Alcohol Consumption Over Time and Risk of Lymphoid Malignancies in the California Teachers Study Cohort

Abstract and Introduction

Abstract

Several previous studies found inverse associations between alcohol
consumption and risk of non-Hodgkin lymphoma (NHL) and multiple myeloma.
However, most studies were retrospective, and few distinguished former
drinkers or infrequent drinkers from consistent nondrinkers. Therefore,
the authors investigated whether history of alcohol drinking affected
risks of NHL and multiple myeloma among 102,721 eligible women in the
California Teachers Study, a prospective cohort study in which 496 women
were diagnosed with B-cell NHL and 101 were diagnosed with multiple
myeloma between 1995–1996 and December 31, 2007. Incidence rate ratios
and 95% confidence intervals were estimated using Cox proportional
hazards regression. Risk of all types of B-cell NHL combined or multiple
myeloma was not associated with self-reported past consumption of
alcohol, beer, wine, or liquor at ages 18–22 years, at ages 30–35 years,
or during the year before baseline. NHL subtypes were inconsistently
associated with alcohol intake. However, women who were former alcohol
drinkers at baseline were at elevated risk of overall B-cell NHL (rate
ratio = 1.46, 95% confidence interval: 1.08, 1.97) and follicular
lymphoma (rate ratio = 1.81, 95% confidence interval: 1.00, 3.28). The
higher risk among former drinkers emphasizes the importance of
classifying both current and past alcohol consumption and suggests that
factors related to quitting drinking, rather than alcohol itself, may
increase B-cell NHL risk.

Introduction

Alcohol intake can modulate immune function,^{[1, 2]} an important etiologic factor for lymphoid malignancies.^[3–6]
A pooled analysis of 9 case-control studies of non-Hodgkin lymphoma
(NHL) revealed that ever drinkers, compared with never drinkers, had a
17% lower risk of NHL, a finding potentially explained by a beneficial
effect of moderate alcohol consumption on immune function.^[7]
However, the results showed no evident dose-response relations,
possibly arguing against a biologic basis for the inverse association.
Results of case-control studies of multiple myeloma, another B-cell
malignancy that may be etiologically related to immune perturbation,^[8] have been variable, with some investigators finding no association^[9–12] and others reporting at least a marginal inverse association.^[13–15]
In 6 large prospective cohort studies of alcohol and NHL, investigators
found that moderate alcohol intake was associated with a 41% reduction
in risk among Iowa women,^[16] while heavier alcohol intake was associated with risk reductions of 33% among United Kingdom women,^[17] 23% among retired US men and women,^[18] and 40% among Japanese men.^[19] However, alcohol intake was not associated with NHL risk among Finnish male smokers^[20] or US men and women in a cancer screening trial^[21] or with multiple myeloma risk in the Finnish and Japanese cohorts.^{[19, 20]}

Recent media reports have highlighted findings of a possible protective effect of alcohol against lymphoma development,^[7]
contributing to public confusion over whether alcohol is good or bad
for general health. Thus, it is important from a public health
standpoint to clarify whether modifying alcohol consumption can reduce
lymphoma risk. In support of the premise that alcohol use is not
protective against lymphoma, it has been documented for decades that a
sizeable proportion of persons with preclinical lymphoma experience
acute, intense pain and/or intolerance upon ingestion of alcohol,
usually leading to voluntary cessation of alcohol consumption.^{[22, 23]} In addition, several chronic diseases are associated with increased risk of lymphoid malignancies^[24–26]
and can also influence lifestyle choices, including cessation of
alcohol use. Therefore, failure to distinguish former drinkers from
never drinkers could result in an artifactual association between
current alcohol consumption and reduced lymphoma risk.
Because most previous studies have not addressed this issue, we
examined the association between alcohol intake and risk of lymphoid
malignancies in a large, prospective cohort study, the California
Teachers Study. In the California Teachers Study, we have collected
detailed data on alcohol consumption at and before cohort entry, along
with data from more than a decade of follow-up.
Materials and Methods

