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\begin{document}

\title{Evaluation of barriers to referral for cancer predisposition syndromes
in pediatric oncology patients}



\author[1]{Rosemarie Venier}%
\author[2]{Robin Grubs}%
\author[2]{Elena Kessler}%
\author[3]{Kelly  Bailey}%
\author[3]{Julia Meade}%
\affil[1]{University of Pittsburgh}%
\affil[2]{University of Pittsburgh Graduate School of Public Health}%
\affil[3]{University of Pittsburgh School of Medicine}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Cancer predisposition syndromes (CPS) are underdiagnosed in
the pediatric population, though the diagnosis of a CPS has important
implications for the child and their family. CPS are often diagnosed by
geneticists or oncologists with expertise in CPS following a malignancy.
This requires a member of the care team, most commonly, the treating
oncologist to suspect a CPS and refer the patient for assessment.
Procedure: An online survey was distributed to members of the Children's
Oncology Group to elucidate current referral practices and barriers to
referral for patients suspected to have a CPS. Results: Of the 189
respondents, 80.4\% were pediatric oncologists and most (69\%) used
formal guidelines to aid in referral assessment. Most respondents
indicated they would rarely refer patients with tumors highly associated
with CPS. Participants were more likely to refer patients with
malignancy and additional features of a CPS than for a specific type of
cancer, despite the use of guidelines. Parent knowledge of family
history was considered the most challenging barrier to obtaining a
family history, though a thorough pedigree was not consistently
elicited. Providers indicated the most significant barrier to referral
was priority given the patient's more immediate care needs. Conclusions:
Provider education about CPS and creation of clear referral guidelines
should increase appropriate referrals. Utilization of a genetic
counselor within the pediatric oncology clinic may encourage CPS
assessment and enable oncologists to focus on the patient's immediate
care needs.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Cancer predisposition syndromes (CPS) are caused by pathogenic germline
mutations in tumor suppressor genes, or more rarely oncogenes, which
confer an increased lifetime risk for cancer. Historical data estimated
10\% of all pediatric cancers were due to a
CPS.\textsuperscript{1,2}Data now suggest 7.6-35.5\% of childhood
cancers are due to an underlying CPS.\textsuperscript{3-10} While the
proportion of individuals with a CPS varies based on tumor type, study
population, and classification of mutations, these data illustrate that
overall, CPS are underdiagnosed in the pediatric population.

Individuals with a CPS are at an increased risk to develop treatment
toxicity and secondary cancers, and thus benefit from early diagnosis,
which may inform management and surveillance.\textsuperscript{1,11-13}To
facilitate the identification of patients with a suspected CPS, referral
guidelines have been established.\textsuperscript{14-17}

Numerous barriers to genetics referrals have been identified in the
primary care and adult oncology literature and can be broadly
categorized as knowledge, clinical validity, and system barriers. Some
healthcare providers (HCP) perceive genetic services lack clinical
utility and are not integral to their
practice.\textsuperscript{18-20}Unsurprisingly, this perception has been
linked to lack of genetics knowledge and poor adherence to
guidelines.\textsuperscript{20,21} In adult oncology, further distance
from a genetic counselor or genetics clinic has been correlated with
decreased referral likelihood for CPS evaluation.\textsuperscript{18,22}
In addition, some research suggests that the referral process itself may
be a hinderance, as primary care providers (PCP) are unaware which
clinic to refer to, or how to initiate the
process.\textsuperscript{18,23,24} Cost has also been considered a
barrier to genetics referral by the HCP and uptake by the
patient.\textsuperscript{18,25-27}

Given that most research on the topic of barriers to genetics referrals
focuses on data from primary care and adult oncology, this study
investigates current referral practices of HCP involved in the care of
pediatric oncology patients with a suspected CPS.

\textbf{METHODS}

An electronic survey link was emailed to 3,219 active COG members
located in the United States who indicated their specialty was
hematology/oncology, surgery, pathology, cellular therapy, or
cytogenetics. Responses were recorded February 5, 2020 -- March 2, 2020.
A reminder was sent one week prior to closure of the survey. In total,
230 responses were returned. Forty-one incomplete responses were
excluded. The total number of complete responses was 189. The response
rate was 5.8\%. This study was approved by the University of Pittsburgh
Institutional Review Board as an exempt protocol (STUDY19090002).

