\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{Weathering the storm when the end of the road is near: A qualitative
analysis of supportive care needs during CAR T cell therapy in
pediatrics}



\author[1]{Angela Steineck}%
\author[2]{Sara Silbert}%
\author[1]{Kallie Palm}%
\author[3]{Jordyn Nepper}%
\author[4]{Dagny Vaughn}%
\author[5]{Kelly Shipman}%
\author[2]{Haneen Shalabi}%
\author[2]{Lori Wiener}%
\author[6]{Liam Comiskey}%
\author[3]{Jennifer M. Knight}%
\author[7]{Deena Levine}%
\affil[1]{Medical College of Wisconsin Department of Pediatrics}%
\affil[2]{National Cancer Institute Pediatric Oncology Branch}%
\affil[3]{Medical College of Wisconsin}%
\affil[4]{The University of Tennessee Health Science Center College of Medicine}%
\affil[5]{University of Pennsylvania Perelman School of Medicine}%
\affil[6]{Dana-Farber Cancer Institute Department of Psychosocial Oncology and Palliative Care}%
\affil[7]{St Jude Children's Research Hospital Department of Oncology}%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Chimeric Antigen Receptor (CAR) T cell therapy
provides promising outcomes in relapsed/refractory B Acute Lymphoblastic
Leukemia (ALL) yet still carries high toxicities rates and relatively
poor long-term survival. Efficacy has yet to be demonstrated in other
diagnoses while toxicity and risk profiles remain formidable. To date,
treatment-related symptom burden is gleaned from clinical trial toxicity
reports; the patient perspective remains understudied. \textbf{Methods:}
English or Spanish-speaking patients (ages 8-25 years) undergoing CAR T
cell therapy for any malignancy and their primary caregiver were
recruited from Seattle Children's Hospital (SCH), St. Jude Children's
Research Hospital (SJCRH), and the Pediatric Oncology Branch of the
National Cancer Institute (NCI). Both patient and caregiver completed
semi-structured dyadic interviews 3-months post-treatment. We used
directed content analysis for codebook development and thematic network
analysis for inductive qualitative analysis. \textbf{Results:} Twenty
families completed interviews (13 patients, 15 parents). Patients were a
median age 16.5 years, predominantly female (65\%), white (75\%), and
diagnosed with ALL (75\%). Global themes included ``A clear decision,''
``Coping with symptoms,'' and ``Unforeseen psychosocial challenges.''
When families were asked to describe the ``most challenging part of
treatment,'' most described ``the unknown.'' Most reported ``the
symptoms really weren't that bad,'' even among patients hospitalized for
severe toxicity events. Fatigue, pain, and nausea were the most
prevalent symptoms. Importantly, only one family would have chosen a
different therapy, if given another opportunity. \textbf{Conclusions:}
Although physical symptoms were largely tolerable, recognizing
supportive care opportunities remains imperative, particularly
psychosocial concerns.%
\end{abstract}%



\sloppy


\textbf{Introduction}

The modern era of cancer treatment is ripe in number and variety of
therapies.\textsuperscript{1, 2} Chimeric antigen receptor (CAR) T cell
therapy is a prime example of this complex paradigmatic shift. Promising
early response outcomes in acute lymphoblastic leukemia (ALL) opened the
door to applying adoptive cell therapies to other malignancies and
patient populations.\textsuperscript{3-5} Despite this promise, CAR T
cell therapy remains an experience of advanced cancer; CAR T cell
therapy is exclusively used in advanced disease and survival after
therapy for all indications remains relatively
unfavorable.\textsuperscript{6, 7}

Best practices in palliative and supportive care need to parallel this
evolution in cancer care.\textsuperscript{8-12} Decision-making becomes
increasingly complex for both clinicians and families. Prognostic
uncertainty, unfamiliar toxicity profiles, and the unclear significance
of tumor-specific molecular profiles are now routine considerations in
the family decision-making process.\textsuperscript{13} Cytokine release
syndrome (CRS) and immune effector cell-associated neurotoxicity
syndrome (ICANS), two hallmark acute toxicity events following CAR T
cell therapy, are commonly encountered in the first month after
therapy.\textsuperscript{14} Symptom burden has been described as
significant in adults after CAR T cell therapy, particularly those who
experience CRS and ICANS.\textsuperscript{15-17} Different from other
early phase clinical trials, CAR T cell therapy clinical trials often
require family relocation to one of a limited number of centers,
typically for weeks of close observation for acute toxicity. However,
few patient-centered supportive care recommendations exist for this
population.\textsuperscript{18} Further, supportive care needs,
particularly from the perspective of the patient and family, are largely
undescribed.\textsuperscript{19-21}

The objective of this qualitative study was to understand supportive
care needs during CAR T cell therapy from the perspectives of pediatric
patients and their parent caregivers. We aimed to identify opportunities
for improvement in symptom management, communication, and psychosocial
support, with the greater goal of informing optimal supportive care
management.

