IJC

International Journal of Cancer

Lycopene, tomato products and prostate cancer-specific

mortality among men diagnosed with nonmetastatic prostate
cancer in the Cancer Prevention Study II Nutrition Cohort
Ying Wang, Eric J. Jacobs, Christina C. Newton and Marjorie L. McCullough
Epidemiology Research Program, American Cancer Society, Atlanta, GA

While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited
evidence for an association between consumption of lycopene and tomato products and prostate-cancer specific mortality
(PCSM). We examined the associations of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with
PCSM in a large prospective cohort. This analysis included men diagnosed with nonmetastatic prostate cancer between enroll-
Cancer Epidemiology

ment in the Cancer Prevention Study II Nutrition Cohort in 1992 or 1993 and June 2011. Prediagnosis dietary data, collected
at baseline, were available for 8,898 men, of whom 526 died of prostate cancer through 2012. Postdiagnosis dietary data,
collected on follow-up surveys in 1999 and/or 2003, were available for 5,643 men, of whom 363 died of prostate cancer
through 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals
(CIs) for PCSM. Neither prediagnosis nor postdiagnosis dietary lycopene intake was associated with PCSM (fourth vs. first
quartile HR 5 1.00, 95% CI 0.78–1.28; HR 5 1.22, 95% CI 0.91–1.64, respectively). Similarly, neither prediagnosis nor post-
diagnosis consumption of tomato products was associated with PCSM. Among men with high-risk cancers (T3–T4 or Gleason
score 8–10, or nodal involvement), consistently reporting lycopene intake  median on both postdiagnosis surveys was asso-
ciated with lower PCSM (HR 5 0.41, 95% CI 0.17–0.99, based on ten PCSM cases consistently  median intake) compared to
consistently reporting intake < median. Future studies are needed to confirm the potential inverse association of consistently
high lycopene intake with PCSM among men with high-risk prostate cancers.

Prostate cancer is the most commonly diagnosed cancer, and
the second leading cause of cancer death among men in the
United States.1 There are nearly 3 million prostate cancer
survivors currently living in the United States, accounting for
20% of all cancer survivors, and the number is still increasing
with 220,000 new cases diagnosed each year.2 Despite a gen-
erally good prognosis, death from prostate cancer, even for
men diagnosed with localized prostate cancer, is still a con-
cern.3 Although localized prostate cancer is mostly indolent,
local progression and distant metastasis can develop over the
long term and cause prostate cancer death.4 In addition, men
with high-grade tumors (Gleason score 8–10) are at least
four times as likely to die from prostate cancer as men with
low-grade tumors (Gleason score 2–6).5 Although data are
still limited, a growing number of studies suggest that long-
Key words: lycopene, tomato, prostate cancer, survival, mortality
Conflict of interest: Nothing to report
Grant sponsor: American Cancer Society
DOI: 10.1002/ijc.30027
History: Received 25 Sep 2015; Accepted 19 Jan 2016; Online 2 Feb
2016
Correspondence to: Ying Wang, PhD, Epidemiology Research
Program, American Cancer Society, Inc. 250 Williams Street,
6D-222, Atlanta, GA 30303, USA, Tel.: 1404-329-4341,
Fax: 404-321-4669, E-mail: ying.wang@cancer.org
term postdiagnosis diet plays a role in prostate cancer pro-
gression and eventually prostate cancer mortality.6–9
Lycopene, found predominantly in tomato products, is a
major carotenoid widely distributed in the human body.
Lycopene accumulates in several key organs including the
prostate gland.10 Lycopene is hypothesized to have anticarci-
nogenic effects primarily due to its antioxidant capacity,
which is the highest of the six major carotenoids in human
plasma.11 In addition, other proposed mechanisms include
antiproliferative effects resulting from interference with the
IGF-1 signaling pathway and cell cycle progression,12
decreasing cholesterol required by tumor cells to prolifer-
ate13,14 and stimulation of gap junction communication,
which is downregulated in most tumor cells, through increas-
ing connexin43 mRNA expression.15 These mechanisms, plus
the potential antiangiogenic effects of dietary lycopene on
prostate tumors,16 might play a role in prostate cancer
progression.
Epidemiologic studies using dietary questionnaires suggest
that higher intakes of dietary lycopene and tomato products
are associated with modestly lower risk of incident prostate
cancer,17,18 although studies are inconsistent.19 In addition,
case–control studies found that lycopene concentrations, but
not other carotenoids in blood and prostate tissues, were sig-
nificantly lower in prostate cancer patients than in
controls.20,21

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Wang et al. 2847

What’s new?
While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited
evidence for an association between their consumption and prostate-cancer specific mortality (PCSM). This is the first study
to comprehensively examine the associations of pre- and post-diagnosis lycopene and tomato product intake with PCSM
among men with nonmetastatic prostate cancer. No association was observed between pre- or post-diagnosis intake and
PCSM using a single dietary measurement. However, consistently high intake of lycopene after diagnosis assessed using
repeated dietary questionnaires was associated with significantly lower risk of PCSM among men diagnosed with high-risk
prostate cancer.

Limited evidence suggests that lycopene or tomato prod- by self-report and subsequently verified through medical
ucts might influence prostate cancer progression. Short-term records or linkage with state cancer registries (n 5 10,419).
lycopene supplementation in men with localized prostate An additional 161 cases that were not self-reported were
cancer was shown to lower serum prostate-specific antigen identified during the process of verifying another cancer