Data were analyzed by descriptive statistics. Totals vary by question as
some questions allowed respondents to select all choices that apply.
Proportion of response was calculated based on the number of total
responses for each individual question. Pearson's
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}test was used to assess relationships between
guideline use and demographic factors. Z-test for proportions was used
to compare guideline use and Likert scale questions. Analyses were
performed with Stata (v.16).

\textbf{RESULTS}

\textbf{Demographics}

Participant demographic data are summarized in Table 1. The majority of
respondents were staff physicians (80.4\%, 152/189), other respondents
were fellows (15.3\%, 29/189), PhDs (7.4\%,14/189), or a genetic
counselor (0.5\%, 1/189). Of those participants who possessed a PhD,
13/14 were also MDs.

The majority of respondents identified their specialty as pediatric
hematology/oncology (70.4\%, 131/186). Additional specialties included
surgery (7.5\%, 14/186), pediatrics (3.8\%, 7/186), pathology (1.6\%,
3/186), genetics (0.5\%, 1/186), or other (3.8\%, 7/186). Those
participants who chose other indicated specialties in ophthalmology,
pediatric urology, subspecialties of oncology or multiple specialties
such as genetics and oncology.

The most common practice settings were children's hospitals within an
academic center (55.7\%, 108/194), or freestanding children's hospitals
(40.2\%, 78/194). Most participants indicated a clinical volume of less
than 100 patients/year (42.8\%, 80/187) or 100-250 patients/year
(36.9\%, 69/187). Respondents estimated their patient population was
comparable to the known CPS population prevalence of approximately 10\%.
Those respondents who indicated more than 10\% of their patients had a
diagnosed CPS (6.5\%, 12/186) practiced within a cancer predisposition
clinic.

\textbf{Access to Genetics Services}

Greater than half (59.7\%, 108/181) of respondents indicated their
institution had a cancer predisposition clinic, with 70.8\% (75/108)
situated within the pediatric hematology/oncology division (Table 2).
Furthermore, 97.3\% (182/187) indicated they had access to a genetics
specialist including a geneticist or genetic counselor. A large majority
(87\%, 160/184) of participants reported they consult with genetics or
CPS specialists if they suspect a patient has a CPS. Feedback from the
genetics clinic regarding referral appropriateness was common for 62.6\%
(114/182) of respondents. Some participants received feedback before
referral at tumor board meetings or during consultations. Respondents
also obtained genetics information from the scientific literature
(95.2\%, 177/186) and personal communication with genetics professionals
(82.3\%, 153).

\textbf{Referral Practices}

The majority of respondents believed a hematologist/oncologist was the
most appropriate provider to initiate a CPS referral (83.9\%, 151/180),
whereas 5.6\% (10/180) thought a medical geneticist was most appropriate
(Table 3). Conversely, participants felt medical geneticists (62\%,
111/179) were the most appropriate provider to diagnose a patient with a
CPS, whereas 19.6\% (35/179) thought hematologists/oncologists were most
appropriate to make the diagnosis.

Respondents indicated that they rarely (42.6\%, 78/183) or sometimes
(30.1\%, 55/183) referred patients for a CPS evaluation. Frequency was
not correlated with use of referral guidelines. Formal referral
guidelines were used always (34.2\%, 63/184) or sometimes (34.8\%,
64/184) and most respondents were somewhat (44.4\%, 56/126) or extremely
(15.9\%, 20/126) satisfied with the guidelines they use, while 32.5\%
(41/126) were indifferent. A quarter of participants (45/180) did not
use the same guidelines as their colleagues, and 58.9\% (106/180) were
unsure of which, if any, guidelines their colleagues used. Use of
guidelines was dependent on clinical volume of CPS patients (Pearson's
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}, p = 0.01).

