Communication about the Risks and Benefits of Phase I Pediatric Oncology Trials

Abstract

Introduction:
Phase 1 pediatric oncology trials offer only a small chance of direct benefit and may have significant risks and an impact on quality of life. To date, research has not examined discussions of risks and benefits during informed consent conferences for phase 1 pediatric oncology trials. The objective of the current study was to examine clinician and family communication about risks, benefits, and quality of life during informed consent conferences for phase 1 pediatric oncology trials.

Methods:
Participants included clinician investigators, parents, and children recruited from 6 sites conducting phase 1 pediatric oncology trials. Eighty-five informed consent conferences were observed and audiotaped. Trained coders assessed discussions of risks, benefits, and quality of life. Types of risks discussed were coded (e.g., unanticipated risks, digestive system risks, and death). Types of benefits were categorized as therapeutic (e.g., discussion of how participation may or may not directly benefit child), psychological, bridge to future trial, and altruism.

Results:
Risks and benefits were discussed in 95% and 88% of informed consent conferences, respectively. Therapeutic benefit was the most frequently discussed benefit. The impact of trial participation on quality of life was discussed in the majority (88%) of informed consent conferences.

Conclusion:
Therapeutic benefit, risks, and quality of life were frequently discussed. The range of information discussed during informed consent conferences suggests the need for considering a staged process of informed consent for phase 1 pediatric oncology trials.

Full text

Communication about the Risks and Benefits of Phase I
Pediatric Oncology Trials
Rebecca A. Hazen, PhDa, Stephen Zyzanski, PhDb, Justin Baker, MDc, Dennis Drotar, PhDd,
and Eric Kodish, MDe
aDepartment of Pediatrics, Case Western Reserve University and Rainbow Babies and Children’s
Hospital, 10524 Euclid Ave, Cleveland, OH, 44106, rebecca.hazen@uhhospitals.org
bDepartment of Family Medicine, Case Western Reserve University, 11100 Euclid Ave,
Cleveland, OH 44106, sjz@case.edu
cSt. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678,
justin.baker@stjude.org
dDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnett Ave,
Cincinnati, OH 45229-3026, dennis.drotar@cchmc.org
eCenter for Ethics, Humanities, and Spiritual Care, Cleveland Clinic, 9500 Euclid Ave JJ60
Cleveland, OH, 44195, kodishe@ccf.org
Abstract
Introduction—Phase 1 pediatric oncology trials offer only a small chance of direct benefit and
may have significant risks and an impact on quality of life. To date, research has not examined
discussions of risks and benefits during informed consent conferences for phase 1 pediatric
oncology trials. The objective of the current study was to examine clinician and family
communication about risks, benefits, and quality of life during informed consent conferences for
phase 1 pediatric oncology trials.
Methods—Participants included clinician investigators, parents, and children recruited from 6
sites conducting phase 1 pediatric oncology trials. Eighty-five informed consent conferences were
observed and audiotaped. Trained coders assessed discussions of risks, benefits, and quality of
life. Types of risks discussed were coded (e.g., unanticipated risks, digestive system risks, death).
Types of benefits were categorized as therapeutic (e.g. discussion of how participation may or
may not directly benefit child), psychological, bridge to future trial, and altruism.
© 2015 Published by Elsevier Inc.
This manuscript version is made available under the CC BY-NC-ND 4.0 license.
Corresponding Author and Reprints: Rebecca A. Hazen, Ph.D., Department of Pediatrics, Case Western Reserve University, Rainbow
Babies and Children’s Hospital, 10524 Euclid Ave, Cleveland, OH, 44106, Phone: 216-844-3230, rebecca.hazen@uhhospitals.org.
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The authors have no conflicts of interest to report.
HHS Public Access
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Contemp Clin Trials. Author manuscript; available in PMC 2016 March 01.
Published in final edited form as:
Contemp Clin Trials. 2015 March ; 41: 139–145. doi:10.1016/j.cct.2015.01.015.