(PSA) levels (as a measure of prostate cancer progression)
over 3 weeks to 1 year, though only two of four studies were
placebo-controlled.15,22–24 In the only epidemiologic study to
date, in 1,202 men in the Health Professionals Follow-up
Study with localized/regional prostate cancer, being in the
highest quartile of postdiagnosis tomato sauce intake, com-
pared to being in the lowest quartile, was associated with
lower risk of prostate cancer progression (defined as PSA
recurrence, metastasis or prostate cancer death) [hazard ratio
(HR) 5 0.56, 95% confidence interval (CI) 0.38–0.82].6 No
previous study has examined the association of dietary lyco-
pene intake or tomato products with prostate cancer-specific
mortality (PCSM).
The aim of this study was to investigate the association of
prediagnosis and postdiagnosis dietary lycopene and tomato
product consumption with PCSM in men diagnosed with
nonmetastatic prostate cancer during follow-up of the Cancer
Prevention Study II (CPS-II) Nutrition Cohort. The CPS-II
Nutrition Cohort is well suited for this analysis because it
includes a large number of men diagnosed with prostate can-
cer and because dietary information was collected at multiple
time points.
Material and Methods
Study population
Men in this study were drawn from the CPS-II Nutrition
Cohort, initiated by the American Cancer Society in 1992.25
A total of 86,402 men from 21 states enrolled in the Nutri-
tion Cohort in 1992 and 1993. At baseline (1992–1993), a
ten-page self-reported questionnaire that included informa-
tion on demographics, medical conditions, weight history,
diet and other lifestyle factors was mailed to all participants.
Follow-up questionnaires were sent to the participants in
1997 and every 2 years thereafter to update the exposures
and ascertain newly diagnosed cancers. The CPS-II Nutrition
Cohort has been approved by the Institutional Research
Board at Emory University.
A total of 10,864 men were identified as having been diag-
nosed with nonmetastatic prostate cancer between baseline
and June 30, 2011. Most of the cases were initially identified
Cancer Epidemiology
through linkage with the state cancer registry. Finally, 284
cases were initially identified as cancer deaths through link-
age with the National Death Index (NDI). We subsequently
excluded prostate cancer cases identified through NDI that
could not be verified through medical records or linkage with
state cancer registries (n 5 158), as no diagnosis date was
available. We also excluded men with implausible diagnosis
dates (n 5 33), unknown stage (n 5 300), nonadenocarcinoma
histology (n 5 9), distant stage (n 5 283) or prostate tumors
classified as carcinoma in situ (n 5 6). Metastatic prostate
cancer cases were not included because the 5-year survival
rate is much lower than nonmetastatic cases and it is unlikely
that diet would substantially affect long-term survival.
We conducted separate analyses of prediagnosis and post-
diagnosis intakes. In analyses of prediagnosis dietary intake
we further excluded men with invalid dietary data or missing
information on tomato product intake (n 5 1,177). In analy-
ses of postdiagnosis dietary intake we excluded men with
implausible dietary data or missing tomato product intake in
postdiagnosis surveys (n 5 4,432). After exclusions, there
were 8,898 prostate cancer patients included in the analyses
of prediagnosis dietary intake and 5,643 included in the anal-
yses of postdiagnosis dietary intake. A total of 5,018 prostate
cancer patients who had eligible prediagnosis and postdiag-
nosis dietary data were included in both prediagnosis and
postdiagnosis analyses.
Diet assessment
Dietary information was assessed at baseline using a vali-
dated, modified brief Block Food Frequency Questionnaire
(FFQ)25–27 and subsequently updated in 1999 and 2003 using
a modified Willett FFQ.25,28,29 On all FFQs, participants were
asked to report, on average in the past year, how often they
consumed a portion of each food or foods listed. In 1992,
tomato product intakes were estimated from three questions,
including “Tomatoes, tomato juice,” “Spaghetti, lasagna, other
pasta with tomato sauce” and “Vegetable and tomato soups,
including vegetable beef, minestrone.” Comparable questions
were asked in 1999 and 2003 using modified Willett FFQs.
These questions included “Tomatoes,” “Tomato or V8 juice”