The main reason for not using guidelines was the lack of guideline
availability (34.4\%, 45/131), with an additional 8.4\% (11/131) who
were unaware guidelines existed. About a quarter (32/131) of
participants felt confident referring without guidelines, and 15.3\%
(20/131) indicated conflicting guidelines from different sources
discouraged their use.

Of the cancer types recommended to result in referral regardless of
family history, pheochromocytoma/paraganglioma (PPGL) and choroid plexus
carcinoma (CPC) were the most likely to always result in referral,
however, this was only indicated by 31.3\% (51/163) and 29.4\% (47/160)
of respondents, respectively (Figure 1A). Participants who used
guidelines were significantly more likely to always refer a patient with
PPGL (one tailed z-test, p\textless{}0.05).

The majority of respondents indicated they rarely refer patients with
medulloblastoma, osteosarcoma, rhabdomyosarcoma, glioma, neuroblastoma,
Wilms tumor, acute myeloid leukemia, or Ewing sarcoma, many of which are
linked to a CPS.\textsuperscript{1,14,15} Most respondents also
specified they rarely referred patients with Hodgkin lymphoma, a cancer
that is often sporadic, for genetics referral. Hodgkin lymphoma was
included to ensure the internal validity of the question.

While the majority of respondents were likely to refer patients with
concerning features of a CPS, the certainty with which they did so
varied. Well understood indications were extremely likely to be
referred, such as a patient with a malignancy and genetic test results
indicating a germline mutation in a cancer predisposition gene (89.1\%,
164/184) or multiple malignancies (85.9\%, 158/184) (Figure 1B). In
contrast, a patient presenting with a malignancy and developmental
delay/intellectual disability was extremely likely to be referred by
only 12.5\% (23/184) of respondents, with most somewhat likely (45.1\%,
83/184) or neither likely nor unlikely (34.2\%, 63/184) to refer for
genetic evaluation indicating physician uncertainty despite published
guidelines that recommend referral for these
indications.\textsuperscript{11,14,17}

When familiarity with published guidelines for referral/evaluation of a
CPS was used to stratify responses, those who did not use guidelines
were significantly less likely to refer patients with a malignancy and
immunodeficiency (one tailed z-test, p\textless{}0.05). Overall
likelihood to refer patients with other features were not associated
with guideline use, however tendency was significantly associated for
some features. Patients with features of abnormal growth such as
macrocephaly, or hemihyperplasia were extremely likely to be referred by
41.2\% (52/126) of respondents who used referral guidelines compared to
23.6\% (13/55) of respondents who did not use referral guidelines (one
tailed z-test, p\textless{}0.05). Those participants who did not use
guidelines still indicated they were somewhat likely to refer patients
with abnormal growth (60\%, 33/55). A similar trend was observed for the
patients with excessive toxicity to cancer therapy; 23.8\% (30/126) of
respondents who use guidelines were extremely likely to refer compared
to 10.9\% (6/55) of those who do not use guidelines (z-test,
p\textless{}0.05). These data suggest that guideline use increases
confidence in appropriate referrals.

\textbf{Family History Elicitation}

Family history was considered essential to assessment of new pediatric
oncology patients by greater than 90\% of respondents regardless of
whether or not a CPS was suspected. We asked respondents to indicate the
frequency with which they ask about particular family members when
eliciting family history for a routine pediatric oncology patient or a
pediatric oncology patient with a suspected CPS (Table 4). Regardless of
evaluation type, almost all respondents always collect information about
the patient's mother, father, and full siblings (routine pediatric
oncology patient 96\%, or suspected CPS 98\%). However, aunts/uncles and
half siblings were asked about less often than grandparents despite the
same degree of relationship to the patient. Grandparents were always
included by 82.9\% (150/181) of participants taking a family history for
a routine patient whereas aunts/uncles were included by 56.7\%
(101/178). For most routine patients, family history was reviewed only
if the patient mentioned an update (58.1\%, 108/186) but if the patient
was suspected to have a CPS, family history was reviewed most of the
time (40.9\%, 74/181).

