown.
DISCUSSION
The number of "significant" associations, both positive and
negative, was well below the 600 that might be naively expected
by chance alone (12,040 hypothesis tests x 0.05). However, for
both positive and negative associations, the highest possible
"significant" P value (at 0.05, two tailed) was generally well
below 0.05 because of the small size of expected values for
many tests and the discrete nature of observed values. We may
estimate the actual number of associations that would be ex
pected to fall below this cutoff by chance in these data by
calculating the average highest possible significant one-tailed P
value (i.e., P < 0.025 for each tail) among the 12,040 tests. For
positive associations, across the 12,040 tests the average highest
possible P value below 0.025 was 0.010, yielding 120 associa
tions. For protective associations, if the expected number of
cases was less than 3.69, even zero observed cases would not be
statistically significant. Through 1984, only 1,873 associations
had an expected number of 3.69 or more. For these, the average
highest possible P value below 0.025 was 0.016, yielding 30
additional associations. Combining these, only 150 of 12,040
tests would be expected to be significant by chance at P < 0.05,
two-tailed. That the observed number, 227, is substantially
higher than this suggests that some associations are due either
to confounding or to a causal relationship.
Comments on Positive Associations (Table 1)
Most positive associations that were noted in follow-up
through 1976 and 1978 have been discussed previously (2, 3)
and are not reconsidered here.
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SCREENING DRUGS FOR CARCINOGENICITY
Table 2 Drugs with at least one significant (P < 0.05) negative association, follow-up through 1984
To be included in this table, the significance must persist in the 2-year lag analysis, or the increase in the SMR (toward 1.0) must be less than one-third of the
original difference from 1.0.
DrugAmphetaminesAspirin
casesObserved017708812270124761214105708071145750521641334702480431011111718810044
of
of
type
year
Value<0.05<0.05<0.05<0.002<0.05<0.05<0.05<0.01
when0.051984198019841978198419821
P<
users3,30821,1584,1225,3293406,23912,9283745.9652,9898,0094,6507842,5172,1785,6215,4535291,4652.37830.2164545,8343.64311.98
siteSkinAll
or
cancerSalivaryAll
codeine/j-Methasone
with
cancerPancreasAll
(topical)Bronchodilators,
cancerUterusAll
systemicCarbamide
cancerAll
(topical)ChlordiazepoxideDiazepamEphedrine
peroxide
cancerCervix
uteriKidney,
urinaryAll
cancerLarge
intestineHodgkinsAll
cancerAll
sulfateEstrogensFluocinolone
cancerCervix
uteriAll
cancerSkinProstateBladderAll
(topical)Glyceryl
cancerCervix
guaiacolateHydrocortisone
uteriAll
cancerKidney,
(topical)Hydrocortisone,
urinaryAll
cancerProstateAll
propanediol diacetate. & ace
(topical)HydroxyzineMeclizineMeprobamateMethocarbamolMethylphenidate
tic acid
cancerBreastAll
cancerPancreasLungAll
cancerRectumThyroidAll
cancerOvaryAll
cancerAll
hydrochlorideNapha/oline
(topical)Nicotinic
cancerSkinAll
lympho-mas/leukemiasAll
cancerEsophagusAll
acidPenicillinPhcnformin
cancerLipAll
cancerLarge
hydrochloridePhénobarbitalPhenylbutazonePhenylephrineNo.
intestineAll
cancerLarge
intestineBladderAll
cancerBladderAll
cancerSkinProstateAll
cancerContinues5739Number
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SCREENING
DRUGS FOR CARCINOGENICITY
Table 2—Continued
DrugPolymyxin-neomycin
(topical)PotassiumPrednisolone.
casesObserved2
of
of
type
year
users8.6821,9761,9245.3982,85018.47717.9369524,2271,3387,81811,6592,34115,29081814,881Cancer
siteBrain
or
Value<0.05 when0.05198019841978
P<
cancerProstate
All
488S128i:14792851
421.511.9
1.160.42
cancerBreast
All
117.122.0
1.090.54
cancerCervix
All
170.919.3277.17.3
0.860.47
uteri
cancerAll
All
1.030.14
<0.002<0.05<0.05<0.05<0.05<0.05<0.01
injectedPrednisoneProgestérones
progestagensPromethazine
&
lymphomas/leukemias
cancerSkin
All
12418
125.829.9
0.990.60
cancerSkin
All
1,04019
996.936.5
1.040.52
Uterus
All
cancerBladder
46
62.5
1,1740106124640
1.164.13.9
19761978198219761976
expectorantPropoxypheneQuinine
0.74
1.010.00
<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05
1980198419801982
sulfateRauwolfiaSimethiconeSulfacetamide
All
cancerBladder
110.021.2463.24.190.146.2
0.960.57
All
cancerRectum
1.000.00
All
cancerProstate
9332
1.030.69
cancerRectum
All
48411
494.720.4
0.980.54
cancerLarge
All
56349516
538.111.1
1.050.36
108.226.0
0.880.61
1982197619781980
(topical)SulfisoxazoleTolnaftate
(topical)Triamcinolone
intestine
cancerStomach
All
19801976
(topical)Trimethobenzamide
Brain
All
cancerBreast
67X61309
13.1787.15.7 0.46
1.000.17
<0.05<0.05<0.05
198219821984
<0.05
<0.05First
1984
1980
hydrochlorideTriprolidineNo.
cancerStomach
All
32.017.5
Rectum
All cancerNumber
* SMR. standardized morbidity ratio, or observed cases divided by expected cases.