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 2848
and “Tomato sauce, e.g., spaghetti sauce.” Estimated lycopene
intake from all FFQs included tomato products and other
food items such as grapefruits, but did not include supple-
ment use. The modified Willett FFQ also assessed salsa and
ketchup or red chili sauce intake, which contributed to lyco-
pene estimates but due to low intake levels in our study pop-
ulation and small portion sizes, salsa or ketchup were not
included in our analyses of intake of tomato products (serv-
ings/day). Information on lycopene supplement use was first
asked in 2001.
The 1992 baseline FFQ was used to assess prediagnosis
dietary intake. Postdiagnosis dietary intake was assessed from
the 1999 FFQ for patients diagnosed after baseline and before
the date the 1999 survey was completed, and from the 2003
FFQ for patients diagnosed after 1999 and before the date
Cancer Epidemiology
the 2003 survey was completed. Postdiagnosis dietary data
were unavailable for men who did not return either the 1999
or the 2003 surveys after their diagnosis date, including all
men diagnosed after completion of the 2003 survey.
Outcome ascertainment
The outcome of interest in this study is PCSM. Deaths were
ascertained through December 31, 2012 by linkage with the
NDI.30 PCSM is defined as deaths with prostate cancer coded
as the singular underlying cause of death (International Clas-
sification of Diseases 9th revision code: 185; 10th revision
code: C61).
Statistical analysis
Questionnaire-specific quartiles were created for intakes of
dietary lycopene and individual tomato products and for total
intake of tomato products. Cox proportional hazards models
were used to calculate hazard ratios (HRs) and 95% confi-
dence intervals (CIs) of PCSM. Time since diagnosis was
used as the underlying time axis for all analyses. For prediag-
nosis dietary analyses, follow-up time started from prostate
cancer diagnosis date and ended on death date or end of
follow-up. For postdiagnosis dietary analyses, a late-entry
model was applied, with follow-up starting from the date of
completion of the postdiagnosis FFQ and ending on death
date or end of follow-up.
All Cox regression models were stratified on single year of
age at diagnosis, and included calendar year of diagnosis,
race, tumor extent (T1–T2, T3–T4), Gleason score (2–6, 7,
8–10, unknown) and nodal involvement (none, any) as basic
covariates. Other covariates that were associated with both
outcome and exposure were further included in prediagnosis
or postdiagnosis multivariable models. In prediagnosis mod-
els, we included the following additional covariates assessed
from the baseline survey or follow-up surveys as shown in
Table 1: education, body mass index (BMI), physical activity,
smoking status, multivitamin supplement use, total fish
intake and a history of prediagnosis PSA testing not leading
to prostate cancer diagnosis. History of PSA testing was first
asked on the 1997 survey and biennially thereafter. The 1997
Lycopene, tomato products and prostate cancer survival
survey asked about timing of PSA testing and was used to
retrospectively assess PSA testing history for patients diag-
nosed between baseline and completion of 1997 survey. Any
“PSA testing not leading to prostate cancer diagnosis” was
defined as PSA testing self-reported on a questionnaire that
was completed before prostate cancer diagnosis, or for the
1997 survey, PSA testing reported as having occurred at least
180 days before diagnosis. Additional covariates included in
the postdiagnosis dietary analysis were assessed at the time of
postdiagnostic diet report (except education, prediagnosis
PSA testing, and initial treatment), including history of cardi-
ovascular disease, physical activity, smoking status and total
dairy intake (in quartiles).
The proportional hazards assumption was evaluated using
the likelihood ratio test by examining if there was a signifi-
cant interaction between lycopene and total tomato product
intakes, and log-transformed survival time. No significant
deviation from proportional hazards was observed.
Among men diagnosed with clinically localized prostate
cancer, PCSM is substantially higher among men with high-
grade (Gleason score 8–10) than those with low-grade (Glea-
son score 2–6) prostate cancers.5 Therefore, we examined
results stratified by cancer risk category. A “lower risk” group
was defined as low- to intermediate-risk prostate cancer (T1–
T2 and Gleason score 2–7), and a high-risk group was
defined as high to very high-risk prostate cancer (T3–T4 or
Gleason score 8–10, or nodal involvement) according to
National Comprehensive Cancer Network guidelines.31
We examined interactions between lycopene intake and
BMI (<25 vs. 25 kg/m2), smoking status (never smokers vs.
ever smokers), diagnosis year (diagnosed with prostate can-
cer < 5 years or  5 years after completion of the baseline
survey, and < 5 years or  5 years before postdiagnosis sur-
vey), treatment (prostatectomy vs. radiation, the major two
treatments), current multivitamin use (yes vs. no) in prediag-
nosis models and multivitamin or any lycopene supplement
use (yes vs. no) in postdiagnosis models. Information on use
of any lycopene supplement was not available on the baseline
survey.
We also conducted sensitivity analyses: (i) assessing pre-
diagnosis dietary intake from the FFQ completed closest to
diagnosis rather than from the baseline questionnaire; (ii)
applying a 2-year lag in both prediagnosis and postdiagnosis
analyses and (iii) excluding men who completed their survey
within 1 year of diagnosis (1 year before diagnosis for pre-
diagnosis analyses, and 1 year after diagnosis for postdiagno-
sis analyses) due to concerns that treatment or illness may
influence diet close to diagnosis.
An analysis by consistency of intake was conducted
among 5,018 men with both prediagnosis and postdiagnosis
dietary data. This analysis compared PCSM risk among men
whose lycopene or total tomato product consumption was
consistently high (at or above median) with that among men
whose lycopene intake was consistently low (below median)
on both prediagnosis and postdiagnosis FFQs. A similar
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Wang et al. 2849

Table 1. Selected characteristics by prediagnosis dietary lycopene intake among men in the CPS-II Nutrition Cohort diagnosed with nonmeta-
static prostate cancer1
Quartiles of dietary lycopene intake
First (n52,224) Second (n52,225) Third (n52,225) Fourth (n52,224)
N (%) N (%) N (%) N (%)
Age at diagnosis
<65 221 (9.7) 238 (10.7) 209 (9.7) 283 (12.7)
652<70 557 (24.7) 541 (24.3) 547 (24.9) 534 (24.0)
702<75 739 (33.3) 731 (32.8) 682 (30.7) 679 (30.5)
752<80 488 (22.2) 496 (22.3) 567 (25.1) 511 (23)
802<85 176 (8.1) 172 (7.7) 178 (7.8) 172 (7.7)
85 43 (2.0) 47 (2.1) 42 (1.8) 45 (2.0)
Diagnosis year2

Cancer Epidemiology
1992–1998 904 (40.6) 869 (39.1) 839 (37.7) 876 (39.4)
1999–2005 950 (42.7) 968 (43.5) 974 (43.8) 958 (43.1)
2006 2 2011 370 (16.6) 388 (17.4) 412 (18.5) 390 (17.5)
Race
White 2,131 (95.8) 2,181 (98) 2,194 (98.6) 2,177 (97.9)
Black 65 (2.9) 27 (1.2) 16 (0.7) 19 (0.9)
Other/unknown 28 (1.3) 17 (0.8) 15 (0.7) 28 (1.3)
Tumor extent (T), nodal involvement (N) and Gleason score (GS)
T1–T2 and N0, GS 2 2 6 1,071 (48.1) 1,042 (46.8) 1,099 (49.5) 1,132 (50.9)
T1–T2 and N0, GS 7 492 (22.4) 498 (22.4) 513 (22.8) 449 (20.2)
T1–T2 and N0, GS unknown 252 (11.2) 226 (10.2) 231 (10.5) 256 (11.5)
T1–T2 and N0, GS 8 2 10 221 (10) 246 (11.1) 209 (9.3) 218 (9.8)
T3–T4 and N0, GS 2 2 7 or unknown 125 (5.6) 139 (6.3) 91 (4.2) 100 (4.5)
T3–T4 and N0, GS 8 2 10; or N1 63 (2.8) 74 (3.3) 82 (3.7) 69 (3.1)
3
First course of treatment
Prostatectomy 735 (32.7) 741 (33.3) 684 (31.1) 678 (30.5)
Cryosurgery 58 (2.7) 43 (1.9) 57 (2.5) 41 (1.8)
Radiation therapy 763 (34.5) 777 (34.9) 829 (37.1) 807 (36.3)
Watchful waiting or hormone therapy only 251 (11.5) 280 (12.6) 272 (12) 299 (13.5)
Unknown 417 (18.7) 384 (17.3) 383 (17.2) 399 (17.9)
Any history of prediagnosis PSA testing not leading to prostate cancer diagnosis4
No 399 (17.4) 331 (14.9) 293 (13.6) 346 (15.5)
Yes 1,663 (75.4) 1,753 (78.7) 1,770 (79) 1,744 (78.5)
Unknown 162 (7.1) 141 (6.3) 162 (7.4) 134 (6.0)
Education at baseline
<High school 209 (9.3) 128 (5.8) 101 (4.5) 101 (4.5)
High school graduate 481 (21.6) 376 (16.9) 330 (14.9) 260 (11.7)
Some college 584 (26.3) 554 (24.9) 507 (22.8) 505 (22.7)
College graduate 950 (42.8) 1,167 (52.5) 1,287 (57.7) 1,358 (61.1)
Body mass index at baseline (kg/m2)
<22.5 221 (9.9) 232 (10.4) 251 (11.3) 253 (11.4)
22.52<25 534 (24) 576 (25.9) 593 (26.6) 618 (27.8)
252<30 1,153 (51.8) 1,134 (51) 1,101 (49.5) 1,058 (47.6)
30 283 (12.7) 259 (11.6) 256 (11.5) 267 (12)
Unknown 33 (1.5) 24 (1.1) 24 (1.1) 28 (1.3)

