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The Radiotherapy cancer patient: female inclusive, but male dominated

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 International Journal of Radiation Biology

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The radiotherapy cancer patient: female inclusive,

but male dominated

Armelle Meunier & Laure Marignol

To cite this article: Armelle Meunier & Laure Marignol (2020): The radiotherapy cancer
patient: female inclusive, but male dominated, International Journal of Radiation Biology, DOI:
10.1080/09553002.2020.1741720

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INTERNATIONAL JOURNAL OF RADIATION BIOLOGY
https://doi.org/10.1080/09553002.2020.1741720

ORIGINAL ARTICLE

The radiotherapy cancer patient: female inclusive, but male dominated

Armelle Meunier and Laure Marignol
Translational Radiation Biology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity Translational Medicine Institute, Trinity
College Dublin, Dublin, Ireland

ABSTRACT ARTICLE HISTORY

Background: The sex-neutral language used in preclinical and clinical research intends to be Received 15 November 2019
inclusive of both the female and the male population, but the practice of data pooling prevents Revised 12 February 2020
the detection of the impact of sex on cancer biology and response to medications and treatment. Accepted 26 February 2020
This study aimed to examine the consideration of sex as biological variable in the evaluation of
KEYWORDS
radiation therapy in preclinical and clinical studies. Sex; radiotherapy; male;
Methods: Preclinical and clinical studies published over a 12-month period were reviewed for the female; patient
reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both
study design and data analysis.
Results: A total of 321 articles met the inclusion criteria: 41 (13%) preclinical and 280 (87%) clin-
ical studies. Two articles reported separate outcome data for males and females. Where the sex of
participants was stated (230/280 (82%), 81% reported a larger number of male participants, com-
pared to females. Less than half (45%) of studies used sex as a variable in data analysis. Sex dis-
parity was not dependent on study location but may be more prominent in certain cancer sites.
In preclinical studies, sex was at best stated in those reporting on animals (48% of studies).
Conclusion: Referring to a radiotherapy cancer patient, the literature is female inclusive, but a
gap does exist when it comes to consideration of sex in data analysis. The pooled analysis of
female and male data could introduce statistical biases and prevent the identification of key sex-
specific biological subtilities that do affect radiation responses.

Introduction related to shorter survival time and radiotherapy resistance

Patient, cells, and animals are part of a sex-neutral language
commonly used in preclinical and clinical radiotherapy stud-
ies. Although female inclusive since the U.S. congress passed
The Revitalization Act to increase the enrollment of women
in clinical research in 1993, this language masks the fact
that mammalian organisms are biologically defined by the Y
chromosome whose presence or absence is associated with
modifications in the functions of the both innate and adap-
tive immune systems (Klein and Flanagan 2016), regulation
of miRNAs and mRNA (Yuan et al. 2016; Guo et al. 2017),
genetic polymorphism in antibody responses (Scepanovic
et al. 2018), and the microbiome (Rizzetto et al. 2018).
Sex is a fundamental biological variable, and these differ-
ences have an impact on the efficacy of medications and
treatments (Jager et al. 2012; Rose et al. 2016; Cristina et al.
2018). For instance, aspirin does not provide the same car-
diovascular protective effect between men and women
(Berger et al. 2006). A few reports do support the hypothesis
that sex does matter in the cellular radiation response.
Exposure to low-dose radiation was associated with sex-spe-
cific modifications in the expression of Ras superfamily
members, protein kinase C isoforms, and AP-1 factor com-
ponents (Besplug et al. 2005). In female glioma patients,
concomitant AIB1 and HER2 amplification were closely
(Sui et al. 2018). Furthermore, studies in mice have identi-
fied that cell death programs are differentially regulated in
males and females. The data suggests that males are prone
to PARP-1 necrosis, whereas in females, cell death is PARP-
1 independent and dominated by caspase-dependent apop-
tosis (Jog and Caricchio 2013). This process is likely medi-
ated by poly-(ADP-ribose) polymerase-1 (PARP-1) and
estrogens (Ortona et al. 2014). These findings are supported
by reports of sex differences in basal redox state (Malorni
et al. 2007), response to oxidative stress (Penaloza et al.
2009), sensitivity to both apoptosis and autophagy (Lista
et al. 2011). All of these processes are involved in the bio-
logical radiation response (Good and Harrington 2013).
Early policies from the US Food and Drug
Administration (FDA) in 1977 advised that women of child-
bearing potential should be excluded from drug trials. While
these guidelines contributed to the development of novel
therapies in a male population and a lack of testing of the
efficacy of these drugs in females, the data collected was
statistically generalizable to the male patient population. The
subsequent recommendation by the US National Institute of
Health for researchers to factor sex into the design, analysis
and reporting of vertebrate animal and human studies
(Clayton and Collins 2014), in an attempt to enhance