Antibiotics and Lung Cancer. Ampicillin, tetracycline, and
erythromycin use were each significantly (P < 0.01) associated
with an increased risk for lung cancer; three other antibiotics
were also associated with lung cancer with P values between
0.01 and 0.05: cephalexin (9 observed, 3.3 expected, P = 0.01),
cloxacillin (7 observed, 2.7 expected, P = 0.04), and sulfamethoxazole (23 observed, 14.5 expected, P = 0.05). Except for
cephalexin, these six associations first became significant with
follow-up through 1982 or later. Lag analyses (1- and 2-year)
did not diminish any of the associations substantially. Risk was
also increased slightly among 30,216 users of penicillin (118
observed, 102.8 expected, P = 0.15). For three other antibiotics,
sulfisoxazole, doxycycline, and clindamycin, SMRs were 1.0 or
slightly below.
We hypothesized that antibiotic use for respiratory infections
related to cigarette smoking and chronic obstructive pulmonary
disease could explain this cluster of associations. However,
when indications for antibiotic prescriptions were obtained by
linking to the outpatient diagnosis file, confounding by indica
tion for use did not explain the association. Risk was as high
or higher for each antibiotic when prescribed for nonsmokingrelated indications (e.g., urethritis, cystitis, evilulitis) as for
20.1
11469Expected7.5
0.940.51
0.55
5 13.6SMR0.27
0.91P
indications related to smoking (e.g., acute and chronic bronchi
tis, emphysema, cough, pneumonia). We also conducted longi
tudinal analyses in the 30,567 adult pharmacy cohort mem
bers who took at least one MHC using Cox proportional haz
ards models to control for cigarette smoking status (scored as
never-, ex-, or current smoker of <1, 1-2, or >2 packs per day).
Relative hazards for use of five of the six antibiotics were
increased somewhat after adjustment. Thus, the associations
are not the result of excess cigarette smoking among antibiotic
users. Although chance could explain these findings, the possiblity that susceptibility to bacterial infection may reflect an
increased susceptibility to cancer as well as has been raised (9)
and should be investigated further.
Antacids and Cancer of the Esophagus. The association of
antacid use with esophageal cancer was diminished only slightly
in the 2-year lag analysis, suggesting that antacid use for early
symptoms of esophageal cancer is not the principal explanation
for this association. In the United States, 80 to 90% of all
esophageal cancer has been attributed to the combined effects
of alcohol and cigarette smoking (10). The antacids-esophageal
cancer association may therefore reflect use of antacids for
other smoking and alcohol-related illnesses such as peptic ulcer
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SCREENING DRUGS FOR CARCINOGENICITY
disease and gastritis. An excess of stomach cancer was also
noted among antacid users (18 observed, 7.3 expected, P =
0.001), but this association was almost completely eliminated
in the 2-year lag analysis (7 observed, 6.0 expected).
Aspirin with Codeine and Cancer of the Lung. Aspirin with
codeine, a frequently used narcotic analgesic, was associated
with a slight increase in risk of lung cancer with follow-up
through 1984. An increase in cancer of the floor of the mouth
has been present since the initial analyses (follow-up through
1976). This, together with increases in both lung and pharyngeal
cancer among recipients of pentazocine (Table 1) suggests that
users of narcotic analgesics may more frequently be cigarette
smokers, and at increased risk for a variety of cancers because
of this behavior.
Belladonna and Cancer of the Stomach. An excess of stomach
cancer was noted among users of belladonna preparations in
follow-up through 1984. Risk was confined to the 91% of
belladonna users who received oral rather than topical prepa
rations. These preparations were almost exclusively antispasmodic combinations used to treat acute or chronic gastrointes
tinal symptoms. Risk declined in the 2-year lag analysis (from
SMR = 1.93 to SMR = 1.67), suggesting that the drug was
sometimes used for treatment of early cancer symptoms.
Phénobarbitalwas often combined with belladonna in these
preparations. We have previously reported increased risks for
several cancers (not including stomach cancer) among barbitu
rate users in this dataset (2,3, 11, 12). Risk was lower (SMR
= 1.47) among 1,402 persons receiving belladonna preparations
without phénobarbitalthan in the much larger group of 13,229
persons who also received phénobarbital(SMR = 1.96). More
over, the SMR declined to 1.00 in the 2-year lag analysis in the
former group, but remained elevated in those receiving phéno
barbital (SMR = 1.76, 31 observed, 17.6 expected, P = 0.005).
Risk for stomach cancer was not increased among recipients of
phénobarbitalprescriptions (5 observed, 5.23 expected) in fol
low-up through 1984. Thus, our data do not provide consistent
evidence for an association of either belladonna or phénobar
bital with stomach cancer.
Folie Acid and Cancers of the Oropharynx, Hypopharynx, and
All Cancer. Folie acid has been associated with an increased
incidence of all cancer since its first analysis with follow-up
through 1978 (3). The cancers occurring in excess have been
largely smoking and/or alcohol-related and we have previously
noted that most folie acid recipients have a diagnosis of alco
holism in their medical records. Thus, alcohol and cigarettes in
this group is the likely explanation for their excess of cancers.
Erythromycin and Multiple Myeloma. An association between
erythromycin and multiple myeloma was first noted in followup through 1980. We are unaware of other reports of possible
carcinogenic effects of erythromycin. However, erythromycin
is known to inhibit hepatic enzymes responsible for metabolism
of at least two drugs, theophylline (13) and cyclosporine (14).
Erythromycin could alter metabolism of potentially carcino
genic compounds as well, resulting in excessive or prolonged
exposure to such agents.
Duration or intensity of exposure to erythromycin did not
differ between the 14 erythromycin users who developed mul
tiple myeloma and 28 randomly selected age-, sex-matched
controls who had also used erythromycin but did not develop
myeloma. Nor did indications for erythromycin use differ to
suggest possible confounding factors. The age distribution at
diagnosis (mean age, 68 years) was not unusual for multiple
myeloma. Thus we find no supporting evidence for either a
causal association or a confounded relationship and suspect
that chance may have produced this finding. Other antibiotics
were not, in general, associated with an increased risk for
myeloma.