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 2850 Lycopene, tomato products and prostate cancer survival

Table 1. Selected characteristics by prediagnosis dietary lycopene intake among men in the CPS-II Nutrition Cohort diagnosed with nonmeta-
static prostate cancer (Continued)
Quartiles of dietary lycopene intake
First (n52,224) Second (n52,225) Third (n52,225) Fourth (n52,224)
N (%) N (%) N (%) N (%)
Smoking status at baseline
Never 799 (35.9) 790 (35.5) 817 (36.6) 809 (36.4)
Current 189 (8.5) 153 (6.9) 130 (5.9) 100 (4.5)
Former 1,222 (54.9) 1,271 (57.1) 1,270 (57.1) 1,309 (58.9)
Unknown 14 (0.6) 11 (0.5) 8 (0.4) 6 (0.3)
Physical activity at baseline (MET-hour/week)
<4 952 (42.7) 804 (36.1) 695 (31.3) 627 (28.2)
42<11 301 (13.6) 352 (15.8) 338 (15.1) 379 (17.0)
Cancer Epidemiology

112<21 498 (22.4) 544 (24.4) 593 (26.7) 558 (25.1)

21 451 (20.3) 508 (22.8) 580 (26) 639 (28.7)
Unknown 22 (1.0) 17 (0.8) 19 (0.9) 21 (0.9)
Multivitamin use at baseline
No current use 1,526 (68.7) 1,467 (65.9) 1,449 (65.1) 1,422 (63.9)
Current use 671 (30.1) 731 (32.9) 751 (33.8) 770 (34.6)
Unknown 27 (1.2) 27 (1.2) 25 (1.1) 32 (1.4)
Fish intake at baseline (serving/week)
<0.6 773 (34.7) 570 (25.6) 445 (20) 425 (19.1)
0.62<1.3 636 (28.6) 599 (26.9) 572 (25.7) 454 (20.4)
1.32<2.2 454 (20.5) 571 (25.7) 642 (28.8) 569 (25.6)
2.2 361 (16.2) 485 (21.8) 566 (25.5) 776 (34.9)
1
Standardized on calendar period of diagnosis unless otherwise indicated.
2
Not standardized on calendar period of diagnosis.
3
Self-reported on questionnaire mailed to participant after initial report of prostate cancer.
4
Based on self-reports of PSA test made on biennial follow-up questionnaires completed before diagnosis of prostate cancer.
Abbreviations: CPS: Cancer Prevention Study; PSA: prostate-specific antigen; MET, metabolic equivalent task.

analysis by consistency of intake was conducted among men
with postdiagnosis intake information from both 1999 and
2003 (n 5 2,581). This analysis compared PCSM risk among
men whose lycopene or total tomato product intake was con-
sistently high on both postdiagnosis FFQs with men whose
intake was consistently low. SAS release 9.2 (SAS Institute,
Cary, NC) was used for all statistical analyses.
Results
Baseline characteristics of prostate cancer patients according
to prediagnosis lycopene intake are shown in Table 1. The
average age at diagnosis of prostate cancer in this study was
72 years. Men who had higher prediagnosis dietary lycopene
intake were similar to those with lower lycopene intake with
respect to age at diagnosis, tumor stage and grade, history of
PSA screening, treatment type and BMI. However, compared
to men with low lycopene intake, those with high lycopene
intake were slightly more likely to be highly educated, to
have a high fish intake, to be physically active and to take
multivitamin supplements. Men with high lycopene intake
were less likely to be Black than men with low lycopene
intake but the great majority of prostate cancer patients in all
lycopene intake categories were White.
In the prediagnosis dietary analysis, 526 of 8,898 men died
from prostate cancer during up to 20 years (mean 10.2 years)
of follow-up. As shown in Table 2, no statistically significant
association was observed between prediagnosis dietary lyco-
pene intake and PCSM (fourth vs. first quartile HR 5 1.00,
95% CI 0.78–1.28; p for trend 0.92). Neither intake of individ-
ual tomato products nor total tomato product intake was asso-
ciated with PCSM. Null results were also seen when (i)
prediagnosis diet was updated using the latest available survey
before diagnosis, (ii) a 2-year lag was applied or (iii) diet
assessed less than 1 year before diagnosis was excluded (data
not shown). Stratified analyses further indicated that results
did not differ by prostate cancer risk category (Table 2) or any
other stratification factors, including BMI, smoking, diagnosis
year, treatment and multivitamin use (data not shown).
In the postdiagnosis dietary analysis, 363 of 5,643 men
died from prostate cancer during up to 13.3 years (mean 9.6
years) of follow-up. The average time from diagnosis to
return of the postdiagnosis survey was 2.9 years. Null