CONTACT Laure Marignol marignl@tcd.ie Discipline of Radiation Therapy, Applied Radiation Therapy Trinity, Trinity College Dublin, Dublin, Ireland
Copyright ß 2020 Taylor & Francis Group LLC.
2 A. MEUNIER AND L. MARIGNOL
reproducibility (Collins and Tabak 2014), has led to more
women being involved in clinical trials, with several studies
carefully matching their patient population for sex.
Nonetheless, analysis of the literature indicates a high preva-
lence of male dominance and avoidance of sex-related
reporting. In preclinical studies involving cell lines and/or
animals, sex remains an underreported variable. An analysis
of basic and translational research in surgical biomedical
research highlighted that 76% of cell lines studies did not
specify the sex. Of those that did, only 21% included female
cell lines and 1% reported sex-based results (Yoon et al.
2014). Similar data exist in otolaryngology (Stephenson et al.
2019) and orthopedic (Bryant et al. 2018) research.
This study aimed to establish the prevalence of sex-based
reporting and the consideration of sex as a statistically con-
trolled variable in preclinical and clinical radiation therapy
studies over a 12-month period. Our analysis identifies that
while the radiotherapy cancer patient research population is
female inclusive, male dominance is prevalent and pooling
of male and female data is a common practice.
Materials and methods
Data collection
All manuscripts published in Radiotherapy and Oncology
and the International Journal of Radiation Oncology, Biology,
Physics from August 2018 to July 2019 were reviewed for
inclusion in this study. These journals were selected for their
relevance to the field of Radiation Oncology. Letters to the
editor, review articles, systematic reviews, meta-analysis, and
editorials were excluded. Articles related to sex-specific dis-
eases (e.g. prostate, cervical) including breast cancer
were excluded.
Variables extracted
The following data were extracted from each article: (1) the
type of study. Studies were categorized as clinical if the data
was collected from patients. Studies were categorized as pre-
clinical if the data was collected from animals and/or cells
(primary or cell lines); (2) the first author name, (3) the title
of the manuscript, (3) the institution affiliation of the first
author, (4) the disease site or normal tissue studied, (5) the
disclosure of the sex of the patients studied, (6) the number
of each male and female patients included, (7) the disclosure
of the sex of each animal used, (8) the sex of each animal
used, (9) the disclosure of sex of the cell line used, (10) the
name of cell line used, (11) the presence of sex-based
reporting. Sex-based reporting was defined as presenting the
results for both males and females separately. (12) The
inclusion of sex as a variable in data analysis. Manuscripts
that reported the sex of the patients used but did not
include the results stratified by sex were classified as not
including sex-based reporting. Manuscripts that included sex
as a variable in univariate and/or multivariate analysis of
outcome data were classified as sex-inclusive studies.
Data analysis
The distribution of articles according to the type of study
(clinical, preclinical) and their subtypes (clinical trials, clin-
ical studies, cell only studies, animal only studies, mixed
studies), the location of the institution (North America,
Europe, Asia/Australia), and sex considerations in study
design and analysis were reported as frequencies and per-
centages. The ratio of the number of male patients to the
number of female patients was calculated for each study.
The distribution of the articles according to the value of the
ratio (<1, 1, >1, and > 5) was reported as frequency and
percentage. The mean, standard deviation, and range of the
ratios were calculated. Where applicable, articles were cate-
gorized according to disease site (anal/rectal, head and neck,
central nervous system (CNS), lung, upper GI) and the
number of articles reviewed, the total number of male and
female patients included across all studies, the mean and
range of the male-of-female ratio reported in these studies
were reported for each of these sites. A chi-square test was
used to compare the frequency distributions. An independ-
ent t-test was used to compare the mean number of male
and females in clinical studies. A one-sample t-test was also
used to test whether the mean of the differences between
the number of male and female participants of each clinical
studies was different from zero. The sex of the cell line used
was searched by reviewing the product sheet provided by
the America Type Culture Collection or the ExPaSy portal.
A p value <.05 was deemed statistically significant.
Results
Sex disparity exists in preclinical and clinical radiation
therapy studies
A total of 321 articles met the inclusion criteria and were
reviewed. Of these, 41 (13%) were preclinical studies that
reported the use of cells and/or animals and 280 (87%) were
clinical studies including patients consented to participate in
clinical trials (17 (6%)) or clinical studies (263 (94%))
(Figure 1). Of the 280 clinical studies, 50 (18%) did not state
the sex of the patient population. Of the 230 studies that did
specify the sex of the patients, 127 (55%) did not consider
sex in their analysis, 103 (45%) did include sex as a variable
in data analysis and 2 (1%) specifically analyzed some of
their outcome in the male and the female patient population
included in their study (Figure 2). There was no relationship
between the reporting of patient sex and the location of the
author’s institution (chi-square test, p ¼ .5).
Clinical studies are more likely to include male patients
A total of 262,674 patients were included across the 230
clinical studies reviewed. Of these, 149,617 were males
(57%) and 113,057 (43%) were females. The mean male-to-
female ratio across all 230 studies was 2.56 ± 4.3, with a
range from 0 to 61.5. The majority of studies (186/230
(81%)) reported a larger number of male participants, com-
pared to females: 163 (71%) had an male-to-female ratio