\textbf{Methods}

\emph{Design, Setting, and Participants}

The ``CAR T Patient Reported Outcome (PRO)'' study was a prospective,
mixed methods study with a primary objective to describe
patient-centered outcomes in children and young adults during CAR T cell
therapy. Seattle Children's Hospital (SCH), St. Jude Children's Research
Hospital (SJ), and the Pediatric Oncology Branch of the National Cancer
Institute (NCI) served as study sites. All sites are large referral
centers for CAR T cell therapy, primarily delivered as part of clinical
trials. Local IRB approval was granted at all centers in accordance with
the US Federal Policy for the Protection of Human Subjects.

Recruitment took place from February 2020 through December 2022. Patient
and parent caregiver (``parent'') participants were recruited as dyads
(patient and parent together). Enrollment of both patient and parent was
not required for study participation. Patient eligibility criteria
included age 8-25 years, ability to speak/read English or Spanish, and
scheduled to receive CAR T cell therapy for any malignancy. Parent
eligibility included being a primary caregiver of a patient aged 2-25
years undergoing treatment with CAR T cell therapy as described above
and ability to speak/read English or Spanish. Exclusion criteria
included lack of fluency in English or Spanish, impairment preventing
interview participation, or parent refusal to allow minor participation.
Study staff reviewed clinic schedules to identify eligible participants.
Participants were sequentially recruited in-person before
lymphodepleting chemotherapy. Per institutional standards, written
informed consent (\emph{\textgreater{}} 18 years)/written assent with
parental permission (\textless{}18 years) was obtained by a trained
study member. As participants approached three-months post-infusion,
they were sequentially invited to participate in an optional interview.
Recruitment continued until thematic saturation was achieved, determined
by study team consensus.

\emph{Data Collection}

Demographic and clinical data were abstracted from the patient's medical
record at time of enrollment. Additional self-reported demographic data
were collected from both patient and parent participants at time of
enrollment via REDCap. Qualitative data collection and analysis followed
the Standards for Reporting Qualitative Research
guidelines.\textsuperscript{22} Study staff trained in qualitative
methods conducted interviews at their local institution (SCH: AS, KS;
SJ: AK; NCI: LW). Interviews occurred between April 2020 and August
2022. The interview guide was based on models of HRQOL and symptom
burden\textsuperscript{23, 24} and informed by the research team's
clinical experience. The finalized interview guide consisted of
open-ended questions and optional probes to facilitate semi-structured
interviews (Appendix A). The primary aim of the interview was to explore
supportive care needs during CAR T cell therapy, focusing on symptom
burden, communication needs/preferences, and psychosocial support.
Interviews were completed by phone three months post-infusion (+/- four
weeks). For families where both the child and parent participated,
families chose joint or separate interviews per personal preference.
Interviews were audio-recorded, de-identified, and transcribed verbatim.
The mean duration was 34 minutes (range 10-70 minutes). A \$25 gift card
was offered to each participant following interview completion.

\emph{Data Analysis}

We used directed content analysis for codebook creation followed by
in-depth thematic networks analysis to explore supportive care needs
with CAR T cell therapy in pediatrics.\textsuperscript{25-29} The
multi-disciplinary analysis team included a health services investigator
with qualitative research expertise (KS), physician-researchers trained
in palliative care and pediatric oncology (AS, SS, DL, HS), a social
work clinician-researcher (LW), and clinical research staff with
qualitative research experience (KP, JN, DV). The research team used
directed content analysis to guide iterative codebook development and
coding structure, applying models of HRQOL and symptom burden (Appendix
B).\textsuperscript{23, 24} Starting with 5 transcripts, two coders (KS,
AS) independently reviewed transcripts in their entirety and deductively
applied the existing \emph{a priori} codes for codebook refinement and
addition of codes thought to be missing. Separate codes for ``patient
viewpoint'' and ``parent viewpoint'' were used to organize perspectives.
We continued this process until no further code categories emerged and
consensus was reached.