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Wang et al. 2851

Table 2. Prostate cancer-specific mortality by prediagnosis lycopene and tomato product consumption among men diagnosed with nonmeta-
static prostate cancer, CPS-II Nutrition Cohort (1992–2012)
All prostate cancer1 Lower risk prostate cancer2 High-risk prostate cancer3
Deaths/ Deaths/ Deaths/
person-years HR (95% CI)4 person-years HR (95% CI)4 person-years HR (95% CI)4
5
Prediagnosis dietary lycopene intake (mg/day)
<2.8 150/22,513 1.00 (ref) 62/15,774 1.00 (ref) 68/3,927 1.00 (ref)
2.82<4.2 129/22,670 0.89 (0.70–1.13) 57/15,843 1.00 (0.69–1.45) 57/4,342 0.82 (0.57–1.20)
4.22<6.1 114/22,404 0.85 (0.66–1.09) 42/16,245 0.73 (0.49–1.09) 58/3,628 1.00 (0.69–1.46)
6.1 2 30.2 133/23,013 1.00 (0.78–1.28) 57/16,447 1.02 (0.69–1.49) 54/3,806 0.85 (0.58–1.26)
p-trend 0.92 0.92 0.59
Prediagnosis tomato and tomato juice intake (servings/week)
<0.3 143/22,213 1.00 (ref) 58/15,273 1.00 (ref) 64/4,019 1.00 (ref)

Cancer Epidemiology
0.32<0.7 149/27,207 0.95 (0.75–1.20) 57/19,473 0.85 (0.58–1.23) 70/4,462 1.11 (0.77–1.59)
0.72<2.2 97/18,070 0.92 (0.71–1.20) 46/13,067 1.08 (0.72–1.60) 41/3,158 0.93 (0.61–1.40)
2.2 2 17.4 137/23,110 0.96 (0.75–1.22) 57/16,496 1.00 (0.68–1.46) 62/4,064 0.98 (0.67–1.42)
p-trend 0.76 0.72 0.70
Prediagnosis vegetable soup intake (servings/week)
<0.6 149/27,465 1.00 (ref) 65/19,143 1.00 (ref) 67/4,873 1.00 (ref)
0.62<1.2 151/21,436 1.16 (0.92–1.46) 51/15,298 0.76 (0.52–1.10) 81/3,618 1.50 (1.06–2.13)
1.22<2.0 86/18,425 1.00 (0.76–1.31) 37/13,466 0.84 (0.56–1.27) 31/2,872 0.88 (0.56–1.38)
2.02<27.7 140/23,273 1.14 (0.89–1.44) 65/16,401 1.20 (0.84–1.72) 58/4,339 1.00 (0.68–1.46)
p-trend 0.45 0.12 0.46
Prediagnosis pasta sauce intake (servings/week)
<0.5 157/23,133 1.00 (ref) 63/16,002 1.00 (ref) 70/4,226 1.00 (ref)
0.52<1 105/22,223 0.81 (0.63–1.05) 42/15,403 0.80 (0.53–1.19) 51/4,041 0.89 (0.61–1.32)
12<1.5 140/21,130 1.19 (0.94–1.50) 56/15,347 1.04 (0.71–1.50) 65/3,660 1.30 (0.91–1.88)
1.52<20.9 124/24,113 1.15 (0.89–1.48) 57/17,557 1.12 (0.77–1.64) 51/3,775 1.14 (0.77–1.71)
p-trend 0.05 0.36 0.19
Prediagnosis total tomato product intake (serving/week)
<2.2 146/22,616 1.00 (ref) 58/15,364 1.00 (ref) 68/4,309 1.00 (ref)
2.22<3.6 121/22,699 1.03 (0.80–1.32) 47/16,768 0.81 (0.55–1.20) 58/3,594 1.14 (0.78–1.67)
3.62<5.8 127/22,344 1.06 (0.82–1.35) 49/15,891 0.89 (0.60–1.31) 60/3,755 1.13 (0.78–1.66)
5.82<45.1 132/22,941 1.03 (0.81–1.33) 64/16,286 1.15 (0.79–1.68) 51/4,045 0.89 (0.60–1.32)
p-trend 0.81 0.23 0.43
1
Includes T1–T2 cancers with unknown Gleason score not included in lower risk or high-risk categories.
2
Defined as T1–T2 and Gleason score 2–7.
3
Defined as T3–T4, or Gleason score 8–10, or nodal involvement.
4
Adjusted for age at diagnosis, race, calendar year of diagnosis, tumor extent, nodal involvement, Gleason score, history of prediagnosis prostate-
specific antigen testing, education, physical activity, BMI, smoking, multivitamin supplement use, and fish intake.
5
Prediagnosis dietary intake was based on 1992 questionnaire.
Abbreviation: CPS: Cancer Prevention Study; HR: hazard ratio; CI: confidence interval.

associations were observed for postdiagnosis dietary intake of
lycopene and tomato products with PCSM (Table 3). Results
were materially unchanged when excluding deaths that
occurred within 2 years of the postdiagnosis survey comple-
tion or excluding surveys returned within 1 year after diagno-
sis (data not shown). The associations of postdiagnostic
lycopene and tomato product intake with PCSM did not dif-
fer by BMI, smoking, diagnosis year, treatment and multivita-
min or lycopene supplement use (data not shown).
Because higher doses of lycopene may be required to
influence prostate cancer progression, we also conducted
analyses in which we subdivided the highest category of lyco-
pene exposure in order to examine very high intake of lyco-
pene. No association with very high intake of lycopene

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 2852 Lycopene, tomato products and prostate cancer survival