greater than 1, and 23 (10%) greater than 5. Thirty studies
(13%) included a greater proportion of female than male
participants (ratio <1), and 13 (6%) studies had an equal
number of male and female participants (ratio ¼ 1) (Figure
2). The dependency between an male-to-female ratio of <1
or >5 and the location of the author’s institution was not
significant (chi-square test, p ¼ .86). There was a significant
Figure 1. Box diagram of the number of manuscripts identified among the two
radiation oncology journals reviewed.
Figure 2. Box diagram of the number of clinical manuscript reporting data from human participants.
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY 3
relationship between an male-to-female ratio of <1 or >5
and cancer site (chi-square test, p ¼ .86). Articles with a
male-to-female ratio <1 included patients with anal/rectal
cancer (7 studies), CNS (5 studies), H&N (2 studies) and
lung (11 studies), and upper GI (4 studies) cancers. Articles
with a male-to-female ratio >5 included patients with anal/
rectal cancer (2 studies), H&N (12 studies), lung (3 studies),
and upper GI (5 studies) cancer.
Sex disparity may be site specific
The most commonly represented cancer sites in the
reviewed clinical studies were anal/rectal cancer, CNS, head
and neck, lung, and upper GI (Table 1). The total number
of male patients was generally higher than that of female
patients within each site category. Studies reporting on anal/
rectal cancer patients had the highest mean male-to-female
ratio (4.3) and the widest range (0.2–61.5). The difference in
the number of male and female patient included was signifi-
cant in studies reporting on CNS, head and neck, and upper
GI patients (Table 1).
The inclusion of sex in clinical studies is limited to univari-
ate and multivariate analysis of outcome. Of the 103 studies
that did consider sex in their data analysis, sex was included
as a variable in univariate and multivariate analysis of survival
outcomes (94 studies (97%)) or toxicity (7 studies (7%)). Only
two studies (2%) included sex as a variable in both survival
4 A. MEUNIER AND L. MARIGNOL

Table 1. Analysis of the number of male and female patients included in clinical studies according to cancer sites.
Most common Number Number of Number of Mean (range) of
cancer sites of articles male patients female patients reported male-to-female ratios Paired t-test
Anal/rectal cancer 27 18686 15514 4.3 (0.2–61.5) p ¼ .23
CNS 22 2429 1864 1.5 (0–3.1) p ¼ .02
H&N 46 14922 5388 3.8 (0.4–13) p ¼ .02
Lung 56 57932 55815 1.8 (0.4–6.4) p ¼ .54
Upper GI 39 16504 7528 2.7 (0.2–17.1) p ¼ .02
p < .05.