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Results—Risks and benefits were discussed in 95% and 88% of informed consent conferences,
respectively. Therapeutic benefit was the most frequently discussed benefit. The impact of trial
participation on quality of life was discussed in the majority (88%) of informed consent
conferences.
Conclusion—Therapeutic benefit, risks, and quality of life were frequently discussed. The range
of information discussed during informed consent conferences suggests the need for considering a
staged process of informed consent for phase 1 pediatric oncology trials.
Keywords
ethics; informed consent; phase 1 trials
Participation of children in phase 1 oncology trials has raised a number of ethical questions
and debates [1,2]. The primary scientific purposes of phase 1 pediatric oncology trials are
not to test the efficacy of cancer drugs but rather to establish the maximum tolerated dose
(e.g. safe dose) for cancer drugs, which can then be tested in phase 2 trials [3]. Thus, the
balance of risks and benefits for the individual child is one of the primary ethical concerns
[3]. Although phase 1 pediatric oncology trials offer only a small likelihood of direct benefit
to the patient (average response of 5–10%) [4,5], phase 1 trials for pediatric cancers are
typically approved by institutional review boards under the federal category “greater than
minimal risk but presenting the prospect of direct benefit to individual subjects” (Part
46.405 Subpart D) [3]. Despite these circumstances, little is known about how clinicians and
families communicate about the risks and benefits of pediatric phase I trials. Furthermore,
recent ethical debates regarding risks and benefits from a study of premature infants [6,7]
suggests the importance of obtaining data on discussions between research clinicians and
families about these topics.
Parents rate communication with treating clinicians as important in deciding about phase 1
trials [8]. Research on parental decision-making about phase 1 oncology trials suggests that
parents often perceive a variety of benefits of participation, including altruism, prolonging
life, and curing their child’s cancer [9]. The impact of participation on quality of life (QOL)
is also considered to be an important factor when considering participation in phase 1
clinical trials [10]. Effective communication about risks and benefits of participation in
phase 1 clinical trials is thought to be complicated by “therapeutic misconception,” which
refers to the belief that the purpose of research is to directly benefit the individual patient
[11]. This is common for participants in clinical trials [12–14]. Given the existence of the
therapeutic misconception, the small chance of direct benefit to the individual patient, and
the potential risks, communication about risks, benefits, and QOL during informed consent
conferences (ICCs) is of particular importance.
To our knowledge, research has not yet examined how clinician investigators and families
communicate about risks and benefits during ICCs for phase 1 pediatric oncology trials.
Using observational methods, the primary goal of the current study was to examine clinician
investigator and family communication about risks, benefits, and impact of participation on
QOL during ICCs for phase 1 pediatric oncology trials. A secondary goal was to examine
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observer ratings of the quality of clinician investigator communication about risks and
benefits.
Methods
Recruitment & Study Procedures
Data for the current study were collected as part of a multi-site project examining
communication about phase 1 pediatric oncology trials across six research sites, which were
chosen based on their participation in phase 1 pediatric oncology trials [15–19]. Institutional
review board (IRB) approval was obtained at Cleveland Clinic (coordinating site) and the
six data collection sites.
Inclusion criteria were that the family was considering participation for the child in an open
phase 1 pediatric oncology trial and spoke either English or Spanish. Families who spoke
other languages were excluded due to difficulty with translating study instruments. Pediatric
oncology trials were defined as Phase 1 trials that enrolled individuals ages 22 and under
with any cancer diagnosis.
Members of the healthcare team obtained permission from families for a research assistant
(RA) to contact them. Prior to the ICC, RAs obtained written consent from participating
physicians, parents, and patients age 18 or above. Assent was obtained for children between
7 and 17 years old. One hundred six families were approached regarding participation in the
study, 85 families (80%) consented to allowing the ICC to be observed and audiotaped, and
60 of these families agreed to be interviewed after the ICC. Data from the parent interview
were previously reported [15,16,18]. Demographic and disease information for those who
declined participation in the current study was not available.
ICCs were silently observed by RAs, who digitally audio recorded the ICCs. Participants in
ICCs included clinician investigators, patients, and family members.