\textbf{Barriers to Complete Family History}

Overall, respondents felt the patient/parent's lack of knowledge of the
family history interfered a lot (43.2\%, 79/183) or a great deal
(16.4\%, 30/183) with obtaining a family history. Eighty percent
(46/183) felt this was the most challenging aspect. Patient or parent's
anxiety (70.5\%, 129/183), timing of family history elicitation in
relation to diagnosis (53.6\%, 98/183), and allocation of the provider's
time (55.2\%, 101/183) interfered a little or not at all (Figure 2A).

\textbf{Barriers to Genetics Referrals}

Respondents indicated that hematologists/oncologists are the most
appropriate provider to refer a child for assessment for a CPS, yet the
majority of participants rarely refer patients. Patient knowledge of
family history was probably (59.4\%, 107/180) or definitely (12.8\%,
23/180) a barrier for most respondents (Figure 2B). Other barriers
identified by at least half of respondents included priority given other
immediate care needs (63.1\%, 113/180), and patient understanding of
genetic risk (52.2\%, 93/178).

Lack of available genetics services, and insufficient institutional
resources were definitely not barriers for 51.1\% (92/180) and 55\%
(99/180) of respondents. In addition, 41.1\% (74/180) and 30\% (54/180)
of participants indicated patient eligibility for genetics services was
probably not or definitely not a barrier to referrals for their
patients. Other issues including familiarity with genetic conditions,
limited time at appointments, cost and/or insurance coverage, and lack
of referral guidelines were less likely to be considered barriers.

When asked about the most challenging barrier to referral, 24\% (44/183)
of respondents indicated priority of the referral compared to other
patient needs was the most challenging barrier. Patient knowledge of
family history was not only considered a barrier to collection of family
history information but also to genetics referral (21.3\%, 39/183), as
was cost/insurance coverage (12\%, 22/183). Other issues were
acknowledged by less than 10\% of the respondents as the most
significant barrier to referral.

\textbf{DISCUSSION}

This study assessed current referral practices of American pediatric
hematologists/oncologists for patients with a suspected CPS. Nearly 84\%
of respondents indicated that hematologists/oncologists were the most
appropriate provider to refer a patient with a suspected CPS for
genetics evaluation. Of these participants, 72.7\% were
hematologists/oncologists themselves, yet close to three quarters of all
participants indicated they only sometimes or rarely refer such
patients. Recent data suggest the prevalence of CPS in the pediatric
cancer population ranges from 7.6-35.5\%.\textsuperscript{3-10} Thus
respondents may have indicated they rarely refer patients because they
rarely encounter appropriate patients for referral, or because other
barriers prevent it.

The majority of respondents indicated they used guidelines to assess
patients for referral and more than half were satisfied with the
guidelines they use. Guideline use was associated with CPS clinical
volume over 5\%. Overall, participants were more likely to refer
patients with malignancy and additional features of a CPS than they were
for a specific type of cancer. PPGL was the only type of cancer the
largest proportion of participants indicated they were likely to always
refer for evaluation of a CPS, although guidelines recommend all index
cases of PPGL be assessed for a CPS. These guidelines also recommend
referral for cases of CPC, medulloblastoma, and sarcoma regardless of
family history yet most respondents indicated they rarely refer patients
with such malignancies for genetics evaluation despite their strong
association with CPS.\textsuperscript{11,15,17} Regardless of guideline
usage, these data suggest further education and guidance is required for
providers. Indeed, tumor and germline sequencing in pediatric oncology
has already discovered new candidate cancer predisposition genes, which
may become relevant to patient care.\textsuperscript{7,28}

For CPS-associated features, likelihood to refer varied by the specific
feature, and was generally not associated with guideline use except for
immunodeficiencies. Most respondents were likely to refer patients with
malignancy and abnormal growth or excessive toxicity to cancer therapy,
however, unfamiliarity with guidelines led to significantly decreased
tendency to refer. The features described in this section of the survey
were based on criteria described by European groups and thus may not be
familiar to our American cohort.\textsuperscript{11,14} Nonetheless,
inconsistency to refer for each CPS feature suggests participants may
consider additional factors and/or be using different guidelines to
assess whether to refer a patient for a suspected CPS.