Study Population

The California Teachers Study cohort includes 133,479 active and
retired female public school teachers and administrators who completed a
mailed, self-administered baseline questionnaire in 1995–1996
evaluating a range of factors related to cancer risk and women's health.^[27] For this analysis, we sequentially excluded participants who, at baseline, were not residents of California (n = 8,867); had an unknown prior history of cancer (n = 663); consented to participate only in analyses of breast cancer (n = 18); had previously been diagnosed with NHL, multiple myeloma, Hodgkin lymphoma, or leukemia (n = 536); were aged 85 years or older (n = 2,179) or under age 30 years (n = 5,373); or had invalid or inconsistent data on alcohol intake (n = 10,664) or missing data on alcohol intake during the year before baseline (n
= 2,458). Of the 102,721 remaining women included in this analysis, 496
were diagnosed with B-cell NHL (including chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL); International Classification of Diseases for Oncology,
Third Edition (ICDO-3), morphology codes 9591, 9670–9699, 9727, 9823,
9832, 9835, 9836, and 9940) and 101 were diagnosed with multiple myeloma
(including plasmacytoma; ICDO-3 codes 9731–9734)^[28]
after joining the cohort, through December 31, 2007. The 3 most common
B-cell NHL histologic subtypes were diffuse large B-cell lymphoma
(DLBCL) (n = 139; ICDO-3 codes 9678–9680 and 9684), follicular lymphoma (n = 111; ICDO-3 codes 9690, 9691, 9695, and 9698), and CLL/SLL (n = 111; ICDO-3 codes 9670 and 9823).
Human subjects research in this study was approved by the institutional review boards at all participating institutions.

Alcohol Assessment

On the baseline questionnaire, participants reported average weekly
consumption (0, ≤3, 4–10, 11–17, 18–24, or ≥25 drinks per week) of beer,
wine/champagne, and cocktails/liquor during the year before study
entry, at ages 30–35 years, and at ages 18–22 years. They also reported
how many days per week they usually drank each beverage. A typical drink
was defined as 1 bottle, can, or glass of beer; 1 glass of wine or
champagne or 1 wine cooler; or 1 cocktail, shot, or mixed drink of
liquor. A single drink of beer, wine, or liquor was assumed to contain
13.2 g, 13.3 g, or 20.0 g of alcohol, respectively, for women aged
<30 years; 13.2 g, 11.1 g, or 15.0 g of alcohol, respectively, for
women aged 30–59 years; and 13.2 g, 9.2 g, or 15.0 g of alcohol,
respectively, for women aged ≥60 years.^{[29, 30]}
On the basis of these standards, we calculated daily intake of alcohol
in grams from each type of drink during each time period, and we
classified intake using cutoffs approximately equivalent to half or full
drinks of wine (the most commonly consumed alcoholic beverage in the
cohort) per day. Alcohol intake as reported in our food frequency
questionnaire was reproducible (ρ = 0.87) and valid (ρ = 0.74) in
comparison with multiple 24-hour recalls in a subset of cohort members
(31).
For analyses of alcohol intake during the year before baseline, we
classified women as former drinkers if they reported no baseline alcohol
consumption but did report having consumed alcohol at ages 18–22 years
and/or 30–35 years. Women who reported not having consumed alcohol
during all 3 time periods were classified as consistent nondrinkers. For
analyses of alcohol intake at ages 30–35 years, we classified women as
former drinkers if they reported no alcohol consumption at that age but
did report having consumed alcohol at ages 18–22 years. Women who
reported not having consumed alcohol at ages 18–22 or 30–35 years but
who did consume alcohol during the year before baseline were classified
separately. For analyses of beer, wine, and liquor intake, we classified
women as current, former, or consistent nondrinkers of that specific
type of alcoholic beverage, using the same logic.


Follow-up


Participants were followed from the date of completion of the
baseline questionnaire to the date of a first diagnosis with a
hematopoietic malignancy, relocation out of California, death, or
December 31, 2007, whichever occurred earliest. Participants diagnosed
with T-cell NHL (n = 43), NHL of unknown histologic type (n = 22), Hodgkin lymphoma (n = 33), or leukemia (n
= 116; other ICDO-3 morphology codes between 9590 and 9989) during
follow-up were censored at the date of diagnosis. Information on
incident cancers was obtained through annual linkage of cohort members
to the population-based California Cancer Registry, which is over 99%
complete. Linkages with the California state mortality file and the
national Social Security Administration death master file were used to
ascertain date and cause of death. Address changes were obtained through
record linkages with multiple sources, including the National Change of
Address database, change-of-address forms from annual mailed
newsletters, and proactive notifications by participants.


