November 27
2019Mehrnaz Ghasemiesfe, MD1,4;
Brooke Barrow, BA2; Samuel Leonard, MS1; et al Salomeh Keyhani, MD, MPH3,4;
Deborah Korenstein, MD5,6
Author Affiliations Article Information
1Northern California Institute of Research and
Education, San Francisco
2Currently a medical student at Warren Alpert Medical
School of Brown University, Providence, Rhode Island
3Department of Medicine, University of California, San
Francisco
4San Francisco Veterans Affairs Medical Center, San
Francisco, California
5Department of Medicine, Memorial Sloan Kettering Cancer
Center, New York, New York
6Weill Cornell Medical College, New York, New York
JAMA Netw Open. 2019;2(11):e1916318. doi:10.1001/jamanetworkopen.2019.16318
Key Points
español 中文 (chinese)
Question What
is the association between marijuana use and cancer development in adults with
at least 1 joint-year exposure (equivalent to 1 joint per day for 1 year)?
Findings This
systematic review and meta-analysis identified 25 English-language studies
assessing marijuana use and the risk for developing lung, head and neck,
urogenital, and other cancers. In meta-analyses, regular marijuana use was
associated with development of testicular germ cell tumors, although the
strength of evidence was low; evidence regarding other cancers was insufficient.
Meaning Sustained
marijuana use may increase the risk for testicular cancer, but overall, the
association of marijuana use and cancer development remains unclear.
Abstract
Importance Marijuana
use is common and growing in the United States amid a trend toward
legalization. Exposure to tobacco smoke is a well-described preventable cause
of many cancers; the association of marijuana use with the development of cancer
is not clear.
Objective To
assess the association of marijuana use with cancer development.
Data Sources A
search of PubMed, Embase, PsycINFO, MEDLINE, and the Cochrane Library was
conducted on June 11, 2018, and updated on April 30, 2019. A systematic review
and meta-analysis of studies published from January 1, 1973, to April 30, 2019,
and references of included studies were performed, with data analyzed from
January 2 through October 4, 2019.
Study Selection
English-language studies involving adult
marijuana users and reporting cancer development. The search strategy contained
the following 2 concepts linked together with the AND operator: marijuana OR
marihuana OR tetrahydrocannabinol OR cannabinoid OR cannabis; AND cancer OR
malignancy OR carcinoma OR tumor OR neoplasm.
Data Extraction and Synthesis
Two reviewers independently reviewed
titles, abstracts, and full-text articles; 3 reviewers independently assessed
study characteristics and graded evidence strength by consensus.
Main Outcomes and Measures
Rates of cancer in marijuana users, with
ever use defined as at least 1 joint-year exposure (equivalent to 1 joint per
day for 1 year), compared with nonusers. Meta-analysis was conducted if there
were at least 2 studies of the same design addressing the same cancer without
high risk of bias when heterogeneity was low to moderate for the following 4
cancers: lung, head and neck squamous cell carcinoma, oral squamous cell
carcinoma, and testicular germ cell tumor (TGCT), with comparisons expressed as
odds ratios (ORs) with 95% CIs.
Results Twenty-five
English-language studies (19 case-control, 5 cohort, and 1 cross-sectional)
were included; few studies (n = 2) were at low risk of bias. In pooled analysis
of case-control studies, ever use of marijuana was not associated with head and
neck squamous cell carcinoma or oral cancer. In pooled analysis of 3
case-control studies, more than 10 years of marijuana use (joint-years not
reported) was associated with TGCT (OR, 1.36; 95% CI, 1.03-1.81;
P = .03;
I2 = 0%)
and nonseminoma TGCT (OR, 1.85; 95% CI,
1.10-3.11; P = .04;
I2 = 0%).
Evaluations of ever use generally found
no association with cancers, but exposure levels were low and poorly defined.