Interviews and the finalized codebook were imported into Dedoose for
analysis {[}Dedoose Version 7.0.23 (2016). Los Angeles, CA:
SocioCultural Research Consultants, LLC www.dedoose.com{]}. A core of
five study team members (AS, SS, KP, JN, DV) reviewed five transcripts
together to establish a standard coding process. For the remaining 17
transcripts, two members of the core analysis team independently and
blindly coded each transcript. A third coder reviewed each transcript,
serving as a tie-breaker in code reconciliation. The core analysis team
met weekly to discuss inconsistencies, resolve discrepancies, refine
code definitions, and reach consensus.

After coding was complete, the full analysis team (AS, SS, KP, JN, DV,
DL, HS, LW) applied thematic networks analysis to examine recurring
concepts among interviews.\textsuperscript{27} The relationship between
concepts was then used to create basic themes. Basic themes were then
used to create three organizing themes. Organizing themes were
reorganized to deductively develop three overarching global themes
representing the unique perspective of pediatric patients treated with
CAR T cell therapy and their parents. Through an iterative process, the
study team refined and synthesized themes within the network until
inductive thematic analysis was reached.\textsuperscript{30}

\textbf{Results}

Twenty families were interviewed (13 patients, 15 parents; \textbf{Table
1} ), at which point we achieved thematic saturation. Of the patient
interviews, six were completed with their parent, two separate from
their parent, and five without a corresponding parent interview. Of the
parent interviews, seven were completed without a corresponding patient
interview. Ten patients were treated at SCH, six at SJ, and four at the
NCI. The median age of the patient participant at time of enrollment was
16.5 years (range: 8-24). Patients predominantly identified as female
(65\%) and white (80\%). Most patients received CAR T cell therapy for
treatment of ALL (80\%). The parent participant median age was 47 years
(range: 31-54). Parents predominantly identified as female (93\%) and
white (93\%). All interview participants spoke English as a primary
language. Three global themes summarize the family-centered experience
with CAR T cell therapy: ``A clear choice,'' ``Coping with symptoms,''
and ``Unforeseen psychosocial challenges.'' (\textbf{Table 2} ).
Responses from the patient perspective did not significantly differ
thematically from the parent perspective.

\emph{``} A clear choice\emph{''}

Deciding to pursue CAR T cell therapy was described as a ``clear
choice'' by all families. Two decision-making paths were cited. Most
commonly (n=13), families felt that CAR T cell therapy was unequivocally
``the next best step.'' For most, this reflected recommendations for the
best chance for cure. Other families described CAR T cell therapy as the
best choice to buy time until another treatment or to extend their
child's life. Alternatively, five families felt they reached the ``end
of a road'' and were faced with no other options. One patient explained,
``It was really the only thing I had left, after 12 rounds of chemo,
radiation, and a bone marrow transplant not working'' (CTP041). Families
also described toxicities from prior therapies leaving few other safe
options, including ineligibility for otherwise standard therapies, such
as stem cell transplant. One parent shared, ``There's no way his body
could've handled such large doses to do that again, to get him into
remission, to get him to transplant. There's just no way'' (CTP051P). Of
the remaining two families, one chose CAR T cell therapy for quality of
life and the other to avoid toxicity. Factors facilitating the family
decision-making process were organized into three themes: hope, trust,
and self-efficacy.

Regardless of the rationale described, expressions of hope were
pervasive when families reflected upon their decision-making process.
Primarily, this took the shape of optimism in CAR T cell therapy for
cure. Hope for comfort and minimal toxicity was also common. For
example, one parent shared, ``We really want what's best for her, what
was her best shot, and what will be the best way for her to be
comfortable'' (CTP055P). Hope for more time was also expressed. One
parent explained, ``That's my goal is just to keep him going as long as
possible in the hope that somebody figures it out.'' (CTP029P).

Families expressed tremendous trust in their medical teams when
reflecting on their decision-making process. Most families disclosed
that they avoided the internet or social connections for information,
but rather turned to their primary oncologist. One patient shared, ``I
mean I have all the trust in the world in my Oncology doctor, and so I
told my mom from the beginning, whatever \textless{}Doctor\textgreater{}
suggested is what I was gonna do. So I didn't really want to spend my
free time looking at it \textless{}the internet\textgreater{}''
(CTP041). Another parent expressed, ``I think getting the doctor's
opinion, from a doctor that knows \textless{}Child\textgreater{} and has
been with her through her whole treatment is probably the most helpful,
because I think he's got her best interest at heart.'' (CTP026P).