In addition to guidelines, family history is often utilized to assess
for a CPS.\textsuperscript{24,29-33} In this study, the most challenging
aspect of obtaining a family history identified by participants was the
patient/parent's lack of knowledge about the family, which influenced
their ability to refer the patient. Nonetheless, survey respondents
reported they do not always collect a full three-generation pedigree,
the gold standard in genetics, or a two-generation pedigree as
recommended by the American Society of Clinical
Oncology.\textsuperscript{34} These data suggest both physician and
patient factors contribute to incomplete family history documentation
and suggest respondents rely on complete, positive family histories to
determine referral for a CPS.\textsuperscript{35} Patient knowledge may
limit family history elicitation, but should not prevent referral of
patients with high-risk tumors for evaluation.\textsuperscript{15}

Patient needs are prioritized during oncology visits and family history
elicitation may initially be deferred, but research in the pediatric
cancer survivor setting has illustrated the importance of frequent
family history review.\textsuperscript{2,36,37} As expected, respondents
indicated they reviewed family history more often for patients with a
suspected CPS, yet only 14.9\% reviewed family history at every
appointment. Instead, the most common answers were most of the time or
if the patient mentioned an update. Some respondents may see their
patients more often than the family history would be expected to change
thus decreasing the proportion of physicians who would review history at
every appointment, however, patients are less likely to mention updates
unprompted and thus these responses may represent missed referral
opportunities.\textsuperscript{24}

In addition to family history review, CPS evaluation may be considered
low priority given other patient needs.\textsuperscript{2,15} Nearly two
thirds of respondents indicated priority was a barrier to genetics
referral and it was considered the most significant barrier by 24\%.
Indeed, the majority of participants surveyed were
hematologists/oncologists and pediatric surgeons whose main concerns are
focused on the acute needs of their patients. Of note, limited time was
not identified as a barrier by most respondents.

Evidence suggests that HCP who deem genetics integral to their practice
are more likely to refer.\textsuperscript{20} While referral to another
specialist at an overwhelming and busy time for the family may not be a
top priority for the treating physician, identification of a CPS can
have immediate effects on the patient's siblings, parents, and other
family members and should be addressed in a timely
manner.\textsuperscript{2} Delegating family history elicitation to a
genetic counselor or establishing specific timepoints by which to review
family history within the clinic may ensure the patient's immediate care
needs are met without forgoing family history assessment. Patients with
an underlying CPS have been identified by family history review in
survivorship clinics which may provide a reasonable option for some
practitioners.\textsuperscript{36,37}

This survey focused on barriers to physician-initiated referrals.
Interestingly, patient understanding of genetic risk, a patient-centered
issue, was considered a barrier by over half of respondents. This issue
is often considered in the context of referral uptake rather than the
initiation of the referral itself.\textsuperscript{38} Other groups have
addressed this problem successfully by embedding genetic counseling
services into adult oncology clinics.\textsuperscript{39,40}

Contrary to other studies, access to genetics services, professionals,
and resources generally and within the respondent's institution were not
perceived as barriers to referral.\textsuperscript{18,19,22,23} In fact,
almost 60\% of participants reported their institution has a cancer
predisposition clinic and most participants receive helpful feedback on
referrals. While most participants also indicated access to a genetic
counselor, geneticist, or other colleague with expertise in CPS for
formal or informal consultations, further implementation of genetics
into the pediatric oncology clinic may be beneficial to the
identification of patients with an underlying CPS, especially since over
a quarter of respondents do not receive feedback following
referral.\textsuperscript{41} While nearly half of respondents indicated
they participate in molecular/genetics tumor boards, 31.9\% of
respondents indicated their institution conducts tumor boards but they
do not attend. This may represent an opportunity for genetic counselors
and others with expertise in CPS to educate colleagues and increase
referrals, and participation from multiple departments should be
encouraged. This may also ensure consistent referral practices within an
institution, as our data suggests only 16\% of respondents use common
institutional referral guidelines.