Statistical Analysis


Associations between alcohol intake and risk of lymphoid malignancies
were estimated using Cox proportional hazards regression, with age (in
days) as the time scale and data stratified by age (in years) at
baseline to adjust for calendar-year effects. Incidence rate ratios were
estimated as hazard ratios and 95% confidence intervals comparing
former or current alcohol drinkers with consistent nondrinkers (of total
alcohol or a specific alcoholic beverage type). On the basis of prior
knowledge and independent associations with risk of overall B-cell NHL,
NHL subtypes, or multiple myeloma, we assessed a broad range of
potential confounders, including race/ethnicity, birthplace, total
energy intake, intake of fruits and vegetables, body mass index, sunburn
history, family history of hematopoietic cancer, personal history of
melanoma or other skin cancer, number of older siblings, age at
menarche, menopausal hormone therapy, pesticide/herbicide/insecticide
use at various ages, urban/rural residence, and neighborhood-level
socioeconomic status. None of these factors altered the associations
with alcohol intake by more than 10% after multivariable adjustment;
therefore, none were included in the final regression models. In models
of associations with specific alcoholic beverage types, all estimates
were mutually adjusted for beer, wine, and liquor intake.
The proportional hazards assumption was not violated by any of the
main categories of alcohol consumption, based on significance tests of
interactions between the exposure and the time scale and visual
assessment of the time-to-event curves. All tests of statistical
significance were 2-sided. Analyses were performed using SAS, version
9.1.3 (SAS Institute, Inc., Cary, North Carolina).

Results

Table 1 shows the distribution of selected baseline characteristics in the study population. As shown in Table 2,
which presents the associations with alcohol intake in the year before
baseline, we found a statistically significant positive association
between former alcohol consumption, compared with consistent
nondrinking, and risk of overall B-cell NHL. We observed no association
of overall B-cell NHL risk with any level of alcohol consumption in the
year before baseline. Likewise, baseline and former beer, wine, and
liquor consumption were not statistically significantly associated with
overall B-cell NHL risk, nor was frequency of consuming each type of
beverage (1–4 days/week or 5–7 days/week vs. consistent nondrinking;
latter data not shown).
For the sake of comparison with results from previous studies, when
we combined former drinkers with consistent nondrinkers as the reference
group, the rate ratios for associations with alcohol intake in the year
before baseline decreased (for baseline total alcohol intake of <5
g/day vs. never/former drinking, rate ratio (RR) = 1.00 (95% confidence
interval (CI): 0.79, 1.28); for 5–<10 g/day, RR = 0.84 (95% CI: 0.65,
1.09); for 10–<20 g/day, RR = 0.86 (95% CI: 0.66, 1.11); and for ≥20
g/day, RR = 1.00 (95% CI: 0.73, 1.39)). By contrast, when we combined
former drinkers with persons who consumed alcohol during the year before
baseline, the rate ratio for any drinking versus consistent nondrinking
was increased (RR = 1.12, 95% CI: 0.90, 1.40).
In analyses of B-cell NHL subtypes, former consumption of total
alcohol or wine at baseline was associated with increased risk of
follicular lymphoma (Table 2).
Average intake of <10 g/day (but not ≥10 g/day) of alcohol was
marginally associated with reduced risk of DLBCL, whereas any alcohol
intake during the year before baseline was associated with increased
risk of CLL/SLL. We observed no apparent associations between alcohol
consumption in the year before baseline and risk of multiple myeloma.
As Table 3
shows, we observed no association of total alcohol consumption at ages
18–22 years or 30–35 years with risk of overall B-cell NHL, DLBCL,
follicular lymphoma, or multiple myeloma, whereas consumption of any
alcohol during either age interval was associated with increased risk of
CLL/SLL. When we examined intake of specific alcoholic beverages at
ages 18–22 years and 30–35 years, we did not detect any consistent
inverse or positive associations with risk of any lymphoid malignancies
(see Web Table 1, which is posted on the Journal's Web site (http://aje.oxfordjournals.org/)).
The results for alcohol intake at ages 30–35 years were unchanged when
the analysis was limited to women aged ≥40 years at baseline, thereby
ensuring that reported intake was at least 5 years in the past (data not
shown). When we examined changes in alcohol intake across the time
periods assessed, including total alcohol intake of ≥20 g/day in all 3
periods (1% of the cohort; n = 5 cases), we observed no meaningful patterns of association (data not shown).
To assess whether the positive associations of former drinking during
the year before baseline with risks of overall B-cell NHL and
follicular lymphoma were due to prodromal symptoms, we performed a
secondary analysis after excluding the first 3 years of follow-up (n = 381 B-cell NHL cases, n = 102 DLBCL cases, n = 85 follicular lymphoma cases, n = 82 CLL/SLL cases, and n
= 78 multiple myeloma cases). The results were not appreciably
affected, with the exception that former alcohol consumption was
associated with increased risk of CLL/SLL (RR = 2.85, 95% CI: 1.08,
7.51) as well as overall B-cell NHL and follicular lymphoma (other data
not shown).
To examine associations with recent alcohol drinking, we performed a
secondary analysis of baseline alcohol consumption limited to the first 5
years of follow-up (through December 31, 2000; n = 201 B-cell
NHL cases). In this analysis, the relation between recent alcohol
consumption and overall B-cell NHL risk showed evidence suggestive of a
U-shaped curve. The rate ratios for B-cell NHL associated with total
alcohol intake, versus consistent nondrinking, were 1.19 (95% CI: 0.79,
1.79) for <5 g/day, 0.67 (95% CI: 0.41, 1.09) for 5–<10 g/day,
0.77 (95% CI: 0.48, 1.24) for 10–<20 g/day, and 1.38 (95% CI: 0.84,
2.27) for ≥20 g/day.
Finally, to examine whether associations with alcohol consumption
changed after exclusion of cases with rapidly fatal disease, who are
less likely to be included in case-control studies, we performed a
secondary analysis excluding B-cell NHL cases who died within 18 months
of diagnosis (n = 88 cases). The results did not differ appreciably from those in the primary analysis (data not shown).