Findings for lung cancer were mixed, confounded by few marijuana-only smokers,
poor exposure assessment, and inadequate adjustment; meta-analysis was not
performed for several outcomes.
Conclusions and Relevance
Low-strength evidence suggests that
smoking marijuana is associated with developing TGCT; its association with other
cancers and the consequences of higher levels of use are unclear. Long-term
studies in marijuana-only smokers would improve understanding of marijuana’s
association with lung, oral, and other cancers.
Introduction
Marijuana is the most widely used illicit substance in
the United States, with almost half of adults reporting lifetime use.1 Rates are increasing,2 with use among young adults (age range, 18-29 years)
doubling from 10.5% in 2002 to 21.2% in 2014. Smoking remains the main route of
marijuana exposure.3,4
Marijuana smoke and tobacco smoke share carcinogens,
including toxic gases, reactive oxygen species, and polycyclic aromatic
hydrocarbons, such as benzo[α]pyrene and phenols,5 which are 20 times higher in unfiltered marijuana than
in cigarette smoke.6 The larger the puff volume, the greater the depth of
inhalation,7 and longer breath-holding time with marijuana compared
with cigarette smoking leads to higher tar and carbon monoxide exposure.8 Furthermore, marijuana use is associated with
histopathologic bronchial inflammatory changes comparable to changes observed
with smoking tobacco.9 Given that cancer is the second leading cause of death
in the United States10 and smoking remains the
largest preventable cause of cancer death (responsible for 28.6% of all cancer
deaths in 2014),11
similar toxic effects of marijuana smoke
and tobacco smoke may have important health implications.
Aside from shared properties with tobacco, marijuana
use may alter cancer risk through other mechanisms. Tetrahydrocannabinol, the
primary psychoactive ingredient in marijuana, may have adverse immunomodulatory
effects8,9 associated with cancer. Two proto-oncogenes are
overexpressed in the bronchial epithelium of marijuana-only smokers, with a
higher frequency of gene expression compared with tobacco-only smokers.8,12
In contrast, cannabinoids, including
tetrahydrocannabinol, can inhibit proliferation of some cancer cell types,
impede angiogenesis in vitro, and reduce cancer growth in some animal models.13,14
The net association of marijuana use with
developing cancer is unclear.
The increasing prevalence of marijuana use,
particularly among young adults, raises concerns regarding whether using
marijuana increases the risk for developing cancer. Despite increasing social
acceptance of marijuana use, there remains a dearth of information on the
association between marijuana consumption and health, including its association
with incident cancer. We conducted a systematic review and meta-analysis to
improve the understanding of the association of marijuana use with developing
cancers.
Methods
This systematic review and meta-analysis was
consistent with the Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA) statement.15
The protocol was registered at PROSPERO
at the start of our investigation.
Data Sources and Searches
A systematic literature review was performed using
studies found in a search of several online databases (PubMed, Embase,
PsycINFO, MEDLINE, and the Cochrane Library), as well as references of the
included studies. The search was conducted on June 11, 2018, and was updated on
April 30, 2019. The studies were published from January 1, 1973, to June 11,
2018. We chose 1973 as the start date because Oregon decriminalized possession
of marijuana in that year.16
For PubMed, Embase, MEDLINE, and the
Cochrane Library, we used both controlled vocabulary and text words for
synonymous terminology within titles and abstracts in the development of search
strategies. In PsycINFO, we used text word searching of titles and abstracts.
The search strategy contained the following 2 concepts linked together with the
AND operator17: marijuana OR marihuana
OR tetrahydrocannabinol OR cannabinoid OR cannabis; AND cancer OR malignancy OR
carcinoma OR tumor OR neoplasm (eAppendix 1 in the Supplement). We combined search results using a bibliographic management tool
(EndNote, version X9; Clarivate Analytics) and used the method by Bramer et al18 to eliminate duplicates.