Measures
Demographics—The following demographic information about parents and patients was
collected from parents during parent interviews: age, gender, education, occupation, race,
religious preference, and number of additional children. The Hollingshead Index of Social
Position (ISP) [20] was calculated based on occupation and education and was used to
measure socioeconomic status (SES), with lower ISP scores indicate higher SES.
Demographic data about clinician investigators was obtained from the General Clinician
Questionnaire, which was designed by study investigators [19]. Clinician investigator
demographics included age, gender, race and number of years caring for children with
cancer.
Communication During ICCs—Audiorecorded ICCs were coded using the
ENCOUNTER Codebook, which was created based upon rulebooks that were used in
previous studies [21,22]. The rulebook included detailed instructions, definitions of
terminology, and examples of communication to guide raters. ENCOUNTER, a Web-based
health communication analysis software program, was used to code the audio recordings
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using the ENCOUNTER Codebook. The following data on risks/side effects was coded:
whether risks/side effects were discussed, who raised the topic of risks/side effects (every
occurrence during ICC was coded), whether the clinician investigator described risks/side
effects of participation, and the types of risks discussed (e.g. digestive, sleep/fatigue; see
Table 1 for risk categories). The types of benefits discussed were also coded. Type of
benefits included therapeutic (e.g. tumor shrinkage), psychological (e.g. feeling like they are
not “giving up”), altruism (e.g. helping future children with cancer), and bridge to another
clinical trial (e.g. participating to get some benefit that will allow participation in another
trial). It should be noted that discussion of therapeutic benefits were coded as occurring
regardless of whether the clinician investigator indicated that the child would be likely to
receive direct therapeutic benefit. For example, the small chance of direct benefit could be
highlighted by the clinician investigator. We attempted to further code therapeutic benefit
based on the whether the discussion emphasized low, moderate, or high likelihood of
benefit. However, it was not possible to reliably code discussion of the likelihood of benefit
due to the high level of nuance and ambiguity in these discussions (e.g. “hope it slows down
the tumor but there is no guarantee,” “don’t know if it works….hope it works,” “’it’s
promising but not proven….no promise it will work”). It is noteworthy that none of the ICCs
included clinician investigators discussing the phase 1 study as being likely to cure the
cancer. Finally, clinicians’ effectiveness of communication about risks and benefits were
rated by trained RAs on a 10 point Likert scale, with 1 representing poor communication
and 10 representing optimal communication. Higher scores were given for more complete
discussions of risks and benefits. To receive a high score on this rating scale, the clinician
had to explain the types of risks and benefits and not just list side effects or briefly mention
benefits.
Discussions about QOL (positive, negative, or neutral) and impact of trial participation on
extracurricular activities (e.g. school, sports, social life) were coded as to whether they
occurred (e.g. increasing or decreasing symptoms, changes in child’s daily activities) and
who raised the topics. The first author also coded the discussions about QOL as to whether
they were positive, negative, or neutral.
Given that information on risks and benefits is also provided in the informed consent
documents (ICD), ICDs were also coded to examine how frequently the types of risks and
benefits described above were presented in the ICDs. Specifically, the types of risks (see
Table 1) and benefits (e.g. therapeutic, psychological, bridge to future trial, altruism)
described in the ICDs were coded.
Training for coders of ICCs included 60 hours of training over a four-week period, during
which coders were trained on how to identify specific communication topics. Inter-rater
reliability was examined by double coding 30% of ICCs. Kappa correlations for the
categorical clinician investigator behaviors coded using ENCOUNTER and examined in the
current study ranged from .85–1.0 [23].
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Statistical Analysis
Descriptive statistics were computed, with means and standard deviations used for
continuous variables and percentages used for categorical variables. Ninety five percent
confidence intervals were also computed for all risk categories coded as a percent.