Despite expressing deep trust in their medical teams and hope for
treatment success, families voiced a critical need for taking ownership
in preparing themselves for treatment. This was organized into the theme
``self-efficacy.'' Multiple families shared they felt a duty to ask
questions to advocate for their child. When asked about advice for
future families preparing for CAR T cell therapy, one parent offered,
``Ask a lot of questions and just make sure that you're going into it as
informed as you possibly can. And I think that's really served
\textless{}Child\textgreater{} well, because we know our child better
than anybody else. So just having the ability to not be afraid to ask
questions and follow up with things and make sure that things aren't
forgotten is really important, just to be a part of the medical team''
(CTP002P).

Regardless of the decision-making mechanism, all but one family reported
being satisfied with their decision and would make the same choice
again. Notably, none of the families interviewed had a child who died
before the interview. The sole family expressing decision
dissatisfaction experienced a severe adverse event from treatment.

\emph{``} Coping with symptoms\emph{''}

The three most prevalent symptoms included pain, fatigue, and nausea.
Overwhelmingly, families reported that physical symptoms during CAR T
cell therapy were tolerable. Families were struck by this ``feeling
normal,'' both physically and as a reflection of life returning to
ordinary. This sentiment was organized into the theme ``Normalcy.''
Multiple patient participants noted a resolution of baseline physical
symptoms, such as pain or nausea, and gaining a sense of independence,
with n=4 participants using the word ``normal.'' One participant shared,
``I really enjoyed being somewhat independent, a little bit, considering
the past four years I've kind of been pretty dependent on my parents and
caregivers'' (CTP017). This participant then described being able to
resume college classes in the time since their infusion. Another parent
reflected, ``Its been really nice to be able to be at home and to kind
of feel like we are living a somewhat normal life because he feels
probably better than he can remember feeling\ldots{} He just feels well.
He feels like a normal little boy'' (CTP015P).

Most of the symptoms were attributed to lymphodepleting chemotherapy.
Symptoms from CRS and ICANS were infrequently discussed, including among
patients with reported severe toxicity. Symptoms were often compared to
experiences with prior therapies, including intensive chemotherapy or
hematopoietic stem cell transplant, reporting that symptoms experienced
with these prior therapies were more significant than those experienced
with CAR T cells. To reflect this viewpoint, we organized this
experience into the theme ``Perspective.''

Finally, families acknowledged grappling with a ``symptom paradox,'' a
counterintuitive desire for symptoms to occur with therapy, attributing
the presence of symptoms to be a sign of efficacy. One family explained:
``Strangely enough, it made us sort of feel comforted when he did spike
a high fever because it made us think that maybe it was working, `cause
that's what we were told beforehand\ldots{} It might not happen, but if
it does happen, that could be a good indication that it's working.' So
as soon as it did happen and he spiked a fever, my husband was inpatient
with him and he called me and he was like `He spiked a fever!' and we
both (it was weird) got a little bit excited like `Okay, this is
good!''' (CTP015P).

\emph{``} Unforeseen psychosocial challenges\emph{''}

Challenges of CAR T cell therapy were organized into three themes.
First, families reflected on the emotional and financial sacrifices of
being away from home, organized into the theme ``The toll of being away
from home.'' Many families relocated for treatment, requiring the family
to live local to the treating center for weeks. Although families
acknowledged the benefits of technology for staying connected, they
lamented the physical separation. One parent shared, ``You just don't
see the people you're used to seeing every day. She made a lot of new
friends and with video chat, life has turned out to be a whole lot
different, but it's still hard to not sit and watch movies together, or
eat dinner together as a family, or call her brothers to come over and
visit. You have to call them on video chat. It wasn't awful; it was just
different'' (CTP066P). Other families described the financial costs of
transportation or lodging. For example, one family shared, ``I mean it's
a financial strain. Things work out. You give-and-take in different
places, but just being that far away from home is costly'' (CTP020P).

The second challenge described was navigating unexpected scenarios,
organized into the theme ``The unexpected.'' Predominantly this related
to development of toxicity, requiring longer than expected
hospitalizations or changes in subsequent therapy. One parent shared,
``The last thing I would expect is that the clinical trial would then
cause a reason to not get treatment after that. I mean and in
\textless{}Patient's\textgreater{} case, she's had a lot of progression
since then, so I can't blame anyone and I don't have a magic ball, but
it does make us wonder like if we didn't have that issue and we were
able to get her on another treatment after the trial, would she have
this level of progression since the trial'' (CTP028P).