Methyprylon and Lymphosarcoma. Four cases of lymphoma
occurred among 249 users of methyprylon compared to 0.5
cases expected. The date of diagnosis ranged from 15 months
to 8 years following the first recorded methyprylon prescription.
Three cases were diffuse histiocytic lymphomas; two arose in
the stomach, and the extent of disease could not be defined in
the third. The fourth case was a polymorphous lymphocytic
lymphoma arising in the base of the tongue. Methyprylon, like
barbiturates (see below), induces hepatic microsomal enzymes
(15), which may alter the metabolism of other potential carcin
ogens. Methyprylon has been associated anecdotally with both
neutropenia and thrombocytopenia, but we were unable to
identify previous reports of associations with cancer at any site.
Thus, at present we are inclined to attribute this finding to
chance variation.
Nonprenatal Multivitamins and Various Cancers. Associations
of multivitamin use with cancers of the hypopharynx and esoph
agus have been noted since 1976, with cancers of the mouth
since 1978, with cancer of the tongue since 1980, with cancer
of the floor of the mouth since 1982, and with all cancer since
1984. These associations are likely due to a higher prevalence
of alcoholism and increased cigarette smoking among persons
prescribed multivitamins. Among the 4,676 recipients of pre
natal vitamins there was no significant increase in cancer at any
site and an SMR of 0.95 for all cancers combined.
Phenylbutazone and Cancer of the Rectum. A significant ex
cess of cancer of the rectum was first noted among users of this
nonsteroidal antiinflarnmatory agent in follow-up through 1980
and has persisted with continuing follow-up. No other cancers
occurred to a significant excess in phenylbutazone users. In
animals studies, phenylbutazone does not appear to act as either
a primary carcinogen or as a promoter of tumor development
(16). In humans, the drug has been associated with leukemia
and lymphatic malignancies in case reports. We did not find an
association in a large case-control study of leukemia and lym
phoma (17). We are unaware of any reports linking phenylbu
tazone to cancers outside the lymphatic/hematopoetic
system
and suspect that the association noted here is a chance finding.
Propantheline and All Cancer. The incidence of all cancer was
increased among users of this anticholinergic medication which
is frequently used to treat peptic ulcer disease and other gas
trointestinal symptoms. No single cancer occurred in significant
excess. Small increases were noted in the incidence of stomach,
pancreas, espohagus, and large intestine cancers, but these
declined substantially in the lag analyses suggesting use for
early symptoms of the cancers. Other cancers occurring in slight
excess included lung, melanoma, uterine corpus and cervix, and
urinary bladder. That most of these are smoking-related cancers
suggests that cigarette smoking could have led to both peptic
ulcer disease (with propantheline use) and subsequently to
cancer
Secobarbital and Cancer of the Small Intestine. The associa
tion of secobarbital use with cancer of the small intestine is one
of several positive associations we have noted for users of three
commonly prescribed barbiturate preparations (2, 3, 11, 12).
Incidence of this cancer was not increased among 5,834 phé
nobarbital users or 2,156 pentobarbital users through 1984.
Incidence of lung cancer among users of each preparation has
been significantly increased over expected in each analysis since
1976, although for phénobarbitalthis association was no longer
statistically significant in follow-up through 1984 (71 observed,
58 expected, P = 0.12). Animal studies (18-20) provide biolog
ical plausibility for a tumor-promoting role of barbiturates, but
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SCREENING
epidemiological
DRUGS FOR CARC1NOGENICITY
evidence is inconclusive (20). The question of
potential carcinogenic effects of barbiturates in humans remains
unsettled and deserves further investigation.
Polymyxin B-Neomycin Preparations and All Cancer. Topical
preparations containing polymyxin B and neomycin sulfate
were associated with a significantly increased total cancer inci
dence. Increased incidence of breast cancer (81 observed, 57.8
expected, SMR = 1.40, P = 0.005) and lung cancer (84 ob
served, 65.3 expected, SMR = 1.29, P = 0.03) accounted for
most of the excess. Five other topical medications containing
neomycin including preparations intended for ophthalmic, na
sal, skin and vaginal application, were also screened, including
dexamethasone phosphate and neomycin (718 users), dexamethasone, neomycin, and polymix (371 users), flurandrenolide
and neomycin (398 users), gramicidin-neomycin-nystatintriamcinolone (5,364 users) and hydrocortisone-neomycin (325
users). For each of these, breast cancer incidence was greater
than expected, though differences were not significant (P >
0.05).
The SMR for breast cancer was 1.3 (P = 0.007) for all
neomycin users combined, with some evidence of a dose-re
sponse effect. The SMR was 1.28 (94 observed, 73.6 expected)
in 9,715 members who received only one neomycin prescrip
tion, and 1.75 (13 observed, 7.4 expected) for 912 users of two
or more prescriptions. Lung cancer risk was not consistently
elevated in each small group of users, but for all users combined,
SMRs for lung cancer were similarly elevated: 1.22 for recipi
ents of one neomycin prescription (80 observed, 65.6 expected),
and 1.70 (17 observed, 10.0 expected) for those receiving two
or more prescriptions.
These associations were not entirely specific to the neomycin
component. In 4,697 members receiving a polymyxin B-bacitracin preparation, incidence of breast cancer was also increased
(43 observed, 29.8 expected, SMR = 1.44, P = 0.03), but
incidence of lung cancer was slightly less than expected. In 622
members who received polymyxin B alone, there was no in
crease in breast cancer incidence, but the SMR for lung cancer
was increased (11 observed, 6.44 expected, SMR = 1.71, P =
0.13). No increases for either lung or breast cancer were noted
among users of bacitracin, gramicidin, or topical steroid prep
arations without neomycin or polymyxin B, or in 301 users of
topical gentamicin.