Results
Patient and Parent Demographics
Patient and parent demographic information was available for 60 families who completed
the parent interview and have been reported by Cousino and colleagues [15]. The majority
of patients were male (n = 54; 63%) and the average age of patients was 11 years (SD=5.5;
range = 1–21 years). The most common diagnoses were brain and CNS tumors (n = 28;
33%) and bone or soft tissue cancer (n = 26; 31%). Additional cancer diagnoses included
neuroblastoma (n=17; 20%), leukemia (n=7, 8%), and other less common cancer diagnoses
(n = 7, 8%). The majority of phase 1 protocols that participants consented to were receptor/
signal transduction studies (i.e. kinase inhibitors; 20/33, 61%), 7 (21%) were cytotoxic
chemotherapy studies, 5 (15%) were immunodulator studies (e.g. antibody agents), and one
was an angiangiogenesis study. Sixty five (76%) of the 85 patients had expired at the time of
the current analyses, with an average of 254 (SD = 229.3, range = 17 – 981) days from the
ICC to the patient’s death. Parent participants were predominantly female (n = 43; 72%),
represented the racial majority (n = 51; 85%), and had an average age of 42 years (SD = 8.2;
range = 23–66 years). Socioeconomic status was equally distributed amongst the low (n =
21; 35%; ISP = 4–5), medium (n= 20; 33%; ISP=3), and high (n = 19; 32%; ISP=1–2)
groups on the ISP.
Clinician Investigator and Conference Characteristics
Clinician investigator and conference characteristics were reported previously [15].
Clinician investigators had been caring for children with cancer for an average of 14 years
(SD=8.1) and had an average age of 44 years (SD=6.8) [15]. Fifty-four percent of clinician
investigators were female and 15% were racial/ethnic minorities. A nurse participated in
40% of ICCs. On average, the ICC lasted 45 minutes (SD=20) and there was an average of 5
(SD=1.2) participants in the ICCs. Patients were present in 98% (83/85) of ICCs. The ICD
was provided in 69% of ICCs and signed during 66% of ICCs. Ninety-five percent of
families agreed to enroll their child in a phase I study.
Clinician Investigator-Family Communication About Risks and Benefits
Risks were discussed 271 times in 95% of ICCs (81/85). An examination of conference and
demographic characteristics did not reveal differences for the four ICCs in which risks were
not discussed versus those in which there was discussion of risks. Clinician investigators
raised the topic of risks 75% (204/271) of the time. In addition, parents and patients raised
the topic of risks 20% (53/271) of the time and 5% (14/271) of the time, respectively. The
types of risks discussed are presented in Table 1. The most frequently discussed risks
included digestive risks (80% of ICCs) and hematological/oncologic risks (67% of ICCs).
As shown in table 1, the least frequently discussed risks included loss of confidentiality
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(1.2% of ICCs), immune system risks (8% of ICCs), and risks related to medical procedures
(10% of ICCs). Death was discussed as a risk in 9% of ICCs. Fifty three ICDs were used
across the six research sites and most risks were presented more frequently in ICDs than
during ICCs (Table 1).
Benefits were discussed in 88% (75/85) of ICCs. Therapeutic benefits were discussed 160
times in 85% (72/85) of ICCs and were raised by clinician investigators 84% of the time
(134/160) and patients/families 16% (26/160) of the time. Psychological benefits were
discussed 7 times in 7% (6/85) of ICCs, with 71% (5/7) of these discussions being initiated
by clinician investigators and 29% (2/7) of discussions initiated by families. Discussion of
altruism as a benefit of participation occurred 51 times in 41% (35/85) of ICCs. Altruism
discussions were raised predominantly by clinician investigators (75%, 38/51). Discussion
of participation in the clinical trial as a bridge to extend life for subsequent research
occurred 13 times in 13% (11/85) of ICCs and this was raised primarily by clinician
investigators (11/13; 85%). Parents/family raised the topic of a bridge to another trial 15%
(2/13) of the time. Examples of discussions about risks and benefits are provided in Table 2.
With regard to presentation of benefits in ICDs, all of the ICDs presented therapeutic
benefits and altruism as benefits of participation. However, psychological benefits and
participation as a bridge to extend life for subsequent research were not presented in any of
the ICDs.