Study Selection
Two of us (M.G. and B.B.) independently screened all
titles and abstracts for inclusion. We included studies published in English
involving participants 18 years or older with at least 1 joint-year exposure
(equivalent of 1 joint per day for 1 year) or more cumulative use (defined as
ever use) of marijuana and reporting on the development of cancer. We excluded
review articles, commentaries, case reports, case series, editorial articles,
in vitro and animal studies, studies that did not primarily evaluate marijuana
exposure or include information on cancer outcomes, studies that reported only
outcomes after short-term exposure in a laboratory setting, and studies that
included fewer than 10 marijuana users (eAppendix 5 in the Supplement). The same 2 reviewers (M.G. and B.B.) independently reviewed all full-text
articles using predetermined inclusion and exclusion criteria. Additional
articles were identified through author tracking of first and last authors and
reference tracking. Disagreements regarding publication inclusion were resolved
by discussion or referral to a third reviewer (D.K.) (eAppendix 2 in the Supplement).
Data Extraction and Quality Assessment
For each included study, 2 of us (M.G. and B.B.)
independently collected information on outcomes by cancer type (lung, head and
neck, urogenital, and other cancers). They also extracted data on study design
(eg, case-control vs cohort), study population, participant age, exposure
route, marijuana use intensity and duration, percentage of marijuana-only
smokers, confounders (eg, tobacco or alcohol use and occupational exposure),
and funding source. Risk of bias (ROB) in individual studies was assessed
independently by 3 of us (M.G., S.K., and D.K.) at both study and outcome
levels using the Newcastle-Ottawa Scale for outcomes in observational studies.19
Disagreements were resolved by consensus.
Studies were rated as having low ROB if they provided detail on exposure
assignment (eg, marijuana-only smokers vs marijuana and tobacco smokers), had
robust assessment and adjustment for key confounders, had sufficient follow-up
for outcomes to occur, and quantified marijuana use in terms of joint-years of
exposure (when presented) or years of use.
Statistical Analysis
Data were analyzed from January 2 through October 4,
2019. The meta-analysis was performed if there were at least 2 studies of the
same design (eg, case-control) addressing the same cancer without high ROB when
heterogeneity was low to moderate for the following 4 specific cancers: lung
cancer, head and neck squamous cell carcinoma (HNSCC), oral squamous cell
carcinoma (SCC), and testicular germ cell tumor (TGCT). We extracted binary
outcome odds ratios (ORs) or calculated them (with 95% CIs) when adequate data
were provided. Narrative synthesis was performed when meta-analysis was not
possible. We pooled data using a random-effects model. We used the method by
Paule and Mandel20 to estimate τ2
and the method by Hartung and Knapp21 to adjust for small
sample sizes. For meta-analyses with at least 2 studies, we performed the test
for funnel plot asymmetry based on weighted linear regression using the efficient
score and score variance described by Higgins et al22 and by Harbord et al.23
Statistical analysis was done using R
statistical software (package “meta,”
version 1.1.453; R Project for Statistical Computing). Heterogeneity was
evaluated using forest plots and the I2 statistic; I2
values of 25%, 50%, and 75% were
considered evidence of low, moderate, and high heterogeneity, respectively.23
Tests were 2-tailed and P < .05 was considered statistically significant. Three of us (M.G., S.K., and
D.K.) discussed the overall strength of evidence for each outcome and graded it
as insufficient, low, moderate, or high based on methods outlined by the Agency
for Healthcare Research and Quality.24
Results
Literature Search
Initial searches across databases identified 6554
abstracts; 25 studies ultimately met the inclusion criteria
(Figure 1), including
19 case-control studies, 4 prospective cohort studies, 1 retrospective cohort
study, and 1 cross-sectional study. Eight studies addressed risk of lung
cancer, 9 addressed head and neck cancers, 7 addressed urogenital cancers, and
4 addressed other cancers (eAppendix 3 in the Supplement). All 25 included articles are described in eTable 1, eTable 2, eTable 3,
eTable 4, eAppendix 4, eTable 5, and eTable 6 in the Supplement.