Indications for neomycin use among recipients who devel
oped breast cancer were varied and suggested no obvious con
founding explanations. These associations remain unexplained,
but they could also reflect a factor that increases susceptibility
to both infections and cancer.
Sulfathiazole-sulfacetamide-sulfabenzamide-urea
and All Can
cer. Incidence of all cancer was increased among users of triple
sulfa vaginal preparations, the SMR declining only slightly in
2-year lag analysis: from 1.74 (P< 0.0001) to 1.55 (P= 0.005).
The excess was based largely on an increased incidence of
cervical cancer (26 observed, 11.3 expected) and breast cancer
(18 observed, 9.9 expected). The association with cervical can
cer was greatly reduced by the lag analysis (15 observed, 9.5
expected, P > 0.05), suggesting use of the medication for
symptoms of early cervical cancer or precursor conditions. The
breast cancer association, however, persisted (18 observed, 8.9
expected, P = 0.01). There is no obvious confounding factor to
explain this association.
Other Positive Associations Based on Two or Three Observed
Cases. Positive associations based on two or three observed
cases (Table 1) included progesterone and progestogens and
endocrine cancers, cyproheptadine and laryngeal cancer, dexchlorpheniramine and nasal cancer, 7-benzene hexachloride
and Hodgkin's disease, magaldrate and unspecified leukemia,
senna and thyroid cancer, and trihexylphenidyl hydrochloride
and cancer of the kidney. Medical records of these 19 cases
were reviewed to look for evidence of prolonged exposure,
possible confounding factors, or a specific unusual histológica!
type of cancer that might support a causal relationship. With
the exception of trihexyphenidyl hydrochloride, exposure to
each of these drugs among the cases was limited to one recorded
prescription. Medical records did not suggest confounding by
indication for drug use except for one man who developed
squamous cell carcinoma of the maxillary antrum after receiv
ing dexchlorpheniramine
once for nasal polyps and allergic
rhinitis, and one woman who received medroxyprogesterone
for treatment of amenorrhea which proved to be due to a
pituitary adenoma.
In the three cases of renal cancer, the interval between first
exposure to trihexyphenidyl and cancer diagnosis ranged from
5 to 13 years. In two cases, exposure was prolonged but in the
third, exposure lasted less than 3 weeks. Two cancers were renal
cell carcinomas, one an incidental finding at autopsy; the third
was a clear cell adenocarcinoma.
Positive Associations (P < 0.01) in Follow-up through 1980
or 1982, But Not 1984. Five associations were significant at P
< 0.01 in either the 1980 or 1982 follow-up analyses or both,
but not in 1984. Sulfamethoxazole was associated with in
creased occurrence of multiple myeloma in 1980 (5 cases, 0.94
expected in 1,709 users, SMR = 5.31, P = 0.006). No additional
cases occurred in this group during the next 4 years, the SMR
declining to 3.92 (P = 0.02) in 1984. Lesser increases in risk
were also noted in 1984 analyses for cancer of the lung (23
observed, 14.5 expected, P = 0.05) and uterine cervix (12
observed, 5.9 expected, P = 0.04), and for the combination of
all lymphomas and leukemias (16 observed, 7.6 expected, P =
0.01). A slight excess for all cancer (116 observed, 100.5 ex
pected) was not significant. There is no other epidemiologie
evidence of carcinogenicity of this drug. Sulfamethoxazole has
been reported to produce thyroid tumors in a single study in
rats (22). Interestingly, the closely related drug sulfisoxazole
was not associated with an excess of cancer at any site in our
data.
Pyridoxine and lung cancer were strongly associated in 1980
and 1982 analyses (15 observed cases, 4.28 expected in 1980,
SMR = 3.27, P < 0.0001). Lag analyses markedly decreased
the strength of these associations, but significance (at P < 0.05)
persisted. In 1984, these associations did not remain significant
in the lag analysis. The main indication for pyridoxine use is
coprescription with isoniazid for treatment or chemoprophylaxis of tuberculosis. Similar associations with lung cancer have
been noted for isoniazid since the first analysis (3). The sharp
declines in these associations in lag analyses suggested to us
that in some cases patients may have received antituberculous
therapy for pulmonary lesions that later proved to be cancerous.
Chart review of the isoniazid-associated lung cancer cases con
firmed that this was the case in seven of 18 patients (3). Excess
cigarette smoking among persons who develop tuberculosis and
the known association of lung cancer with tuberculosis (23) are
likely explanations for the associations that remain after lag
analyses.
An association of aminoacridine-sulfanilamide-allantoin
preparations with cervical cancer was noted in 1982 (41 cases
observed, 22.8 expected, P< 0.0001). Lag analyses reduced the
association to nonsignificance in other years, including 1984,
suggesting use for treatment of symptoms of early cervical
cancer or, more likely, associated conditions.
A topical antiseptic, triclobisonium, was associated with
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SCREENING DRUGS FOR CARCINOGENICITY
breast cancer in 1982 (28 observed, 15.7 expected, SMR =
1.78, P= 0.006). By 1984, this association had declined slightly
to an SMR of 1.60 (P = 0.02). An association of polyvinyl
alcohol/chlorbutanol preparations (used to soften ear wax) with
male genital cancers based on two cases was significant in 1982
(2 observed, 0.03 expected, P < 0.001 ). One case was eliminated
in 2-year lag analysis, and by 1984 the lag analysis was no
longer significant.
Comments on Negative Associations (Table 2)
Most of the negative, or protective, associations (Table 2)
involved only a single cancer site with no corresponding deficit
in the incidence of all cancer. In the absence of biological
evidence for a protective effect, we believe that most of these
associations are the result of chance. Associations that were
particularly strong, those that included a significantly lower
incidence of all cancer, and those for which biological expla
nations have been proposed are discussed here.