Ratings of Clinician Communication About Risks and Benefits
Ratings of clinician communication about risks and benefits ranged from 1 to 9, with a mean
of 5.98 out of 10 (SD=1.65, n=85). As shown in Figure 1, the data was skewed, with only
15% of ratings falling below five. Ratings of risks and benefits communication did not differ
significantly based on whether a nurse was present during the ICC (t = .83, p = .41).
Clinician Investigator-Family Communication About QOL
The potential impact of participation on child QOL was discussed 149 times in 88% (75/85)
of ICCs. Clinician investigators raised the topic of QOL 71% (106/149) of the time and
patients and families raised the topic 29% (43/149) of the time. Discussions of the impact of
participation on QOL were predominantly neutral (74/149; 50%) or negative (60/149; 40%),
with only 10% (15/149) of discussions being positive. In addition, the potential impact of
participation on extracurricular activities was discussed 23 times in 21% (18/85) of ICCs.
Families and patients raised the topic of extracurricular activities 70% of the time (18/23)
and clinician investigators raised the topic 30% of the time (7/23). Table 2 provides
examples of communication about QOL and impact on extracurricular activities.
Discussion
The current study provides the first data from directly observed audio-taped communication
about risks, benefits, and QOL during ICCs for phase 1 pediatric oncology trials. Results
indicated that discussion of risks and benefits were common during ICCs, with risks
discussed in 95% of ICCs and benefits discussed in 88% of ICCs.
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Given the concerns about families being able to balance the risks and benefits of
participation in phase 1 studies [1–3], it is encouraging that the overwhelming majority of
ICCs contained discussion about both risks and benefits. Although clinician investigators
most frequently raised the topics of risks and impact on QOL, both parents and children also
raised the topics during the ICCs, suggesting that families are seeking necessary information
prior to deciding on participation. Research by Maurer and colleagues [10] indicated that
parents who identified QOL concerns were less likely to consent to enrolling their child in a
phase 1 trial. In the current study, QOL discussions ranged from negative to positive and
95% of families consented to enrollment in a phase 1 trial. It is important for additional
research to examine how discussions about QOL in ICCs may impact decision making about
phase 1 trials.
A wide variety of risks were discussed during ICCs, with digestive and hematological/
oncologic risks discussed the most frequently. Despite the fact that phase 1 studies always
present a chance for unanticipated risks, approximately 65% of ICCs did not include a
discussion of unanticipated risks. Although risks were frequently discussed during most
ICCs, the results suggest that there are important risks of participation in phase 1 trial that
are frequently omitted. However, coverage of risks by clinician investigators during ICCS is
also likely to be influenced by coverage of risks in the ICDs, which tended to be extensive in
the current study.
In the current study, death was discussed as a risk of participation in 9% of cases. It is
important to consider whether pediatric oncologists should discuss the risk of death from
phase 1 studies. Although death is clearly the most serious outcome, the low rates of death
related to drug toxicity in phase 1 pediatric oncology trials (0.5–0.7%) [4,5] may lead
clinician investigators to conclude that it is not necessary to discuss this risk. Additionally,
clinician investigators may be concerned that discussion of the risk of death due to trial
participation could be confused with the risk of death related to the disease. It should be
noted that discussions about death related to the disease were not coded as a risk of trial
participation and data from this project suggest that discussions about death related to
incurable disease occured in approximately 15% of ICCs [24]. Additional research is needed
to investigate families’ preferences for such information and may provide guidance to
pediatric oncologists on how to balance discussion of risk of death from incurable disease
with risk of death from the phase 1 study.
The most frequently discussed benefit was therapeutic benefit. The presence of discussions
about therapeutic benefits did not necessarily mean that clinician investigators were
promoting trial participation. There was variability in discussions (see Table 2 for
examples), with many clinician investigators highlighting the inability to predict whether
there would be any therapeutic benefit. Qualitative studies of parental decision making
suggest that therapeutic benefit is a primary concern when considering participation for their
child in a phase 1 study [9]. Additionally, research on adult patients with cancer indicates
that therapeutic benefit is their chief reason for participating in phase I trials [25]. Thus,
despite the low probability of therapeutic benefit, it is not surprising that this was the most
frequently discussed benefit. However, altruism and psychological benefits (e.g. feeling
good about having something to fight for) were also discussed during ICCs. Additional
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research is needed to assess whether patients and/or their families perceive psychological
benefits after participating in phase 1 trials.