Table 2. Analysis of the sex of the cell lines used in preclinical studies evaluated.
Cell line Origin Male Female Unknown
U87 Glioblastoma X
LN229 Glioblastoma X
M059K Glioblastoma x
M059J Glioblastoma X
U251 Glioblastoma X
5-8F Nasopharyngeal cancer X
CNE-1 Nasopharyngeal cancer X
HFF-1 Foreskin X
XP17BE Xeroderma pigmentiosum x
UMSCC74A Oropharyngeal squamous cell carcinoma x
Lymphoblastoid cells Primary cells x
LLC Lung cancer (mouse) X
HCT116 Colorectal carcinoma x
HCT15 Colorectal carcinoma x
BxPC3 Pancreatic carcinoma x

Table 3. Analysis of sex of the animals used in the preclin-
ical studies evaluated.
Number of articles
All animal studies 31
Male only 6 (20%)
Female only 6 (20%)
Male and female 3 (10%)
Not specified 16 (52%)
Sex-specific reporting 0 not specify the sex of the patient population. Our analysis of
and toxicity analyses (Figure 2). Sex was identified as signifi-
cantly affecting survival outcome in 17 (18%) of the studies
evaluated, with the majority (77 studies (82%)) reporting a
nonsignificant p value. Of the 17 studies reporting a significant
difference between the survival outcomes, 11 identified a better
outcome for females and 6 for males. There was no statistical
difference between the mean male-to-female ratios of these
studies (t-test, p ¼ .2) or the difference in the number of male
and female patients in these studies (independent t-test,
p ¼ .29, one-sample t-test, p ¼ .17).
Sex is poorly considered in preclinical studies
A total of 41 preclinical studies were evaluated. None of the
studies reporting the use of cells specified the sex. Out of
the 15 cell lines cited, 10 were males, 3 were females and 2
could not be determined (Table 2). Over half (52%) of the
studies reporting the use of animals (mice) did not specify
the sex (Table 3). Of those that did, six (20%) were males
only, six (20%) were females only, and three (10%) were
mixed. None reported sex-specific outcomes.
Discussion
This study is to our knowledge the first to examine the
radiotherapy cancer patient population with regard to the
consideration of female and male patients in research stud-
ies. This analysis is timely as both the dominance of male-
derived data and systematic pooling of male and female data
in statistical analyses are increasingly reported in biomedical
sciences (Yoon et al. 2014; Bryant et al. 2018; Stephenson
et al. 2019) One in five clinical studies (18%) evaluated did
those that did shows that the patient population was unbal-
anced with four out of five studies (81%) enriched with
male patients. This enrichment was significant in three
(CNS, head and neck, and upper GI) of the five most com-
monly reported cancer site categories. The higher incidence
of some cancers in male, compared to female patients, may
be attributed to the male dominance in research studies
(Scelo et al. 2018), and it may be hypothesized that the bal-
ance will be restored in response to the rapid increase in the
incidence of these diseases in females (Akushevich et al.
2019; Viner et al. 2019). However, like a mathematical
model is only robust within the range of values it is derived
from, statistical analyses are only as good as the data ana-
lyzed. In the case of asexualized biological data analysis,
facilitated by the accepted use of sex-neutral language, the
relevance of the reported findings to either the male or the
female population may be questioned.
More than half (55%) of the 230 studies that did specify
the sex of the patients, did not consider sex in their analysis.
In statistics, this practice, known as data ‘pooling’, is used to
obtain a more precise estimate of the value of a characteris-
tic that is assumed to have the same value across small sets
of data. The dangers of data pooling are carefully considered
when it comes to the combination of data from several
interventional studies (Bangdiwala et al. 2016) and with
regard to sex, the lack of sex analysis was proposed to
increase the risk for an effect being lost or claimed where it
only applies to one sex (Miller et al. 2017). The inclusion of