Table 3. Prostate cancer-specific mortality by postdiagnosis lycopene and tomato product consumption among men diagnosed with nonmeta-
static prostate cancer, CPS-II Nutrition Cohort (1992–2012)
All prostate cancer1 Lower risk prostate cancer2 High-risk prostate cancer3
Deaths/ Deaths/ Deaths/
person-years HR (95% CI)4 person-years HR (95% CI)4 person-years HR (95% CI)4
5
Postdiagnosis dietary lycopene (mg/day)
Q1 89/13,230 1.00 (ref) 50/9,655 1.00 (ref) 31/2,196 1.00 (ref)
Q2 95/14,032 1.12 (0.84–1.51) 42/10,186 0.88 (0.58–1.35) 43/2,443 1.44 (0.87–2.36)
Q3 76/13,493 0.96 (0.70–1.32) 38/10,187 0.87 (0.56–1.34) 27/2,173 0.90 (0.52–1.56)
Q4 103/13,650 1.22 (0.91–1.64) 54/9,712 1.22 (0.82–1.83) 32/2,279 0.96 (0.56–1.65)
p-trend 0.23 0.21 0.50
6
Postdiagnosis tomato (serving/week)
Q1 92/13,090 1.00 (ref) 45/9,358 1.00 (ref) 34/2,228 1.00 (ref)
Cancer Epidemiology

Q2 83/12,797 1.15 (0.85–1.57) 43/9,576 0.98 (0.64–1.51) 28/1,918 1.17 (0.68–2.03)

Q3 138/20,875 1.10 (0.84–1.45) 77/15,370 1.25 (0.85–1.82) 44/3,597 0.91 (0.57–1.47)
Q4 50/7,644 0.98 (0.69–1.40) 19/5,437 0.71 (0.41–1.23) 27/1,347 1.15 (0.65–2.03)
p-trend 0.85 0.91 0.63
Postdiagnosis tomato juice (serving/week)
None 131/19,075 1.00 (ref) 68/13,865 1.00 (ref) 51/3,070 1.00 (ref)
<0.5 127/20,253 0.98 (0.77–1.26) 63/15,026 1.04 (0.73–1.48) 51/3,326 0.91 (0.59–1.38)
0.5 105/15,077 1.06 (0.82–1.38) 53/10,849 1.19 (0.82–1.72) 31/2,696 0.72 (0.44–1.16)
p-trend 0.60 0.34 0.17
Postdiagnosis tomato sauce (serving/week)
<0.5 108/14,142 1.00 (ref) 62/10,081 1.00 (ref) 37/2,681 1.00 (ref)
0.52<1 152/24,546 0.99 (0.77–1.28) 75/18,196 0.79 (0.55–1.11) 53/3,798 1.09 (0.70–1.69)
1 103/15,718 1.06 (0.80–1.40) 47/11,463 0.83 (0.55–1.23) 43/2,612 1.25 (0.78–2.01)
p-trend 0.66 0.39 0.35
Postdiagnosis total tomato product intake (serving/day)7
Q1 88/13,208 1.00 (ref) 45/9,503 1.00 (ref) 35/2,237 1.00 (ref)
Q2 95/13,724 1.16 (0.86–1.56) 47/10,331 1.00 (0.66–1.52) 30/2,024 1.16 (0.68–1.98)
Q3 96/14,412 1.11 (0.82–1.49) 55/10,616 1.32 (0.88–1.98) 31/2,477 0.86 (0.51–1.43)
Q4 84/13,061 1.03 (0.76–1.41) 37/9,288 0.93 (0.59–1.46) 37/2,353 1.00 (0.60–1.66)
p-trend 0.90 0.87 0.96
1
Includes T1–T2 cancers with unknown Gleason score not included in lower risk or high-risk categories.
2
Defined as T1–T2 and Gleason score 2–7.
3
Defined as T3–T4, or Gleason score 8–10, or nodal involvement.
4
Adjusted for age at diagnosis, race, calendar year of diagnosis, tumor extent, nodal involvement, Gleason score, history of prediagnosis prostate-
specific antigen testing, education, initial treatment, history of cardiovascular disease, physical activity, smoking status and total dairy intake.
5
The ranges of lycopene intake for quartiles 1–4 in 1999 were <3.1, 3.12<4.4, 4.42<6.2, 6.2–40.9 mg/day, and in 2003 were <3.2, 3.22<4.5,
4.52<6.3, 6.3–43.0 mg/day.
6
The ranges of tomato intake for quartiles 1–4 in 1999 were <1, 12<3, 32<5.6, 5.6–7 servings/week, and in 2003 were <0.5, 0.52<1.5,
1.52<2.8, 2.8–7 servings/week.
7
The ranges of total tomato product intake for quartiles 1–4 in 1999 were <1.5, 1.52<3.3, 3.32<4.5, 4.5–22.6 servings/week, and in 2003 were
<1.1, 1.12<2.0, 2.02<3.4, 3.4–18.5 servings/week.
Abbreviations: CPS: Cancer Prevention Study; HR: hazard ratio; CI: confidence interval.

(10 mg/day) was seen in either prediagnosis analyses
(HR 5 1.06, 95% CI 0.72–1.57) or postdiagnosis analysis
(HR5 1.12, 95% CI 0.75–1.65).
Results by consistency of intake among 5,018 men with
both prediagnosis and postdiagnosis dietary data are shown
in Table 4. Compared with men who consistently consumed
below the median level, those who consistently reported
median or higher dietary lycopene or total tomato product
intake did not have statistically significantly lower PCSM
(HR 5 0.91, 95% CI 0.68–1.23 for lycopene; HR5 0.97, 95%
CI 0.73–1.29 for total tomato products).
Results by consistency of intake among 2,581 men with
dietary data from two postdiagnosis questionnaires (1999 and
2003) are also shown in Table 4. In overall analyses,