Finally, families endorsed the challenges of navigating novel therapies,
organized into the theme ``The unfamiliar.'' One family explained, ``I
feel like if it was farther along in the CAR T development and research
and knowledge, that maybe they could've ironed out a few more kinks and
understand more about how it works and why it works\ldots{} and maybe we
could've had more options about which kinds of CAR Ts we could've done
here, and maybe we would've had better results and been able to get
straight to transplant, but it is what it is and we are where we are''
(CTP047).

\textbf{Discussion}

This qualitative study seeks to describe supportive care needs during
CAR T cell therapy from the child and parent perspectives. Among
families who chose to proceed with CAR T cell therapy, we found most
families felt this was a clear decision. Symptoms were tolerable and
some families reported a ``symptom paradox,'' a desire for some toxicity
to feel like the treatment was working. Families described feeling
challenged by the emotional and financial burdens of relocating and the
unpredictability of navigating a novel therapy. Altogether, these
insights highlight opportunities for future supportive care
intervention.

Families predominantly felt the path to their decision was
straightforward. Hope, trust, and self-efficacy facilitated the
decision-making process. Qualitative decision satisfaction was prevalent
in our sample, with all but one family disclosing they would make the
same decision again. Confirmation bias may partly explain this degree of
decision satisfaction, as described in another general pediatric
oncology study.\textsuperscript{31} Prevalence of hopeful patterns of
thought, trust in the medical team, and perceived self-efficacy were
previously described as protective against
regret,\textsuperscript{31-34} which may also be the case in our sample.
Moreover, these constructs are important mitigators of
uncertainty-related distress, a source of emotional distress common not
only to our pediatric cohort, but another study among adult patients
treated with CAR T cell therapy.\textsuperscript{21, 35} Thus,
supporting hope, trust, and self-efficacy are likely important in
providing quality supportive care for families during CAR T cell
therapy. General psychosocial challenges, though not unique to CAR T
cell therapy, were also commonly endorsed in our study. Altogether, our
findings reinforce the importance of a multidisciplinary team to support
families through the challenges of therapy.\textsuperscript{18}

Although families generally reported tolerable symptoms, our themes
expose risks of inadequate symptom management. Experiential knowledge
undoubtedly produced a response shift affecting families' perception of
symptom burden during therapy.\textsuperscript{36} Symptom normalization
results in the perception, in both clinicians and families, that
symptom-related suffering is a ``normal'' part of treatment and that
adequate symptom control is unattainable.\textsuperscript{37} For
example, when families accept nausea and vomiting to be a ``normal''
part of chemotherapy, they may be less likely to request support in
symptom management. Specific to CAR T cell therapy, normalizing the
experience of CRS and ICANS may lead families to consider symptom
management unnecessary. Further, when early toxicity with CAR T cell
therapy is considered an indication of
efficacy,\textsuperscript{38}symptoms become a welcomed experience,
resulting in a so-called ``symptom paradox'' effect. Uncertainty-related
distress may develop in anticipation of CRS or ICANS. Altogether, this
represents an opportunity for improving family support through both the
language we use when counseling for treatment and the screening of
symptoms during treatment.

Our sampling procedures were limited by interviewing families who chose
and successfully completed treatment with CAR T cell therapy. Thus, the
full spectrum of decision-making is not represented. Importantly, the
rationale and needs probably differ between families that choose CAR T
cell therapy and those who do not. Further, our study does not represent
the experience of families with prohibitive access to such investigative
therapy. The families in our study emphatically articulated the
importance of self-efficacy in accessing CAR T cell therapy and in
adequately preparing themselves for the medical and emotional
complexities of treatment. Paired with the deep sense of trust our
participants shared with their medical team, this poses a serious threat
among disenfranchised people to access CAR T cell
therapy.\textsuperscript{39} Racial, ethnic, and payor disparities exist
in referral practices for CAR T cell therapy and inclusion in clinical
trials.\textsuperscript{40} Identifying interventions to mitigate these
risks must be a priority for future investigation.