Study Characteristics
Most studies were conducted in the United States
(n = 16 [published 1993-2015]), followed by Europe (n = 3), northern Africa
(n = 3), New Zealand (n = 2), and 1 from multiple countries. Methods of
quantifying marijuana use varied (eg, frequency vs duration vs total
joint-years). Two articles did not report the specific route of marijuana
administration (eg, edible or smoked). Among those specifying exposure route
(n = 23 [92%]), smoking predominated. We identified 19 distinct outcomes, of
which 2 had sufficient supporting data from 2 or more studies and could be
pooled in a meta-analysis. eAppendix 4, eTable 4 and eTable 5 in the Supplement describe
ROB assessments for all included studies.
Lung Cancer
Eight studies25-32
(1 prospective cohort, 1
retrospective cohort, 1 cross-sectional, and 5 case-control studies) examined
the association between marijuana use and the development of lung cancer
(Table 1 and
eTable 1 in the Supplement). These studies were published between 1997 and 2015; the smallest was a
case-control study with 33 lung cancer cases, and the largest was a prospective
cohort study with 49 321 male participants. Three studies were undertaken in
the United States, 2 in northern Africa, 1 in Sweden, 1 in New Zealand, and 1
in multiple countries. All studies had a moderate to high ROB and were
generally limited by the small number of marijuana-only smokers (ie, most
marijuana users also used tobacco), minimal exposure to marijuana, poorly
described use assessment, and inadequate adjustment for confounders
(Table 1). There
were 405 individuals across case-control studies with more than 10 joint-years
of marijuana use.
Study results were mixed, and we were unable to pool
data for this outcome. In general, studies were limited by low levels of
marijuana exposure, little information about marijuana-only smokers, and other
methodological flaws. Therefore, we concluded that evidence of the association
between marijuana use and incident lung cancer was insufficient
(Table 2).
Head and Neck Cancer
Nine case-control studies investigated the association
of marijuana exposure with the development of head and neck cancers, including
HNSCC, nasopharyngeal carcinoma, oral cancer, laryngeal cancer, pharyngeal
cancer, and esophageal cancer; 1 of these studies evaluated multiple cancers28 (eTable 2 in the Supplement). Only 1 was rated as having a low ROB,33
and the number of cases ranged from 53 to
636. Four case-control studies (1 with low ROB33 and 3 with moderate ROB34-36)
examined the association between
marijuana use and HNSCC. All had sufficient supporting data for meta-analysis.
Compared with nonsmokers, ever users of marijuana had similar risk of HNSCC
(OR, 1.26; 95% CI, 0.88-1.80; P = .09;
I2 = 55%)
(Figure 2). The
test for funnel plot asymmetry showed evidence of asymmetry
(P = .045),
with a bias coefficient of 3.48 (eFigure
1 in the Supplement). Findings among heavier users were mixed across studies (eTable 2 in the Supplement).
Four other case-control studies (2 with a moderate ROB28,38
and 2 with a high ROB39,40)
evaluated marijuana exposure and
risk of oral cancer. Pooled data from the 2 studies with moderate ROB28,38
revealed no association between
ever use and oral cancer (OR, 1.22; 95% CI, 0.95-1.56; P = .12; I2 = 39%)
(Figure 2); heterogeneity
was moderate, and there was no evidence of funnel plot asymmetry (eFigure 1 in
the Supplement). The 2 studies with a high ROB39,40
reported no association between
marijuana use and the risk of oral SCC, but interpretability is limited by poor
quantification of marijuana use and inadequate adjustment for confounders.