It is noteworthy that psychological benefits were raised predominantly by families and
discussion of other benefits and risks were primarily initiated by clinician investigators.
Differences in the topics raised by families and clinician investigators may reflect
differences in the perceived value of phase 1 studies for pediatric cancers. Consistent with
this notion, research by Mack and colleagues [26] indicated that parent rating of quality of
care at the end of life was associated with physician care and sensitivity in communication
but physician ratings of the quality of care provided was associated with ratings of pain and
days spent in the hospital. Taken together, these results suggest that it is important to better
understand families’ preferences and values for the care for children facing end of life
decisions. Additionally, given the unexpectedly high rate of child presence during the ICC,
it is also important for future research to better understand the child’s views on
communication about risks and benefits. It is not clear if child presence influenced
discussions about risks and benefits but information on the child’s perspective about these
discussions may help to guide decisions about coverage of these important topics.
It should be noted that clinician investigators are faced with the task of explaining a variety
of complicated concepts, such as maximum tolerated dose and dose-limiting toxicities [15],
along with the standard elements of informed consent. Some of these aspects of informed
consent are more general (e.g. confidentiality, right to withdraw), and others, such as risks
and benefits, are quite nuanced for a phase 1 study. However, data from a recent survey of
pediatric oncologists and fellows indicates that only 21% received formal training in
communication about these topics [19]. These data suggest that hematology/oncology
programs that feature Phase I initiatives should integrate training in communication about
informed consent for phase 1 studies as a key component of their efforts.
The finding that the average rating of the quality of clinician communication about risks and
benefits was approximately a 6/10, indicated an area for improvement in discussions about
phase 1 trials. Research has supported the use of question prompt lists during the informed
consent process [27,28] and they may be particularly useful for complex studies, such as
phase 1 trials. Additionally, our previous research on informed consent for phase 3 pediatric
oncology trials has supported the use of a staged consent process model [22,29] in which
certain key topics are covered prior to introducing topics related to the particular trial. The
quantity and complexity of information to be discussed during ICCs for phase 1 trials
suggests that a similar approach may be helpful. Data on family preferences for the informed
consent process from a subset of participants in the current study indicated a preference for
more information on topics such as risks and benefits and more time to weigh options and
ask questions, which provides further support for having multiple ICCs with specific goals
for each ICC [30]. As part of ongoing research, we are currently evaluating family
preferences for how to best use a two-step process of informed consent.
Limitations of the current study include that it is possible that conversations about phase 1
trials occurred outside of the ICCs and were not assessed. For example, patients who
traveled to a study site for the purposes of enrolling in a phase 1 trial may have discussed the
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trial with a treatment provider at another institution. The rating of the discussions about risks
and benefits must be interpreted in light of this limitation. Additionally, the rating of the
communication about risks and benefits assessed how completely risks and benefits were
discussed but did not account for more qualitative aspects of communication, such as
warmth and engagement of the clinician investigator with the family. It may be that families
value these more qualitative aspects of communication more than completeness of
communication. Finally, although study sites were selected based on high levels of phase 1
research activity, clinician investigators and patients from these sites may not be
representative of individuals at other sites. For example, the sample predominantly
represented the racial/ethnic majority and future research is needed with more racially/
ethnically diverse samples.
Strengths of the study include that consent conversations were observed and coded rather
than relying on reports from participants as to topics covered during the ICCs. The use of
this methodology eliminates difficulties related to recall of consent conversations.
Additionally, the sample was diverse with regard to socioeconomic status and cancer
diagnoses, which increases the generalizability of the results.
The current study supports the value of assessing communication during ICCs for families
considering participation for their child in a phase 1 study. Although risks, benefits, and
quality of life were frequently discussed during ICCs, future research is needed to test
models for how to discuss these important aspects of clinical trials as well as methods for
better coding explanation of benefits during communication. Research is also needed to
examine models for discussing the risk of death in clinical trials. Finally, research with other
patient populations is needed to assess the extent to which findings may generalize to other
types of phase 1 studies.