Several additional limitations of this study must also be noted. Despite
recruiting Spanish-speaking participants, only English-speaking
participants volunteered for interview participation. Thus, our findings
likely do not represent the experience of non-English speaking families.
Only one father was represented in the parent participants. Our
participants described predominantly positive experiences. This may
reflect social desirability bias or recall bias. We chose to interview
patients receiving CAR T cell therapy for any malignancy type; we
continued data collection until thematic saturation was achieved and
thematic differences were not appreciated between diagnosis groups.
Finally, because memory impairment and severe illness are common with
CAR T cell therapy, we chose to interview parents and their children
together to capture a cohesive narrative. This approach may limit
participant disclosure from both the parent and child perspectives.
However, we did not appreciate a difference in themes between those
interviewed alone and those interviewed together. Despite these
limitations, our findings expose opportunities for possible intervention
and priorities for future investigation.

Children undergoing CAR T cell therapy and their families, like families
pursuing other advanced cancer therapies, are at risk for distress from
decision making, symptoms, and uncertainty. Supportive care practices
that minimize the impact of these risk factors and support hope, trust,
and self-efficacy are opportunities to improve clinical care and patient
and parent quality of life.

\textbf{Disclosures/Conflict of Interest:} The authors have no conflicts
of interest to disclose.

\textbf{Acknowledgements/Funding:} A. Steineck received funding through
a T32 Training Grant (5T32CA009351-40) and the St. Baldrick's
Foundation. This work was supported, in part, by the Intramural Program
of the National Cancer Institute, National Institutes of Health (LW, SS)
and ALSAC (DL, DV). The authors gratefully acknowledge the study
participants and their families, especially Patrick McSweeney, a patient
advocate who volunteered to ensure fidelity of our study to the patient
and family experience. We additionally would like to thank the patient
care coordinators, research nurses, and data managers at SCRI, SJ, POB,
NCI for their support and involvement in this work. The opinions
reported herein are those of the authors and do not necessarily
represent those of their funders. The content of this publication does
not necessarily reflect the views of policies of the Department of
Health and Human Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the US Government.

\textbf{References:}

1. Butler E, Ludwig K, Pacenta HL, Klesse LJ, Watt TC, Laetsch TW.
Recent progress in the treatment of cancer in children. \emph{CA Cancer
J Clin} . Jul 2021;71(4):315-332. doi:10.3322/caac.21665

2. Scott EC, Baines AC, Gong Y, et al. Trends in the approval of cancer
therapies by the FDA in the twenty-first century. \emph{Nat Rev Drug
Discov} . Aug 2023;22(8):625-640. doi:10.1038/s41573-023-00723-4

3. Hunger SP, Raetz EA. How I treat relapsed acute lymphoblastic
leukemia in the pediatric population. \emph{Blood} . Oct 15
2020;136(16):1803-1812. doi:10.1182/blood.2019004043

4. Lin YJ, Mashouf LA, Lim M. CAR T Cell Therapy in Primary Brain
Tumors: Current Investigations and the Future. \emph{Frontiers in
Immunology} . Feb 21 2022;13doi:ARTN 817296

10.3389/fimmu.2022.817296

5. Del Bufalo F, De Angelis B, Caruana I, et al. GD2-CART01 for Relapsed
or Refractory High-Risk Neuroblastoma. \emph{N Engl J Med} . Apr 6
2023;388(14):1284-1295. doi:10.1056/NEJMoa2210859

6. Shah NN, Lee DW, Yates B, et al. Long-Term Follow-Up of CD19-CAR
T-Cell Therapy in Children and Young Adults With B-ALL. \emph{J Clin
Oncol} . May 20 2021;39(15):1650-1659. doi:10.1200/JCO.20.02262

7. Long KB, Young RM, Boesteanu AC, et al. CAR T Cell Therapy of
Non-hematopoietic Malignancies: Detours on the Road to Clinical
Success.\emph{Front Immunol} . 2018;9:2740. doi:10.3389/fimmu.2018.02740

8. Webb JA, Kamal AH, LeBlanc TW. A New Frontier for Palliative Care:
The Need to Train Palliative-Oncology Subspecialists. \emph{J Palliat
Med} . Dec 2018;21(12):1679-1680. doi:10.1089/jpm.2018.0421

9. Freedman JL, Beeler DM, Bowers A, et al. Supportive Care in Pediatric
Oncology: Opportunities and Future Directions. \emph{Cancers (Basel)} .
Nov 23 2023;15(23)doi:10.3390/cancers15235549

10. Sampetrean A, Aldea M, Mateus C. Precision medicine's new frontier:
integrating palliative care at the right time. \emph{ESMO Open} . Oct
2023;8(5):101632. doi:10.1016/j.esmoop.2023.101632