Bronchodilators and Uterine Cancer. A low incidence of uter
ine cancer has been observed among users of bronchodilators
since the 1978 analysis. Two possible confounding factors of
this protective association are a higher prevalence of smoking
among users of bronchodilators and a higher prevalence of
allergies and asthma in this group. Cigarette smoking has an
antiestrogenic effect leading to earlier menopause, less postmenopausal bleeding, and an apparently lower risk for endometrial cancer (24, 25). Excess cigarette smoking among users
of bronchodilators was suggested by a significantly increased
incidence of lung cancer in this group since the initial analysis
in 1976 (Table 1) and by a slightly higher prevalence of current
cigarette smoking in the 768 women in the MHC subgroup
who had received bronchodilators compared with those who
had not (41 versus 38%). Bronchodilator use is also a marker
for asthma. The allergic state itself has been suggested to protect
against occurrence of cancer in several studies (26).
Estrogens and Cancer of the Uterine Cervix. The negative
estrogen-cervical cancer association is most likely explained by
a higher prevalence of hysterectomy, which precludes subse
quent cervical cancer, among women using estrogens. A com
mon indication for estrogen replacement therapy is surgical
menopause induced by hysterectomy with oophorectomy.
Vitamin E and Lowered Incidence of AH Cancer. An apparent
protective association of vitamin E use with incidence of all
cancer (23 observed, 34.6 expected in 476 users, SMR = 0.67,
P = 0.05) was noted in the 1982 analysis. By 1984, the SMR
had risen to 0.73, P = 0.10, and the association is therefore not
shown in Table 2. However, because vitamin E has been sug
gested to have preventive effects for cancer (27), we investigated
this association further. Nearly all of the apparent protection
was among female users of vitamin E (8 observed, 18.36 ex
pected in 288 users, SMR = 0.44). Largest deficits were for
breast cancer (1 observed, 4.68 expected), lung cancer (3 ob
served, 5.20 expected) and colon cancer (3 observed, 4.46
expected).
There was no evidence of a dose-response effect. Persons
who received only one vitamin E prescription appeared to be
protected (9 observed cancers, 22.4 expected), whereas those
receiving two or more prescriptions had no apparent protection
(14 observed, 12.1 expected). The outpatient diagnosis file
revealed that 85.6% of all prescriptions were issued from the
otolaryngology clinic, almost all of these by a single physician.
Consequently, the major indications for vitamin E use were
ENT conditions, including tinnitus, vertigo, and sensorineural
hearing loss. None of these diagnoses were themselves associ
ated with a significantly lowered risk of all cancer in the cohort.
The absence of a dose-response effect and the isolation of the
effect to women do not support a causal protective association.
Diazepam, Colon Cancer, and Hodgkin's Disease. Concern
has been raised regarding the possible carcinogenicity of diazepam in humans on the basis of reports of enhanced growth of
mammary tumors in rats (28). In the 12,928 users of diazepam
in this cohort, the incidence of cancer at two sites, large bowel
and Hodgkin's lymphoma, was significantly (P < 0.05) lower
than expected. Consistent with results of three recent casecontrol studies (29-31), the incidence of breast cancer was not
significantly different than expected (155 observed, 143.8 ex
pected, SMR = 1.08, P = 0.37). No significant positive associ
ations of diazepam use were noted for cancer at any site. For
another benzodiazepine, chlordiazepoxide, deficits of cervical
and kidney cancer were noted (Table 2). Slight excesses of lung
cancer (73 observed, 57.1 expected, SMR = 1.28, P = 0.05)
and cancer of the floor of the mouth (6 observed, 2.1 expected,
SMR = 2.90, P = 0.04) suggest an association of drug use and
cigarette smoking. Our data therefore provide no evidence to
date to suggest that these widely used anxiolytics present a
carcinogenic risk.
Meclizine and Lowered Incidence of AH Cancer. An apparent
protective effect of meclizine was seen on incidence of all cancer
(188 observed, 219.0 expected among 2,105 users, SMR =
0.86, P = 0.03). Significant deficits were noted for lung cancer
(17 observed, 28.1 expected, SMR = 0.61, P = 0.03) and
pancreatic cancer (1 observed, 6.2 expected, SMR = 0.16, P =
0.03). No substantial deficits were noted for any other cancer
site. The analyses of cancer incidence by indication described
for vitamin E above showed no association of vertigo, the
principle indication for the use of meclizine, with lowered
cancer incidence. Overlap of this group of meclizine cases with
vitamin E users in our database was minimal; less than 2% of
meclizine users also received vitamin E. That both cancer sites
with reduced incidence are smoking-related suggests that, for
some unknown reason, meclizine users may smoke less than
nonusers.
Phenylephine, Triprolidine, and Naphazoline and Lowered
Incidence of AH Cancer. These three commonly prescribed
groups of medications were each associated with significantly
lowered incidence of all cancer as well as cancer of at least one
specific site. In addition to lowered incidence of skin, prostate,
stomach and rectal cancer shown for one or more of these
groups in Table 2, smaller nonsignificant deficits of lung cancer,
pancreatic and bladder cancer were seen in all three groups.
Among 3,410 users of pseudoephedrine (without an antihistamine), incidence of lung, skin, prostate, and pancreatic cancer
were again reduced (though not significantly), as was all cancer
incidence (95 observed, 108.3 expected, SMR = 0.08, P =
0.21).
The phenylephrine group included both topical (ophthalmic)
and oral preparations, often combined with antihistamines.
Triprolidine was usually combined with pseudoephedrine, and
the naphazoline group included both ophthalmic and nasal
preparations. Thus it is difficult to isolate individual compo
nents or preparations in this group of medications. Each of
these medications is often used for allergic symptoms, again
suggesting the explanation that the allergic state may be asso
ciated with lower cancer incidence (2). Persons with allergies
may also smoke less, although the cancers showing lowered
incidence were not uniformly smoking related.