Discussion

In this large, prospective cohort study of California women, we found
little evidence that alcohol consumption during various time periods in
adulthood is associated with risk of overall B-cell NHL or multiple
myeloma, although we may have lacked sufficient statistical power to
detect associations. We detected a weak inverse association of moderate
baseline alcohol intake with risk of DLBCL, but the association was not
consistent across different types of alcoholic beverages, nor did risk
decline with increasing total alcohol intake, suggesting that the
observed association was not due to an effect of alcohol itself.
Conversely, we found positive associations of alcohol intake at all
assessed time points with risk of CLL/SLL, although most of these
associations lacked evidence of a dose-response trend. Thus, the
observed associations with risk of DLBCL and CLL/SLL may have been due
to chance or confounding. Alternatively, these associations may reflect
true biologic heterogeneity between NHL subtypes and could perhaps point
to an effect of alcohol on B-cell differentiation.
Most notably, we observed positive associations between former intake
of alcohol in the year before baseline and risk of overall B-cell NHL,
follicular lymphoma, and possibly CLL/SLL. This result was not explained
by the wide array of confounders examined and may point to an etiologic
role of other factors, such as illness or efforts to improve general
health, that lead to cessation of alcohol use. The persistence of the
positive association with former drinking after we excluded diagnoses
made within 3 years of baseline indicates that such factors are unlikely
to be alcohol pain/intolerance or other preclinical symptoms of
lymphoma or that such symptoms occur more than 3 years before diagnosis.
This general premise is consistent with our observation that recent
moderate alcohol consumption (within the past 5 years) was suggestively
associated with decreased risk of overall B-cell NHL, indicating that
current alcohol consumption may be a surrogate for better current
health.
The limited evidence of an inverse association with DLBCL risk in our
study accords with the inverse association detected in an InterLymph
pooled analysis of 9 NHL case-control studies^[7] and several other studies^{[10, 12, 32–34]} and in 4 of 6 prospective cohort studies of NHL.^[16–19]
A number of biologically plausible mechanisms could underlie such a
protective effect. Whereas heavy alcohol intake has been shown to have
immunosuppressive effects that result in increased susceptibility to
infections and impaired host response to injury,^[1] light or moderate alcohol consumption can have a beneficial attenuating effect on proinflammatory cytokines and chemokines^{[35, 36]} that may otherwise promote lymphomagenesis.^[37] Alcohol can also increase insulin sensitivity,^[38] which may in turn decrease NHL risk.^[39] Antioxidants such as resveratrol in wine and flavonoids in beer may have additional anticarcinogenic effects,^{[40, 41]} and alcoholics have been found to have better DNA repair capacity than nonalcoholics.^[42]