11. Weaver MS, Heinze KE, Kelly KP, et al. Palliative Care as a Standard
of Care in Pediatric Oncology. \emph{Pediatr Blood Cancer} . Dec 2015;62
Suppl 5:S829-33. doi:10.1002/pbc.25695

12. Wiener L, Kazak AE, Noll RB, Patenaude AF, Kupst MJ. Standards for
the Psychosocial Care of Children With Cancer and Their Families: An
Introduction to the Special Issue. \emph{Pediatr Blood Cancer} . Dec
2015;62 Suppl 5:S419-24. doi:10.1002/pbc.25675

13. Temel JS, Shaw AT, Greer JA. Challenge of Prognostic Uncertainty in
the Modern Era of Cancer Therapeutics. \emph{J Clin Oncol} . Oct 20
2016;34(30):3605-3608. doi:10.1200/JCO.2016.67.8573

14. Maude SL. Tisagenlecleucel in pediatric patients with acute
lymphoblastic leukemia. \emph{Clin Adv Hematol Oncol} . Oct
2018;16(10):664-666.

15. Ruark J, Mullane E, Cleary N, et al. Patient-Reported
Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen
Receptor T Cell Therapy. \emph{Biol Blood Marrow Transplant} . Oct 9
2019;doi:10.1016/j.bbmt.2019.09.037

16. Akinola IM, Cusatis R, Pasquini MC, et al. Multi-Stakeholder
Qualitative Interviews to Inform Measurement of Patient Reported
Outcomes After CAR-T. \emph{Transplant Cell Ther} . Apr 2023;29(4):254
e1-254 e9. doi:10.1016/j.jtct.2023.01.004

17. Whisenant MS, Srour SA, Williams LA, et al. The Unique Symptom
Burden of Patients Receiving CAR T-Cell Therapy. \emph{Semin Oncol Nurs}
. Dec 2021;37(6):151216. doi:10.1016/j.soncn.2021.151216

18. Steineck A, Wiener L, Mack JW, Shah NN, Summers C, Rosenberg AR.
Psychosocial care for children receiving chimeric antigen receptor (CAR)
T-cell therapy. \emph{Pediatr Blood Cancer} . May 2020;67(5):e28249.
doi:10.1002/pbc.28249

19. Chakraborty R, Sidana S, Shah GL, Scordo M, Hamilton BK, Majhail NS.
Patient-Reported Outcomes with Chimeric Antigen Receptor T Cell Therapy:
Challenges and Opportunities. \emph{Biol Blood Marrow Transplant} . May
2019;25(5):e155-e162. doi:10.1016/j.bbmt.2018.11.025

20. Efficace F, Cannella L, Sparano F, et al. Chimeric Antigen Receptor
T-cell Therapy in Hematologic Malignancies and Patient-reported
Outcomes: A Scoping Review. \emph{Hemasphere} . Dec 2022;6(12):e802.
doi:10.1097/HS9.0000000000000802

21. Stenson CL, Vidrine J, Dewhurst F, Osborne W, Menne T, Stocker R. A
qualitative service evaluation of patient and caregiver experiences of
CAR-T therapy: Recommendations for service development and implications
for palliative care teams. \emph{Palliat Med} . Feb 2023;37(2):215-220.
doi:10.1177/02692163221138880

22. O'Brien BC, Harris IB, Beckman TJ, Reed DA, Cook DA. Standards for
reporting qualitative research: a synthesis of
recommendations.\emph{Acad Med} . Sep 2014;89(9):1245-51.
doi:10.1097/ACM.0000000000000388

23. Wilson IB, Cleary PD. Linking clinical variables with health-related
quality of life. A conceptual model of patient outcomes. \emph{JAMA} .
Jan 4 1995;273(1):59-65.

24. Collins JJ, Byrnes ME, Dunkel IJ, et al. The measurement of symptoms
in children with cancer. \emph{J Pain Symptom Manage} . May
2000;19(5):363-77.