Drug Cancer Associations Reported Elsewhere. Our data are
of interest in relation to some recent reports of drug-cancer
associations. Concern about hydralazine (32) was partially al
layed by its lack of association with breast cancer in one study
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SCREENING
DRUGS FOR CARCINOGEN1CITY
(33). Our findings to date agree; among 237 female users of
hydralazine, six breast cancers were observed versus 6.3 ex
pected. No other associations were observed among the 400
hydralazine users of both sexes.
Follow-up of 954 recipients of diphenylhydantoin does not
support reports (34, 35) of an association with Hodgkin's and
non-Hodgkin's lymphoma, multiple myeloma, and leukemia.
There were 4 observed and 4.6 expected cases of all lymphomas
and leukemias combined with no statistically significant asso
ciations noted among the individual histological types. We
recently reported (36) a lack of association with multiple mye
loma.
Levodopa has been suspected of enhancing the development
of malignant melanoma in bening nevi (37). Only 100 persons
received levodopa in our cohort; none have developed malignant
melanoma.
An association of methyldopa with cancer of the biliary tract
has been suggested (38), but neither Strom et al. (39) nor we
(one case observed, 0.8 expected) could confirm this.
Concluding Remarks
Reexamination of our data after 11 to 15 years of follow-up
continues to provide limited evidence that, with the exception
of a few known associations, the ordinary clinical use of most
Pharmaceuticals commonly prescribed between 1969 and 1973
does not pose increased risks for cancer. Caution is required
because the number of users of many of the drugs in our study
APPENDIX
was relatively small (see "Appendix A") so that power to detect
modest increases in cancer risk for these drugs is quite low.
Furthermore, if a drug acts as a primary carcinogen only after
a latent period of 20 years or more, our 1,370,000 person-years
of follow-up through 1984 may contribute very little to detect
ing the association.
As the number of person-years of follow-up accumulates,
power to detect a given SMR increases accordingly. However,
if a drug acts as a "promoter" of cancer, its effect may be
expected to be relatively prompt and to last for a limited period
after exposure ceases. Extending follow-up beyond this period
may allow subsequent cancer incidence in both cases and con
trols to "wash out" an early effect. Thus, positive associations
noted in our earlier reports (2, 3) should not be discounted
simply because they are no longer statistically significant.
Many drugs now in common use were not available in 1973
or earlier. Of the 50 drugs prescribed most commonly within
KPMCP during 1986, 14 were first marketed after 1973. Data
are now being collected within our organization and elsewhere
that will, in time, be useful for examining the possible carcinogenicity of these recently introduced drugs.
ACKNOWLEDGMENTS
We wish to express our appreciation to Donna Wells for computer
programming, and to Merril Jackson. Betty Wong, and Betty Jue who
performed chart reviews.
A
Table A1 List of 56 cancer sites (and combinations) studied
ICDA-8code140141142143144145146147148149ISO151152153154155156157CancerLipTongueSalivary
code158159160161162163170171172173174180181182183184185186CancerPeritoneumDigestive,
code18718818919019119219319420020120220.1204205206207208209Ca
genitalBladderKidney,
unspecifiedNose,
earLarynxLung,
glandGumMouth
urinaryEyeBrainNervous
floorMouth,
bronchusOther
trachea,
unspecifiedOropharynxNasopharynxHypopharynxPharynx,
respiratoryBoneConnectiveSkin
& unspecified
systemThyroid
glandEndocrine
glandsLymphosarcomaHodgkinsOther
melanomaSkinBreastCervix
unspecifiedEsophagusStomachSmall
lymphomaMultiple
myelomaLymphatic
leukemiaMyeloid
leukemiaMonocytic
leukemiaOther
leukemiaPolycythemia
& unspecified
veraMyelofibrosisAll
uteriChorionepitheliomaUterusOvaryFemale
intestineLarge
intestineRectumLiverGallbladderPancreasICDA-8
genitalProstateTestisICDA-8
leukemiasAll
lymphomas &
cancers
Table A2—Continued
Table A2 List of 215 medications (or medication groups) studied
Drugs
Systemic drugs
Acetaminophen
Acetaminophen with codeine
Acetazolamide
Allopurinol
Amantadine hydrochloride
Amitriptyline
Amphetamines
Ampicillin
Antacids
Aspirin
Aspirin with codeine
Aspirin-phenacctin-caffeine-butalbital
Aspirin, enteric coated
Aspirin, phenacetin, & caffeine
Atropine
No. of
users
Drugs
3.238
2.612
507
Belladonna
Benztropine mesylate
Bisacodyl
Bismuth magma & paregoric
Brompheniramine
Bronchodilators. systemic
Carisoprodol
Cephalexin
Chloral hydrate
Chlorambucil
Chlordiazepoxide