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Wang et al. 2853

Table 4. Prostate cancer-specific mortality by lycopene and total tomato product intake reported on two questionnaires among men diag-
nosed with nonmetastatic prostate cancer, CPS-II Nutrition Cohort (1992–2012)
All prostate cancer1 Lower risk prostate cancer2 High-risk prostate cancer3
Deaths/ Deaths/ Deaths/
person-years HR (95% CI)4 person-years HR (95% CI)4 person-years HR (95% CI)4
5
Prediagnosis and postdiagnosis dietary lycopene intake
Low prediagnostic, 104/14,892 1.00 (ref) 55/10,771 1.00 (ref) 37/2,545 1.00 (ref)
low post-diagnostic (ref)
Low prediagnostic, 66/9,242 1.00 (0.73–1.37) 36/6,666 1.12 (0.73–1.74) 20/1,740 0.69 (0.38–1.25)
high postdiagnostic
High prediagnostic, 60/9,434 0.90 (0.65–1.25) 30/6,994 0.75 (0.47–1.20) 24/1,600 0.91 (0.52–1.60)
low postdiagnostic
High prediagnostic, 89/15,057 0.91 (0.68–1.23) 40/11,190 0.70 (0.46–1.08) 33/2,226 0.98 (0.58–1.65)
high postdiagnostic
Prediagnosis and postdiagnosis total tomato product intake5

Cancer Epidemiology
Low prediagnostic, 104/15,012 1.00 (ref) 51/11,045 1.00 (ref) 36/2,428 1.00 (ref)
low postdiagnostic (ref)
Low prediagnostic, 52/9,214 0.88 (0.63–1.24) 25/6,668 0.95 (0.58–1.54) 23/1,682 1.02 (0.58–1.81)
high postdiagnostic
High prediagnostic, 61/9,079 1.02 (0.74–1.41) 35/6,763 1.03 (0.66–1.61) 18/1,409 0.84 (0.45–1.58)
low postdiagnostic
High prediagnostic, 102/15,319 0.97 (0.73–1.29) 50/11,143 0.96 (0.64–1.45) 37/2,591 0.88 (0.53–1.47)
high postdiagnostic
Postdiagnosis dietary lycopene intake at two time points6
Low in 1999, low in 2003 (ref) 69/7,330 1.00 (ref) 40/5,350 1.00 (ref) 22/1,309 1.00 (ref)
Low in 1999, high in 2003 20/2,652 0.88 (0.52–1.48) 12/1,983 0.90 (0.45–1.79) 8/452 0.80 (0.31–2.06)
High in 1999, low in 2003 23/3,112 0.77 (0.47–1.26) 14/2,270 0.88 (0.46–1.67) 9/507 0.72 (0.28–1.87)
High in 1999, high in 2003 47/6,943 0.84 (0.57–1.24) 30/5,224 0.98 (0.59–1.64) 10/1,108 0.41 (0.17–0.99)
Postdiagnosis total tomato product intake at two time points6
Low in 1999, low in 2003 (ref) 62/7,116 1.00 (ref) 37/5,262 1.00 (ref) 18/1,190 1.00 (ref)
Low in 1999, high in 2003 25/2,516 1.10 (0.67–1.80) 17/1,881 1.13 (0.62–2.08) 6/442 0.65 (0.21–2.04)
High in 1999, low in 2003 24/3,671 0.74 (0.46–1.21) 14/2,730 0.78 (0.41–1.48) 9/564 0.72 (0.28–1.85)
High in 1999, high in 2003 48/6,734 0.80 (0.54–1.20) 28/4,954 0.86 (0.51–1.44) 16/1,179 0.60 (0.27–1.35)
1
Includes T1–T2 cancers with unknown Gleason score not included in lower risk or high-risk categories.
2
Defined as T1–T2 and Gleason score 2–7.
3
Defined as T3–T4, or Gleason score 8–10, or nodal involvement.
4
Adjusted for age at diagnosis, race, calendar year of diagnosis, tumor extent, nodal involvement, Gleason score, history of prediagnosis prostate-
specific antigen testing, education, initial treatment, history of cardiovascular disease, physical activity, smoking status and total dairy intake.
5
Among 5,018 men with both prediagnosis and postdiagnosis surveys.
6
Among 2,581 men with both 1999 and 2003 postdiagnosis surveys.
Abbreviations: CPS: Cancer Prevention Study; HR: hazard ratio; CI: confidence interval.

consistently reporting median or higher dietary lycopene or
total tomato product intake on both questionnaires was not
associated with significantly lower PCSM. However, among
men with high-risk prostate cancer (T3–T4 or Gleason score 8–
10, or nodal involvement), consistently reporting median or
higher dietary lycopene intake on both questionnaires was asso-
ciated with significantly lower PCSM (HR 5 0.41, 95% CI 0.17–
0.99). To reduce the possibility of reverse causation, we further
excluded deaths that occurred within 1 year of completion of
the second postdiagnosis FFQ. In this analysis, the association
between consistently high lycopene intake and PCSM among
men with high-risk prostate cancer persisted (HR 5 0.37, 95%
CI 0.15–0.95). Consistently high consumption of total tomato
products was also associated with lower PCSM among men
with high-risk cancers; however, this association was not statis-
tically significant (HR 5 0.60, 95% CI 0.27–1.35).
Discussion
In this large prospective analysis of men diagnosed with non-
metastatic prostate cancer, neither prediagnosis nor postdiag-
nosis dietary intake of lycopene or tomato products was
associated with PCSM. Likewise, combinations of prediagno-
sis and postdiagnosis intakes were unrelated to PCSM. How-
ever, in a subgroup analysis consistently high postdiagnosis