25. Hsieh HF, Shannon SE. Three approaches to qualitative content
analysis. \emph{Qual Health Res} . Nov 2005;15(9):1277-88.
doi:10.1177/1049732305276687

26. Vaismoradi M, Turunen H, Bondas T. Content analysis and thematic
analysis: Implications for conducting a qualitative descriptive
study.\emph{Nurs Health Sci} . Sep 2013;15(3):398-405.
doi:10.1111/nhs.12048

27. Attride-Stirling J. Thematic Networks: an analytic tool for
qualitative research. \emph{Qualitative Research} . Dec 1, 2001
2001;1(3):385-405. doi:10.1177/146879410100100307

28. Elo S, Kyngas H. The qualitative content analysis process. \emph{J
Adv Nurs} . Apr 2008;62(1):107-15. doi:10.1111/j.1365-2648.2007.04569.x

29. Burns NaG, S.K. \emph{The Practice of Nursing Research: Conduct,
Critique and Utilization} . 5th ed. Elsevier Saunders; 2005.

30. Saunders B, Sim J, Kingstone T, et al. Saturation in qualitative
research: exploring its conceptualization and
operationalization.\emph{Qual Quant} . 2018;52(4):1893-1907.
doi:10.1007/s11135-017-0574-8

31. Robertson EG, Wakefield CE, Shaw J, et al. Decision-making in
childhood cancer: parents' and adolescents' views and
perceptions.\emph{Support Care Cancer} . Nov 2019;27(11):4331-4340.
doi:10.1007/s00520-019-04728-x

32. Sisk BA, Kang TI, Mack JW. The evolution of regret: decision-making
for parents of children with cancer. \emph{Support Care Cancer} . Mar
2020;28(3):1215-1222. doi:10.1007/s00520-019-04933-8

33. Feifer D, Broden EG, Xiong N, et al. Mixed-methods analysis of
decisional regret in parents following a child's death from
cancer.\emph{Pediatr Blood Cancer} . Oct 2023;70(10):e30541.
doi:10.1002/pbc.30541

34. Wakefield CE, Hetherington K, Robertson EG, et al. Hopes, concerns,
satisfaction and regret in a precision medicine trial for childhood
cancer: a mixed-methods study of parent and patient
perspectives.\emph{Br J Cancer} . Nov 2023;129(10):1634-1644.
doi:10.1038/s41416-023-02429-1

35. Stewart JL, Mishel MH, Lynn MR, Terhorst L. Test of a conceptual
model of uncertainty in children and adolescents with cancer. \emph{Res
Nurs Health} . Jun 2010;33(3):179-91. doi:10.1002/nur.20374

36. Sprangers MA. Response-shift bias: a challenge to the assessment of
patients' quality of life in cancer clinical trials. \emph{Cancer Treat
Rev} . Jan 1996;22 Suppl A:55-62. doi:10.1016/s0305-7372(96)90064-x

37. Requena ML, Avery M, Feraco AM, Uzal LG, Wolfe J, Dussel V.
Normalization of Symptoms in Advanced Child Cancer: The
PediQUEST-Response Case Study. \emph{J Pain Symptom Manage} . Apr
2022;63(4):548-562. doi:10.1016/j.jpainsymman.2021.12.009

38. Brammer JE, Braunstein Z, Katapadi A, et al. Early toxicity and
clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy
for lymphoma. \emph{J Immunother Cancer} . Aug
2021;9(8)doi:10.1136/jitc-2020-002303

39. Newman H, Li Y, Liu H, et al. Impact of poverty and neighborhood
opportunity on outcomes for children treated with CD19-directed CAR
T-cell therapy. \emph{Blood} . Feb 9 2023;141(6):609-619.
doi:10.1182/blood.2022017866

40. Hall AG, Winestone LE, Sullivan EM, et al. Access to Chimeric
Antigen Receptor T Cell Clinical Trials in Underrepresented Populations:
A Multicenter Cohort Study of Pediatric and Young Adult Acute
Lymphobastic Leukemia Patients. \emph{Transplant Cell Ther} . Jun
2023;29(6):356 e1-356 e7. doi:10.1016/j.jtct.2023.03.022

\textbf{Hosted file}

\verb`CTP_qualitative_table1_12.18.23.docx`  available at \url{https://authorea.com/users/772089/articles/856885-weathering-the-storm-when-the-end-of-the-road-is-near-a-qualitative-analysis-of-supportive-care-needs-during-car-t-cell-therapy-in-pediatrics}

\textbf{Hosted file}

\verb`CTP_qualitative_table2_12.13.23.docx`  available at \url{https://authorea.com/users/772089/articles/856885-weathering-the-storm-when-the-end-of-the-road-is-near-a-qualitative-analysis-of-supportive-care-needs-during-car-t-cell-therapy-in-pediatrics}

\selectlanguage{english}
\FloatBarrier
\end{document}