However, our overall finding of no association of alcohol consumption
with risk of B-cell NHL or multiple myeloma is more consistent with the
results of previous case-control studies^{[9, 11, 43–47]} and 2 prospective cohort studies^{[20, 21]}
that similarly detected no association. Some of the heterogeneity among
previous studies may be due in part to the substantial potential for
recall and selection biases in retrospective case-control studies. Given
that alcohol consumption has variable connotations of social and
cultural desirability^[48]
and is well known to affect health, cases may report alcohol intake
differently from controls, resulting in recall bias. In addition, early
symptoms or the diagnosis itself may cause patients to stop drinking
alcohol, leading to a false inverse association between alcohol
consumption and disease risk at the time of the study interview.
Finally, if alcohol consumption is associated not with NHL or multiple
myeloma risk but with more severe or fatal disease, then case-control
studies, in which deceased patients are usually excluded and those with
debilitating disease often do not participate, may again detect a
spurious inverse association with alcohol consumption. Therefore,
prospective cohort studies generally have higher validity for assessing
the etiologic role of alcohol intake.
Nonetheless, in both retrospective and prospective studies, it is
important to collect information on not only current alcohol intake but
also past alcohol intake to distinguish among current, former, and never
drinkers. Given that poor health is a major reason for reducing or
ceasing alcohol consumption,^[30]
former drinkers may have higher disease risk than never drinkers or
current drinkers. Therefore, regardless of study design, combining
former drinkers with never drinkers may produce a spurious inverse
association with current drinking, whereas combining former drinkers
with current drinkers may generate a false-positive association or
obscure a true inverse association. Indeed, in our study, when we
combined never drinkers with former drinkers as the reference group, the
association with current alcohol intake was decreased, whereas
combining former drinkers with current drinkers inflated the association
with ever drinking. Nearly all previous studies of alcohol and risk of
lymphoid malignancies combined former drinkers with either never
drinkers or current drinkers, and many investigators were unclear about
whether "alcohol consumption" referred to current (excluding former)
drinking or ever (including former) drinking. A few studies included in
the InterLymph analysis^[7]
classified former drinkers as a separate group and found no association
between former (versus never) drinking and risk of NHL or its
histologic subtypes. However, none of the previous 5 prospective cohort
studies of alcohol and risk of lymphoid malignancies analyzed former
alcohol intake separately.
Another potential source of misclassification in previous studies of
alcohol and risk of lymphoid malignancies is a failure to distinguish
between never drinkers and occasional drinkers, who can differ markedly
in behaviors, health status, and—particularly if abstinence is due to
religious or cultural reasons—genetic traits.^[30]
Especially in European studies, true abstainers have often been
combined with infrequent drinkers (e.g., <1 drink monthly or weekly)
for comparison with frequent drinkers.^{[10, 12, 33, 47]}
Such variability in the definition of the reference group for relative
risk estimates may explain some of the inconsistency in results among
previous studies.
In the California Teachers Study, we prospectively collected
information on recent and past alcohol consumption, and our
questionnaire distinguished between women who consumed low quantities of
alcohol and those who did not drink at all, enabling us to classify
women according to both past alcohol intake and true abstinence. This
information was necessary to reveal that risks of overall B-cell NHL and
follicular lymphoma differed between former drinkers and never
drinkers.
However, our study had some limitations. First, we did not assess
alcohol intake continuously throughout the participant's lifetime and
therefore could not construct a detailed history of alcohol consumption.
Second, our analyses were constrained by the limited number of incident
cases, which prevented us from examining numerous categories of alcohol
intake, drinking patterns over time, or associations with less common
lymphoma subtypes. Notably, 2 of the previous prospective cohort studies
that observed an inverse association with alcohol consumption had
substantially more incident cases than we did,^{[17, 18]}
giving them considerably more statistical power to detect a true
association. Thus, the absence of an association with risk of overall
B-cell NHL, some NHL subtypes, and multiple myeloma in our study may
have been due to insufficient statistical power. Third, we did not
assess reasons for cessation of alcohol consumption and therefore could
not compare women who quit drinking because of ill health with those who
quit for other reasons. Finally, we could not examine the effects of
changes in alcohol consumption (including cessation or resumption of
drinking) after baseline, which may have influenced subsequent risk of
B-cell NHL or multiple myeloma.
Despite these limitations, ours is the first prospective cohort study
of lymphoid malignancies to examine alcohol intake before baseline and
to distinguish current drinkers from former drinkers at baseline. Our
results are strengthened by detailed covariate data and complete and
valid follow-up for incident cancer among California residents. In
summary, we found that alcohol consumption is not associated with risk
of overall B-cell NHL or multiple myeloma and that former drinkers may
have higher risks of follicular lymphoma and CLL/SLL, for reasons that
may be related to illness, lifestyle changes, or other factors that
prompt people to stop drinking prior to diagnosis. Moreover, the
relation of alcohol consumption with B-cell NHL risk may vary by
histologic subtype. Future studies of the role of alcohol in the
development of lymphoid malignancies or any other health outcomes should
account for former drinking and changing drinking patterns over time.
Only with consistent attention to these distinctions can future
investigators determine whether alcohol truly protects against
lymphomagenesis or whether other factors explain the inverse
associations detected in past studies.


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