Nasopharyngeal carcinoma was examined in a 2004
case-control study with a moderate ROB37; a second
population-based case-control study with a moderate ROB28 evaluated laryngeal,
pharyngeal, and esophageal cancers. The study37 of nasopharyngeal
carcinoma, which was performed in northern Africa and included 636 cases, found
a higher risk of nasopharyngeal carcinoma with both ever marijuana consumption
and lifetime high-dose marijuana smoking (≥2000 times; OR, 2.62; 95% CI,
1.00-6.86), after adjusting for tobacco and baseline variables. The study was
limited by potential selection bias, inconsistent adjustment, and no reported
results on marijuana-only smokers. The case-control study,28
which was based in Los Angeles,
California, found no association of at least 30 joint-years of use with
laryngeal, pharyngeal, or esophageal cancers, but it included too few such
marijuana users (<10 users with ≥30 joint-years) to draw reliable conclusions (eTable 2 in
the Supplement).
Urogenital Cancer
The association between marijuana use and developing
urogenital cancer was evaluated in 1 prospective study,41
a retrospective study,26
and 5 case-control studies42-46
published between 1993 and 2015.
Three case-control studies42-44
(with moderate ROB) assessed
the association of marijuana use with TGCT; all of the studies included young
participants and had a mean follow-up period of 6.6 years. In a pooled analysis
(low heterogeneity), development of TGCT was not associated with ever use
compared with never use (OR, 1.11; 95% CI, 0.81-1.53; P = .52; I2 = 48%),
but it was associated with more than 10
years of marijuana use (OR, 1.36; 95% CI, 1.03-1.81; P = .03; I2 = 0%)
(Figure 3). Subanalysis
by histological type showed association of more than 10 years of marijuana use
with the development of nonseminoma TGCT (OR, 1.85; 95% CI, 1.10-3.11;
P = .04;
I2 = 0%)
but not seminoma TGCT (OR, 0.98; 95% CI,
0.47-2.06; P = .92;
I2 = 0%)
(Figure 3). There
was no significant evidence of funnel plot asymmetry for TGCT (ever use)
(P = .75),
TGCT
(>10 years) (P = .20), and seminoma TGCT (P = .09)
(eFigure 2, eFigure 3, and eFigure 4 in
the Supplement).
Other urogenital cancers were addressed in US-based
single studies26,41,45,46
(eTable 3 in the Supplement). A prospective study41 (with
moderate ROB) found that marijuana-only ever use was associated with a lower
risk of bladder cancer (adjusted hazard ratio, 0.55; 95% CI, 0.31-1.00;
P = .048),
but the study was limited by inadequate
adjustment for confounders. In a small study with low ROB,45
marijuana-only smoking was associated
with transitional cell carcinoma (adjusted OR, 3.3), but there were only 10
marijuana-only smokers. Other studies with a moderate ROB found that marijuana
use was associated with risk for prostate cancer (risk ratio [RR], 3.1; 95% CI,
1.0-9.5) and cervical cancer (RR, 1.4; 95% CI, 1.0-2.1)26 and was not associated
with penile cancer,46
but study design issues limit reliability.
Other Cancers
Four studies26,47-49
addressed marijuana use and the
development of other cancers; all were performed in the United States (eTable 4
in the Supplement). A large, prospective study48 found an association
between the development of malignant primary adult-onset glioma and weekly
(n = 6002; RR, 3.2; 95% CI, 1.1-9.2) and monthly (n = 4699; RR, 3.6; 95% CI,
1.3-10.2) marijuana smoking compared with nonuse. Other studies found no
association between marijuana ever use and breast cancer, colorectal cancer,
and melanoma26 and non-Hodgkin lymphoma49; however, methodological
concerns limit interpretation. Finally, a prospective study47 found that marijuana use
among HIV-infected white men was associated with risk for developing Kaposi
sarcoma (hazard ratio, 1.52; 95% CI, 0.99-2.32) in the 5-year lagged analysis.
However, the study did not quantify exposure or report separately for
marijuana-only smokers.
Strength of Evidence
Low-strength evidence suggests that chronically
smoking marijuana is associated with development of TGCT. Evidence on the
association between marijuana use and other cancer types and evidence of the
consequences of higher levels of use are insufficient (Table 2).