both sexes, generation of sex-based analysis, and publication
of outcomes by sex was proposed as key to improving the
reproducibility of preclinical biomedical research and reduc-
ing the risk of implementing unsafe practices (Collins and
Tabak 2014). Where the data was analyzed according to the
sex of the patients, survival outcomes were most commonly
considered. While nearly 4 out of 5 studies reviewed failed
to identify a significant difference between the sexes, of the
15 studies reporting a significant difference between survival
outcomes, 10 identified a better outcome for females and 5
for males. The detection of a significant difference between
the survival outcomes of female and male patients was not
representative of studies with a balanced number of included
male and female patients.
Our study is limited to a relatively small sample of
articles over a short period of time but our findings are con-
sistent with reports from other fields that despite the recog-
nition that the sex data gap needs to be closed in medical
research, the issues remains poorly addressed. The analysis
of the literature related to orthopedics identified that 35% of
the articles reviewed did not report the sex of animals, cells,
or cadavers used. Of the studies in which the authors did
report sex, 33% utilized both sexes and 13% reported sex-
based results (Bryant et al. 2018). In biomedical research,
the analysis similarly identified the underrepresentation of
female animals and a lack of sex-specific reporting (Beery
and Zucker 2011). A growing number of studies are drawing
attention to the impact of sex on human biology (Deasy
et al. 2007; Nelson et al. 2007; Klein and Flanagan 2016;
Sutti and Tacke 2018) including cancer biology (Mostertz
et al. 2010; Frega et al. 2019; Wang et al. 2019). In lung can-
cer, the analysis of gene expression signatures according to
the sex of the patients included revealed distinct cluster
groups (Mostertz et al. 2010). In bladder cancer, differences
in outcomes between male and female patients are well
documented (Wolff et al. 2015). These differences could not
be related to changes in the expression levels of immune
biomarkers (Holland et al. 2019). Nonetheless, contrasting
functions of both the functions of the both innate and adap-
tive immune systems in males and females have been
reported (Klein and Flanagan 2016). These differences can
be attributed to a number genetic, hormonal, and environ-
mental factors such as differences in the type of regulatory
response genes (Libert et al. 2010), the amount of miRNAs
present between the X and Y chromosomes (Pinheiro et al.
2011), genetic polymorphism linked to sex-specific antibody
responses (Scepanovic et al. 2018), and the microbiome
(Rizzetto et al. 2018).
Our analysis identifies that with regard to the evaluation
of radiotherapy in preclinical and clinical studies,
approaches to data analysis limit our ability to ascertain the
potential impact of sex. Authors should be encouraged to
examine and report their outcomes separately in male and
female. This approach might uncover the need to adapt our
practices in a sex-dependent manner or modify our study
designs. Indeed, study endpoints such as pain (Mogil and
Bailey 2010; Chow et al. 2017), inflammation (Ferguson
et al. 2013), blood counts (Lin et al. 2018; Xu et al. 2018),
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY 5
and even imaging parameters (Chow et al. 2017) could be
associated with different baselines in male and female that
may need to be accounted for. For instance, 30 -deoxy-30 -
(18)F-fluorothymidine ((18) F-FLT, activity was greater in
blood, liver, muscle, heart, kidney, and bone in female than
male mice (Chan et al. 2018). Similarly the analysis of MR
scans identified higher cell proliferative rate, inflammation,
and vasogenic edema in glioma-bearing male rats (Perez-
Carro et al. 2014). Distinct neutrophil-to-lymphocyte ratios
and immune-inflammation indexes were identified in male
patients (Xu et al. 2018).
Conclusion
The radiation therapy patient in research studies is both
more likely to be male and analyzed as a sex-neutral entity.
The systematic separation of male from female data would
impact on our study sample sizes but could improve both
the accuracy and the applicability of our outcome estimates.
Further evidence of the potential impact of sex on the evalu-
ation of radiation therapy is warranted.
Disclosure statement
No potential conflict of interest was reported by the authors.
Notes on contributors
Laure Marignol, MSc, PhD, is an associate professor of Radiobiology
and a principal investigator at the Discipline of Radiation Therapy,
School of Medicine, Trinity College Dublin, Dublin, Ireland.
Armelle Meunier, PhD, is a research assistant and laboratory manager
at the Discipline of Radiation Therapy, School of Medicine, Trinity
College Dublin, Dublin, Ireland.
ORCID
Laure Marignol http://orcid.org/0000-0002-2680-6200
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