Chlorpheniramine
Chlorpromazine
Chlorzoxazone
Clindamycin
491
95
1,957
3,308
6.706
3,054
381
21.158
2.393
393
718
390
No. of
users
16,072
197
503
841
6,964
5.329
837
474
2,290
142
6.239
13.443
869
428
343
Continues
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SCREENING DRUGS FOR CARCINOGENICITY
Table A2—Continued
DrugsClofibrateCloxacillinColchicineColistin
Table A2—Continued
No. of
of
users
Drugs
users1456628499242948838741,30237212.9282.1158802.4664352,17110,1054254.2409543444383743893,06677313,9415
Prednisolone, injected
Prednisone
Prenatal vitamins
Primidone
sulfateCyclophosphamideCyproheptadineDexamethasoneDexbrompheniramineDexchlorpheniramine
Probenecid
Procainamide hydrochloride
Prochlorperazine
Progestérones& progestagens
Promethazine expectorant
maléateDiazepamDicyclomineDiethylpropion
Promethazine hydrochloride
Propantheline
Propoxyphene
hydrochlorideDigitalis
Propranolol hydrochloride
groupDimenhydrinateDioctyl
Propylthiouracil
Pseudoephedrine
sulfosuccinateDiphenhydramineDiphenhydramine
sodium
PS;,Ilium hydrophilic mucilloid
Pyridoxine hydrochloride
phenylpropanolamineDiphenoxylateDiphenylhydantoinDoxycyclineEphedrine
hydrochloride &
Pyrrobutamine phosphate
Pyrvinium pamoate
Quinidine gluconate, quinidine sulfate
Quinine sulfate
guaifcncsinEphedrine
&
Rauwolfia
sulfateEpinephrineErgonovineErgotamine
Secobarbital
Secobarbital & amobarbital
Secobarbital, butabarbital, & phénobarbital
tartrateErythromycinEstrogensEthambutol
Senna
Simethicone
hydrochlorideEthinyl
Spironolactone
methyltestosteroneFluoxymesteroneFlurazepam
estradici &
Sulfamethoxazole
Sulfisoxazole
Sulfisoxazole & phenazopyridine hydrochloride
hydrochlorideFolie
acidFurosemideGlutethimideGlyceryl
Terpin hydrate
Tetracycline
Thiazides
guaiacolateGriseofulvinGuanethidine
Thioridazine
Thyroid hormone
Tolazamide
sulfateHydralazine
hydrochlorideHydrocodone
Tolbutamide
Trifluoperazine hydrochloride
methylbromideHydromorphone
bitartrate & homatropine
hydrochlorideHydroxyzineHydroxyzine-ephedrineImipramine
Trihexyphenidyl hydrochloride
Trimeprazine tartrate
Trimethobenzamide hydrochloride
hydrochlorideIndomethacinInsulin
Tripelennamine hydrochloride
Triprolidine
Vitamin B-complex & vitamin C
suspensionIron,
zinc
prenatalIsoniazidIsophanc
no
Vitamin E
Warfarin sodium
suspensionIsoproterenol
insulin
hydrochlorideIsosorbide
dinitrateLevodopaMagaldrateMeclizineMeprobamateMethocarbamolMethyldopaMethylphenidate
Topical drugs
Acetic acid & aluminum acetate
Aminoacridine-sulfanilamide-allantoin
Bacitracin
Benzalkonium chloride & chlordantoin
Betamethasone
Bismuth resorcin compound
Boric alcohol-hcort-gentian violet ear drops
hydrochlorideMethyprylonMetronidazoleMultivitaminsNicotinic
Calcium propionate & sodium propionate
Candicidin
Carbachol
acidNitrofurantoinNitroglycerinNylidrin
Carbamide peroxide
Dexamethasone Na phosphate & neomycin sulfate
Dexamethasone, neomycin, & polymixin
hydrochlorideOral
Dibucaine
contraceptivesOxycodoneOxytetracyclinePenicillinPentaerythritol
Dienestrol
Echothiophate iodide
Epinephryl borate
Fluocinolone
tetranitratePentazocinePentobarbitalPhenaphen
Fluocinonide
Fluorouracil
Flurandrenolide
codeinePhenazopyridinePhenformin
with
Flurandrenolide & neomycin sulfate
Formaldehyde solution
hydrochloridePheniraminePhenmetrazine
Furazolidone & nifuroxime
7-Benzene hexachloride
hydrochloridePhénobarbitalPhenytbutazonePhenylephrinePhenylpropanolaminePotassiumPotassium
Gentamicin sulfate
Gramicidin-neomycin-nystatin-triamcinolone
Hcortisone. propanediol diacetate, & acetic acid
Hexylcaine hydrochloride
Hydrocortisone
Hydrocortisone & neomycin
iodideNo.
lodochlorhydroxyquin
1,924
5,398
4,474
91
584
322
3,459
2,850
18,477
417
1,600
17,936
269
107
3.410
916
606
352
634
671
952
4,227
2,884
521
170
355
1,338
1,475
1.709
11,659
438
2.614
22,810
12,799
263
2,752
86
719
678
177
689
818
592
14,881
397
436
633
656
3,119
614
546
4,122
716
998
400
652
159
340
718
371
374
1,778
204
184
2,989
708
355
2,251
398
557
500
1,148
301
5,364
784
310
4,650
325
2,068
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SCREENING
DRUGS FOR CARC1NOGENICITY
Table A2—Continued
Table Al—Continued
ofusers5381347,8683053751,4653176,7531,9803711.020622DrugsPolymyxin-neomycinPolyvinyl
ofusers8,6823026226576402,0377,8181,2296672,34115,2903,149Table
DrugslodoquinolLevo-epinephrineLidocaineLidocaine
chlorobutanolPramoxineSalicylic
alcohol &
hydrocortisoneMedrysoneNaphazolineNitrofurazoneNystatinOxymetazolinePhenol,
&
2%Salicylic
acid,
25%Selenium
acid,
sulfideSulfacetamideSulfathiazole-sulfacetamide-sulfabenzamide-ureaTetrahydrozoline
hydrochlorideTolnaftateTriamcinoloneTriclobisoniumNo.
etc.PilocarpinePolymyxin
sodium phcnolate.
sulfateAPPENDIX
B
BNo.