Acknowledgments
This project was supported by the National Institute of Health (R01CA122217), which did not have any role in
study design, data collection, analysis, data interpretation or manuscript writing. This paper represents original
work and has not been previously published. The authors are thankful for the assistance with data management and
analysis provided by Sabahat Hizlan. Angela Leek’s assistance with study management and data coding and the
research assistants’ help with data coding are greatly appreciated. Angela Leek and Sabahat Hizlan are employed
by the Cleveland Clinic and received compensation for their work.
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Figure 1.
Observer Rating of Risks and Benefits Discussions
Ratings of risks and benefits discussions are based on a 1–10 scale, with higher scores
indicating a more balanced presentation of risks and benefits.
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Table 1
Types of Risks Discussed During ICCs
Risk Categories Examples % of ICCs (n)
(95% C.I.) % of ICDs (n)
(95% C.I.)
GI/digestive nausea, vomiting, diarrhea, decreased appetite, liver irritation/
inflammation, increased liver tests 80.0% (68)
(±8.5%) 100% (53)
(±0%)
Hematology/Oncology Bleeding, change in blood counts, blood clots, neutropenia,
bleeding inside tumor, bone marrow suppression 67.1% (57)
(±10.0%) 96.2% (51)
(±5.1%)
Integumentary hair changes (color, loss), hand and foot syndrome, rash, dry skin,
peeling of hands and feet 65.9% (56)
(±10.1%) 98.1% (52)
(±3.7%)
Sleep/Fatigue Fatigue, tired, knocked down, lethargy, sleepiness, decreased
energy, weakness, malaise, bad sleep 57.7% (49)
(±10.5%) 92.5% (49)
(±7.1%)
Cardiovascular high blood pressure, heart failure, heart attack, increased heart
rate 43.5% (37
(±10.5%) 90.6% (48)
(±7.7%)
Pain/Tingling tingling (in hands and feet), numbness, burning, general and
specific pain (e.g. headache, joint pain) 40.0% (34)
(±10.4%) 96.2% (51)
(±5.1%)
Unanticipated Things don’t know, unknown/unexpected side effects, don’t
know safety, 35.5% (30)
(±10.2%) 96.2% (51)
(±5.1%)
Reproductive System risk/damage to fetus, not allowed to father children, fertility
problems 35.3% (30)
(±10.2%) 92.5% (49)
(±3.7%)
Nervous System dizziness, balance difficulties, encephalopathy, seizures 32.9% (28)
(±10.0%) 84.9% (45)
(±9.6%)
Flu-like Symptoms Fever, flushing, cough, sweating, chills, runny nose 29.4% (25)
(±9.7%) 83.0% (44)
(±10.1%)
Musculoskeletal muscle breakdown/weakness, muscle cramps, abnormal bone
growth, abnormalities of bones 28.2% (24)
(±9.6%) 79.2% (42)
(±10.9%)
Urinary System kidney failure/, bladder irritation, decrease protein stores,
increased protein excretion, 24.7% (21)
(±9.2%) 83.0% (44)
(±10.1%)
Respiratory System shortness of breath, airway obstruction, inflammation of lungs,
lung disease 24.7% (21
(±9.2%) 84.9% (45)
(±9.6%)
Eating/Oral dry mouth, taste aversion, parestesia, dysthesia, mouth and
esophagus sores 23.5% (20)
(±9.0%) 67.9% (36)
(±12.6%)
Chemical Imbalances salt, sodium, potassium, calcium, phosphorus, magnesium,
electrolyte abnormalities/levels 23.5% (20)
(±9.0%) 71.7% (38)
(±12.1%)
Infections blood infections, viral/bacterial infection 23.5% (20)
(±9.0%) 75.5% (40)
(±11.6%)
Allergic Reactions allergic reaction to antibody, drug reaction 22.4% (19)
(±8.9%) 52.8% (28)
(±13.4%)
Vision night blindness, floaters in eye, blurry vision, vision changes 20.0% (17)
(±8.5%) 69.8% (37)
(±12.4%)
Mood/Behavior or Mental Status suicidal ideation, calmness, behavior change, mood changes,
confusion, hallucinations 17.7% (15)
(±8.1%) 69.8% (37)
(±12.4%)
Swelling/Fluid Changes swelling in arms/legs, fluid retention 15.3% (13)
(±7.7%) 77.4% (41)
(±11.3%)
ENT hoarse/whispery voice, change in voice, ears, nasal, hearing,
throat sensations 12.9% (11)
(±7.1%) 47.2% (25)
(±13.4%)
Endocrine System change in blood sugars, diabetes, pancreas inflammation/irritation 12.9% (11)
(±7.1%) 75.5% (40)
(±11.6%)
Negative Consequences Due to
Dose of Drug dose limiting toxicity, toxicity of drug 11.8% (10)
(±6.9%) 3.8% (2)
(±5.2%)
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Risk Categories Examples % of ICCs (n)
(95% C.I.) % of ICDs (n)
(95% C.I.)