Although most participants surveyed use referral guidelines, almost half
of those who do not indicated a lack of guideline availability or
unawareness of guidelines as the reason. One respondent commented that
guidelines would be more useful if risk for a CPS was defined relative
to family history, whereas others indicated their institutions refer all
pediatric oncology patients. These comments demonstrate a lack of
consensus on which patients should be referred for CPS evaluation and
how strictly guidelines are followed by the pediatric oncology
community. This is a problem others have
documented.\textsuperscript{42,43} While it may not be feasible for each
cancer predisposition clinic to accept referrals of all pediatric
oncology patients, guidelines aim to ensure a balance between the
benefit of diagnosing children with an underlying CPS and the risks of
over-referring patients to genetics/cancer predisposition clinics. This
must also be balanced with the availability of genetics professionals to
prevent overwhelming the genetics workforce, of which there is a
documented shortage.\textsuperscript{44,45} Therefore, efforts should be
made to develop and distribute sensitive, specific, easy-to-use
guidelines for CPS evaluation and to encourage consultation between
specialties to increase appropriate referrals.

Evidence suggests lack of adherence to guidelines is closely related to
genetics knowledge and perceived clinical
utility.\textsuperscript{21,46} The majority of respondents reported
they received adequate genetics education during their training and
stated scientific literature, personal communications with genetics
professionals, and multidisciplinary tumor board meetings as the major
channels through which they continue to obtain information. Over half of
respondents also indicated familiarity with genetic conditions was not a
barrier to genetics referral. This study was not designed to measure
genetics knowledge, but it does suggest that further education may be
helpful to aid survey respondents in identification of patients who may
benefit from genetics evaluation for a CPS.

Limitations to this study include the low response rate which may have
been due to the short data collection phase, and availability of
respondents. Participants were not asked to specify which guidelines
they use or how closely they are followed, preventing further
association of responses with specific guideline recommendations.
Referral behavior questions addressed likelihood or frequency of
referral and wording was not consistent between these questions which
may have changed respondents' interpretations. This survey focused on
behaviors and attitudes and did not quantify referral rates. Although
the survey was piloted, it was not formally validated with content
validity or reliability measures.\textsuperscript{47}

Future studies may quantify pediatric oncology HCP knowledge to
elucidate the relationship between CPS knowledge and guideline
adherence, or genetics referral. Lastly, survey respondents represent a
small proportion of all pediatric oncology HCP; future work will aim to
collect data from a more representative sample of hematology/oncology
practitioners and other pediatric providers to understand the
perspectives of the care team as a whole.

Identification of individuals with a CPS is important for proper
management and surveillance of the patient and their
family.\textsuperscript{13,48} The results of this study are comparable
to findings in adult oncology, but to our knowledge, this is the first
study in pediatric oncology that investigates these issues. Overall,
these data demonstrate physician, patient, and system level barriers to
genetics evaluation for children with a suspected CPS. Both patient and
physician factors prevent the collection of in-depth family history
information but this should not preclude referral. Education about
features and high-risk cancers associated with CPS, more widely
distributed referral recommendations, and further implementation of
genetics experts into pediatric oncology practices may contribute to
increased genetics referrals and ultimately improve recognition of
at-risk patients.

\textbf{Conflict of Interest}

The authors have no conflicts of interest to declare.

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\textbf{LEGENDS:}

\textbf{Figure 1} Likelihood to refer for CPS evaluation. (A) Likelihood
of respondents to refer a patient for evaluation of a CPS based on
disease type. (B) Likelihood of respondents to refer a patient for
evaluation of a CPS based on features as described by Jongmans et
al.\textsuperscript{11} Abbreviations: CPC choroid plexus carcinoma, MB
medulloblastoma, PPGL pheochromocytoma/paraganglioma, OS osteosarcoma,
ERMS embryonal rhabdomyosarcoma, ARMS alveolar rhabdomyosarcoma, GLI
glioma, NB neuroblastoma, WT Wilms tumor, ES Ewing sarcoma, HL Hodgkins
lymphoma, DD/ID developmental delay/intellectual disability.

\textbf{Figure 2} Barriers perceived by respondents to interfere with
(A) obtaining a complete family history or (B) genetics referral.

\textbf{Hosted file}

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