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 2854
lycopene intake, as measured on two questionnaires, was
associated with lower PCSM among men diagnosed with
high-risk prostate cancer.
Although no previous study, to our knowledge, has exam-
ined the association between dietary lycopene intake and
long-term risk of PCSM among prostate cancer survivors,
incidence studies on dietary lycopene intake and prostate
cancer risk suggest modestly protective effects. In a recent
meta-analysis of nine case–control studies and 17 cohort
studies, the pooled relative risk (RR) of incident prostate can-
cer comparing highest dietary lycopene intake with lowest
intake was 0.91 (95% CI 0.82–1.01), and the association was
stronger for blood lycopene concentrations (pooled
RR 5 0.82, 95% CI 0.71–0.95),18 possibly because biomarkers
may be less subject to measurement error than dietary intake.
Cancer Epidemiology
The lack of association between dietary lycopene intake and
PCSM might be due to a relatively limited range of intake in
this population and does not rule out an effect of higher lyco-
pene intake levels. In this study, the difference between the
median lycopene intake in the highest and lowest quartiles was
6.2, 6.4 and 6.9 mg/day on the 1992, 1999 and 2003 FFQ,
respectively. In contrast, intervention studies among patients
with clinically localized prostate cancer, which reported benefi-
cial effects on markers of prostate cancer progression, used lyco-
pene doses of at least 10 mg/day. In a phase II randomized
clinical trial, 26 patients were randomly assigned to receive
30 mg lycopene supplement per day or no supplement.15 After
3 weeks, an 18% decrease in PSA level and higher prostate lyco-
pene level were observed in the intervention group compared
with a 14% increase in PSA and lower prostate lycopene level in
the control group. In another study,23 37 patients were given a
10 mg lycopene supplement per day for 1 year. Compared with
baseline measurements, their PSA level decreased and DNA
synthesis in prostate epithelial cells was inhibited by the end of
study. We saw no association in analyses comparing intake of
>10 mg/day of lycopene to intake in the bottom quartile
(median 2 mg/day), a difference of >8 mg/day, but lacked suffi-
cient numbers to examine larger differences in lycopene intake.
In the only previous study of tomato products and pros-
tate cancer progression, an analysis of 1,202 localized/regional
prostate cancer cases with 392 cases of progression in the
Health Professional Follow-up Study, Chan et al.6 observed a
20% lower risk of prostate cancer progression for every 2
servings/week increase in tomato sauce after diagnosis
(p 5 0.04). In their analysis, postdiagnosis dietary intake was
updated using up to three postdiagnosis FFQs until the end
of follow-up. We found no significant association between
postdiagnosis tomato product intake estimated from the ini-
tial FFQ administered after a prostate cancer diagnosis and
PCSM in either our overall study population or in lower or
high-risk subgroups. However, in analyses of postdiagnostic
diet, we observed a nonsignificant 40% lower risk of PCSM
with consistently higher postdiagnosis tomato product intake
(over two postdiagnostic FFQs), compared to consistently
lower, but only among men with high-risk prostate cancer.
Lycopene, tomato products and prostate cancer survival
In this study, we also found that men diagnosed with
high-risk prostate cancer who reported consistently high
intake of lycopene had a statistically significant 59% lower
risk of PCSM. The inverse association of consistently high
lycopene intake among men with high-risk cancer may well
be due to chance. However, it is also possible that using data
from two questionnaires reduced measurement error, allow-
ing for detection of an association that might have been
obscured by measurement error when using data from only
one questionnaire.
It is unclear why consistently high lycopene intake after
diagnosis was associated with lower PCSM among men with
high-risk prostate cancer but not among men with lower risk
prostate cancer. Our results are consistent with studies that
suggest dietary and circulating lycopene has stronger inverse
associations with risk of lethal or aggressive diseases.16,32 One
plausible explanation is that low-grade tumors that progress
slowly may not be sensitive to effects of lycopene, while
high-grade tumors that progress rapidly are more susceptible
to inhibition by lycopene. In addition, an average of 10 years
of follow-up may not be long enough to observe an associa-
tion for low-grade tumors, relatively few of which are fatal
within 10 years.
Strengths of this study include large sample size, prospec-
tive study design, long-term follow-up, multiple diet assess-
ments and examination of prediagnosis diet as surrogate of
usual diet. Limited intake range and measurement error from
using a single FFQ to assess lycopene and tomato product
consumption may exist, as discussed above. Measurement
error is likely to be an issue for assessing dietary lycopene
due to the low to modest (0.21–0.47) diet–plasma correla-
tions seen for men in other studies.33–35 The correlations are
approximately twofold higher for men than for women.34,35
Our previous study among postmenopausal women in the
CPS-II revealed an adjusted Spearman partial correlation
coefficient of 0.23 for lycopene.36 Although the association
between dietary lycopene and plasma lycopene concentrations
was not examined for men included in this study, it is
expected that the correlation for men is higher. Because mea-
surement error tends to drive the observed associations
toward the null, the risk estimates observed in this study are
likely to be attenuated. It would be ideal to assess prostate
tissue exposure to lycopene, but that was not possible in this
study. Inability to assess contribution from lycopene supple-
ments is another limitation of this study. A simple yes or no
question about current use of any supplement (including
multivitamins) that contained lycopene was first asked in
2001 questionnaire. However, the prevalence of current use
of any lycopene supplement was 1.6%, thus making contribu-
tion from lycopene supplements negligible.
In conclusion, we observed no overall association between
prediagnostic or postdiagnostic dietary lycopene and tomato
product intake and PCSM during long-term follow-up of a
large cohort of men diagnosed with nonmetastatic prostate
cancer. However, there was a suggestive inverse association
Int. J. Cancer: 138, 2846–2855 (2016) V
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Wang et al. 2855

between consistently high dietary lycopene intake and PCSM Acknowledgements

among the subset of men diagnosed with high-risk prostate
cancer who completed a diet assessment at two points in
time after diagnosis. Future studies using approaches that can
reduce measurement error, such as repeated dietary measure-
ments or use of blood lycopene as a biomarker of lycopene
intake, are needed to confirm our results among men with
high-risk prostate cancers.
The American Cancer Society funds the creation, maintenance and updating
of the Cancer Prevention Study II (CPS-II) cohort. The authors thank the
CPS-II participants and Study Management Group for their invaluable con-
tributions to this research. They also acknowledge the contribution to this
study from central cancer registries supported through the Centers for Dis-
ease Control and Prevention’s National Program of Cancer Registries, as
well as cancer registries supported by the National Cancer Institute’s Surveil-
lance Epidemiology and End Results program.

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