Discussion
Although much is known about the association between
tobacco smoke and cancer, less is known about the association between marijuana
smoke and cancer. Both contain particulate matter and carcinogens. With
increasing marijuana use and the high number of cancer-related deaths,
understanding the association between marijuana use and cancer incidence is
important. Low-strength evidence in the present systematic review and
meta-analysis suggests that more than 10 years of marijuana use (joint-years
were not reported) is associated with the development of TGCT. There was
insufficient evidence to support an association between ever having used
marijuana and other types of cancer. Available studies were limited by a small
number of participants with high levels of use, poor use quantification,
confounding related to cigarette smoking, and other methodological problems.
Our study contributes to the literature on the
association between marijuana use and multiple cancers that has been examined
individually in prior systematic reviews. Two systematic reviews50,51
examined the association between
smoking marijuana and lung cancer. The first study50 offered evidence of
biological plausibility (ie, molecular, cytomorphologic, and histopathologic
changes); the second study51 noted pulmonary toxic
effects and mixed evidence of an association with lung cancer but did not pool
data to estimate an overall association. We found 1 meta-analysis52 examining the association
of smoking marijuana with the development of head and neck cancer; it found no
association but was limited by meta-analytic inconsistencies, pooling head and
neck cancer subtypes in 1 plot and not addressing variable marijuana use, which
may undermine its conclusions. Three other systematic reviews53-55
found an association between
marijuana smoking and increased risk of TGCT but reported conflicting data on
the association with other urogenital cancers. The present study confirms these
findings and builds on the existing literature by assessing ROB, pooling data
when feasible, and providing a clear picture of the gaps in evidence by rating
the strength of the overall evidence.
Our systematic review and meta-analysis found insufficient
evidence on the association between marijuana use and the development of lung
cancer. There are biological reasons for concern about marijuana use and lung
cancer. Several reports have documented changes in the bronchial epithelium of
marijuana smokers that are similar to metaplastic premalignant alterations
observed among tobacco smokers.12,50,56
Furthermore, histopathologic and
molecular alterations and premalignant changes found in marijuana users,12,57,58
including mitotic figures, squamous cell
metaplasia, and cell disorganization, suggest increased risk for respiratory
neoplasm. In addition, marijuana joints with similar weight as tobacco
cigarettes have higher tar burden, which may increase the carcinogenic risk.8,59-61
However, the difference in per weight tar
burden is counterbalanced by the usual practice of smoking far fewer marijuana
joints than tobacco cigarettes per day. Furthermore, lung cancer risk increases
with both the number of daily cigarettes and the lifetime duration of smoking,62
with an increased risk only among those
with high exposure. For example, a 40-year-old smoker of 1 pack per day (14 600
cigarettes) has a lung cancer risk approximately 20 times that of a nonsmoker.
Our systematic review and meta-analysis included few marijuana smokers with
similarly high exposure levels: there were 405 individuals across case-control
lung cancer studies with more than 10 joint-years of use (3650 joints). Hence,
low exposure burden, young participant age, and inadequate follow-up time in
included studies may prevent detection of an association. Longitudinal cohorts
with older populations of heavier marijuana users may be necessary to clarify
the association of marijuana use with developing lung cancer.
Our findings are notable in a time of increasing
marijuana use in the United States,2,3,63
with novel drug delivery methods,
including vaping and edibles, becoming more popular, particularly in states
that have legalized recreational use4 and among adolescents.64,65
However, most of the studies included in
the present systematic review and meta-analysis are not recent, and smoking was
the near-universal form of exposure. Vaped marijuana is believed to have fewer
long-term toxic effects than smoked marijuana,66
but evidence is lacking. Although levels
of tar are lower with marijuana use through vaping compared with smoking,
vaporized marijuana can contain toxic levels of ammonia and heavy metals that
may be associated with cancer, possibly cancers unrelated to smoking.67-69
Furthermore, with legalization may come
heavier and more long-term use that may confer a higher risk for cancer.