Second cancer other tumors or cancers 10.6% (9) (±6.5%) 26.4% (14)
(±11.9%)
Weight Change increased weight, weight loss, change in weight 10.6% (9) (±6.5%) 54.7% (29)
(±13.4%)
Risks Related to Other Medical
Procedures transfusion risks (e.g. HIV), blood draw risks 10.6% (9) (±6.5%) 79.2% (42)
(±10.9%)
Death death, life threatening side effect 9.4% (8) (±6.2%) 88.7% (47)
(±8.5%)
Immune System immune suppression, immune reaction 8.2% (7) (±5.8%) 24.5% (13)
(±11.6%)
Other financial, inconvenience, impact on daily activities 4.7% (4) (±4.5%) 18.9% (10)
(±10.5%)
Loss of Confidentiality ---- 1.2% (1) (±2.3%) 7.5% (4)
(±7.1%)
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Table 2
Example of Communication About Risks, Benefits, and QOL
Topic Communication During ICCs
Benefits
Therapeutic 1Clinician Investigator: “The benefit may be that the disease will get better or stabilize. I think that the
likelihood that it will go completely away is very small.”
2Clinician Investigator: “Hope it’s going to help you…don’t know that”
3Parent: “Does it eliminate the cancer cells? Clinician: “We don’t know.”
4Clinician Investigator: “We know that there have been rare…but some kids have had a response, more
likely stable disease with this medicine.”
Psychological 1Parent: “I want this to be hope for him, try this and say let’s give it a go”…Clinician: “It’s painful to
go through every possible side effect…on the other hand, some people would find it painful not to try
any new medicines…I can’t make that decision for you.”
2Clinician Investigator: “I think you’ve known from the beginning that she has an incurable disease that
we are trying to defy odds with and that’s what this about.”
Altruism Parent: “Do you want to do the spinal tap? Child: “If it will help the study, I will”…. Clinician: “It will not benefit
you, it will benefit the study.”
Bridge To Future Trial Clinician Investigator: “If she is benefiting from this drug, she would take it for a year according to the study…I
don’t anticipate she would be on it for a year…I think at some point we would want to get her to immunotherapy.”
Risks Clinician Investigator: “It has side effects and side effects are not dissimilar to other chemotherapies…This is
obviously an important part for us to spend some time on.”
Quality of Life
Positive Clinician Investigator: “Part of this is maintaining her quality of life as much as possible.”
Neutral Patient: “Do I have to get up at 3:00 in the morning to do weight and height?”
Clinician Investigator: “No, you don’t have to do that.”
Negative Clinician Investigator: “Behind the shield is the key thing, is that we need you behind the shield and you know we
will help you get through this.” (in reference to contact restrictions)
Extracurricular Activities Parent: “My concern for her is there is two things that she does that she absolutely loves, there is dance and
school…
Clinician Investigator: “Yep, the goal is for her to do those things and for you to not notice any difference.”
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