0.01DrugAcetaminophenAcetic
Bl Positive drug-cancer associations with P values < 0.05 but 2
hexachloride"Gentamicin
13/0.62/0.13/0.57/2.44/1.02/0.28/3.18/3.414/7.422/12.72/0.23/0.54/0.837/24.43/0.53/0.59/3.89/3.33/0.69/3.76/2.173/57.1
2/6.
melanomaEsophagusNose,
sulfate"GlutethimideGlyceryl
acetate"AllopurinolAminoacridine-sulfanilamide-allan-toin"AmitriptylineAmpicillinAtropineBelladonnaBetamethasone"BisacodylBismuth,
acid and aluminum
leu-kemiasAll
lymphomas and
earMyelogenous
leukemiaThyroidLiverMyelofibrosisBreastOther
leu-kemiasSalivary
lymphomas and
glandLarynxUterusKidney,
guaiacolatcGramicidin-neomycin-nysta-tin-triamcinolone"Guanethidine
respiratoryThyroidUterusThyroidLarynxKidney,
sulfateHydroxyzine
ephedrineInsulin
uretersBreastBladderBladderLarge
paregoricBronchodilators.
magma and
suspension)lodochlorhydroxyquin"Iron,
(zinc
uretersLarge
intestineSkin
systemicCarbachol"CarisoprodolCephalexinC'hloral
melonomaLarynxAll
nonprenatalIsoniazidIsoproterenol
leu-kemiasLung,
lymphomas and
intestineMyelogenous
leukemiaUnspecified
leukemiaEsophagusLung,
hydrochlorideMeclizineMedrysone"MethyldopaMultivitaminsNicotinicacidNitrofurantoinNitroglycerin
bronchusThyroidUterusKidney
trachea,
bronchusFloor
trachea,
hydrateChlordiazepoxideChlorpheniramineCloxacillinCyprohepatadineDexamethasone
mouthSkin
of
melanomaFloor
mouthLung,
of
bronchusBrainMyelomaLung,
trachea,
phos-phate/neomycin
sodium
sulfate"Dexchlorpheniramine
uretersTongueMouth,
bronchusSkin
trachea,
melanomaAll
cancerLymphosarcomaMyelogenous
unspecifiedUterine
cervixNervous
systemLung,
trachea, bronchus
mouthLarge
Floor of
3/0.48/2.98/3.23/0.65/1.511
PentazocinePhenmetrazine
intestineGallbladderBoneStomachStomach
hydrochloridePhénobarbitalPhenylpropanolaminePilocarpine"
maléateDienestrol"
Diethylpropion hydrochloride
Digitalis
preparationsDioetyl
sulfosuccinatcDiphenylhydantoin
sodium
Hodgkin's
leukemia
ProstateLung
BoneEsophagus
Echothiophate
iodide"EpinephrineEstrogens
Fluocinolone"Fluocinonide"
StomachLarge
intestineAll
cancer
Skin
melanomaUterus
Fluorouracil"FluoxymesteroneFlurandrenolide"Flurazepam
UterusSkin
melanomaHypopharynx
Hodgkin'sMouth,
unspecified
BladderMyelogenous
leukemiaLung,
solution"Furazolidine
bronchusSkin,
trachea,
and nifuroxime"CancerSkin melanomaAll
cancerObserved/expected1
hydrochloride
acidFormaldehyde
Folie
2/0.2
in-neomycin"Polyvinyl
Poly mix
43/29.020/12.13/0.6
alcohol/chlorobutanol"Potassium
4/1.05/1.6575/519.1
iodidePrednisolone.
Potassium
injectedPrednisone
10/4.66/1.7
hydrochlorideProchlorperazine
Procainamide
Progesterones/progestogensPromethazine
4/1.02/0.23/0.6
Lung, trachea, bronchus
UterusStomachLymphocytic
leukemia
BladderKidney,
uretersLung,
trachea, bronchus
Lymphosarcoma
BreastSmall
intestine
SkinLiverLung,
29/19.35/1.35/1.2
8/3.37/2.857/40.5
13/6.4
8/3.43/0.5
5/1.618/10.4194/166.5
expectorantPropoxyphenePropranolol
89/71.27/2.84/1.02/0.23/0.5Continues5746
3/0.62/0.2
hydrochloridePsyllium
3/0.52/0.15/1.33/0.421/14.2Drug7-Benzene
mueilloidPyridoxine
hydrophilic
trachea, bronchus
cervixLung,
Uterine
bronchusOther
trachea,
lymphomaUnspecified
leukemiaEsophagusObserved/expected2/0.22/0.24/1.06/2.25
hydrochlorideCancerLarynxMyelomaAll
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1989 American Association for Cancer Research.
SCREENING DRUGS FOR CARCINOGENICITY
Table Bl—Continued
expected7/2.82/0.113/6.612/5.86/2.19/3.74/1.0155/127.429/19.223/14.512/5.95/1.3DrugSulfathiazole-sulfacetamide-sulfa
expected16/7.618/9.96/1.91209/113
leu-kemiasBreastMyelomaAll
lymphomas and
DrugPyrvinium
pamoateQuinidine
sulfate)Quinine
(gluconate or
sulfateSeeobarbital.
hydrateThiazide
diureticsThyroid
cancerUterusPolycythemia
butabarbital. & phéno bronchusUterusProstateAll
hormoneTolbutamideTriamcinolone"Triclobisonium"Trimeprazine
trachea,
barbitalSelenium
veraUterusNose,
Sulfide"SennaSpironolactoneSulfacetamide"SulfamethoxazoleCancerProstateHodgkin'sBreastUterusLung,
earBreastUterine
cancerRectumLung,
bronchusUterine
trachea,
cervixMyelomaObserved/
tartrateTripelennamine
hydrochlorideTriprolidineCancerAll
cervixGallbladderThyroidHodgkin'sObserved/
°Topical preparations.
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5747
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2017. © 1989 American Association for Cancer Research.
Screening Prescription Drugs for Possible Carcinogenicity:
Eleven to Fifteen Years of Follow-up
Joseph V. Selby, Gary D. Friedman and Bruce H. Fireman
Cancer Res 1989;49:5736-5747.
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