Misinformation may constitute an additional threat to public health; cannabis
is being increasingly marketed as a potential cure for cancer in the absence of
evidence,70
with enormous engagement in this
misinformation on social media, particularly in states that have legalized
recreational use.71
As marijuana smoking and other forms of
marijuana use increase and evolve, it will be critical to develop a better
understanding of the association of these different use behaviors with the
development of cancers and other chronic conditions and to ensure accurate
messaging to the public.
Limitations
This systematic review and meta-analysis has
limitations. Non–English-language articles were excluded; therefore, we may
have overlooked relevant studies. Study populations were young, and few studies
measured longitudinal exposure. The included studies were often limited by
selection bias, recall bias, small sample of marijuana-only smokers, reporting
of outcomes on marijuana users and tobacco users combined, and inadequate
follow-up for the development of cancer. In addition, despite clear
methodological differences across studies, we pooled some data. Although we
used a conservative approach, these pooled estimates provide only a rough
approximation of the association. Most studies poorly assessed exposure, and
some studies did not report details on exposure, preventing meta-analysis for
several outcomes. Understanding of the long-term health consequences of
marijuana use could be improved by standardizing assessment tools to quantify
use, including studies with larger samples of marijuana-only smokers,
performing subanalysis based on form of use, and having longer follow-up times.
Conclusions
Low-strength evidence suggests that smoking marijuana
is associated with the development of TGCT; evidence of an association between
marijuana use and incident lung cancer is of poor quality and inconclusive.
Similarly, evidence regarding other cancer types is insufficient and is limited
by low exposure and duration of follow-up. Increasing rates of marijuana use
and evolution in delivery routes raise concerns about long-term consequences.
Large-scale longitudinal studies with representative samples of marijuana-only
smokers are needed to better understand the association of marijuana use with
the development of lung, oral, and other cancers. In the meantime, clinicians
should discuss marijuana use with patients to raise awareness of the lack of
clarity on potential clinically important harms and to debunk beliefs in
unproven benefits.
Article Information
Accepted for Publication: October 6, 2019.
Correction: This
article was corrected on January 15, 2020, to correct a comment in Table 1 for
the study by Sidney et al.
Open Access: This
is an open access article distributed under the terms of the CC-BY License. © 2019 Ghasemiesfe M et al. JAMA Network Open.
Corresponding Author: Deborah Korenstein, MD, Department of Medicine,
Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065
(korenstd@mskcc.org).
Author Contributions: Dr Korenstein had full access to all of the data in the
study and takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Concept and design: Ghasemiesfe, Keyhani, Korenstein.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Ghasemiesfe, Barrow, Leonard, Korenstein.
Critical revision of the manuscript for important
intellectual content: Keyhani.
Statistical analysis: Ghasemiesfe, Barrow, Leonard.
Obtained funding: Keyhani.
Administrative, technical, or material support:
Ghasemiesfe, Barrow, Keyhani.
Supervision: Korenstein.
Conflict of Interest Disclosures: Dr Keyhani reported receiving grants from the National
Institutes of Health during the conduct of the study. Dr Korenstein
reported receiving grants from the National Cancer Institute during the conduct
of the study and reported that her spouse serves on the scientific advisory
board of Vedanta Biosciences and does consulting work for Takeda. No other
disclosures were reported.
Funding/Support: This article was supported by grant 1R01HL130484-01A1
from the National Heart, Lung, and Blood Institute of the National Institutes
of Health (Dr Keyhani). Dr Korenstein’s work was supported in part by Cancer
Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center
from the National Cancer Institute.
Role of the Funder/Sponsor: The funding sources had no role in the design and
conduct of the study; collection, management, analysis, and interpretation of
the data; preparation, review, or approval of the manuscript; and decision to
submit the manuscript for publication.
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