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\begin{document}

\title{The value of reporting on end-of-treatment outcome of patients in
low-income settings}



\author[1]{Trijn Israels}%
\author[2]{Ramandeep Arora}%
\author[3]{Lillian Sung}%
\affil[1]{International Society of Paediatric Oncology}%
\affil[2]{Max Smart Super Speciality Hospital}%
\affil[3]{The Hospital for Sick Children Paediatric Emergency Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{The value of reporting on end-of-treatment outcome of patients
in low-income settings}

Trijn Israels MD PhD\textsuperscript{1,2}, Ramandeep Singh Arora DCH,
MD\textsuperscript{3}, Lillian Sung MD PhD\textsuperscript{4}

\textsuperscript{1} Collaborative African Network for Childhood Cancer
Care and Research (CANCaRe Africa), \textsuperscript{2} Kamuzu
University of Health Sciences, Blantyre, Malawi, \textsuperscript{3} Max
Super Speciality Hospital, New Delhi, India, \textsuperscript{4} Sick
Children's Hospital, Toronto, Canada

Corresponding author:

Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu
University of Health Sciences (KuHES), Blantyre, Malawi. Email:
cancareafrica@gmail.com

Word count: 1256 words

Number of Tables: 0

Number of Figures: 0

Short running title: End-of-treatment outcome reporting

Key words: childhood cancer, survival, LIC, indicators

LIC Low-income country

HIC High-income country

GICC Global Initiative for Childhood Cancer

EFS Event-free survival

OS Overall survival

TRM Treatment related mortality

DRM Disease related mortality

CANCaRe Africa Collaborative African Network for Childhood Cancer Care
and Research

\textbf{Commentary}

Progress has been made over the past decades in childhood cancer care in
low-income countries (LIC) and there has been a steadily increasing
focus on trained staff, medication availability and locally-adapted
treatment protocols.\textsuperscript{1,2,3} With the launch of the World
Health Organization (WHO) Global Initiative for Childhood Cancer (GICC)
in 2018, there has been a much-needed increment of resources and
efforts. The target of the GICC is to increase survival worldwide to
60\% by 2030, with an initial focus on six common and curable (`index')
childhood cancer types for which survival is currently over 85- 95\% in
high income countries (HIC).

In contrast, estimated overall childhood cancer survival in LICs
including many countries in sub-Saharan Africa is still below
20\%.\textsuperscript{2,4} Local data on outcomes of children with
cancer and impact of interventions to increase survival in LIC settings
are lacking. There is an urgent need to close this survival and research
gap. End points that are relevant, feasible and provide an estimate
within a short time-frame may be desirable. They can serve as proxies
and compliment established end points such as overall survival (OS) and
event free survival (EFS) while data collection mechanisms such as
cancer registries and resources for follow up are strengthened in LIC.

To identify such end points, we need to distinguish three different
types of treatment failure: treatment related mortality (TRM), disease
related mortality and treatment abandonment.\textsuperscript{5} The
frequency distribution and relative importance of these differ by
setting In HIC settings, most treatment failure is disease related
mortality (progression or relapse of disease), while TRM is less common
and treatment abandonment almost non-existent.\textsuperscript{2} In LIC
settings, treatment abandonment is often common and in sub-Saharan
Africa, it is frequently the most common cause of treatment
failure.\textsuperscript{2,6,7} TRM is frequently prominent as
well.\textsuperscript{8}

These different causes of treatment failure require specific and
different interventions. To decrease disease related mortality, required
interventions include early diagnosis and optimisation of the treatment
protocol, which often translates to intensifying the treatment. To
decrease TRM, required interventions may include reducing treatment
intensity or improving supportive care. To decrease and prevent
treatment abandonment, required interventions may include adequate
counselling on the need to complete treatment, introduction of health
insurance, active tracking of patients and financial support with
out-of-pocket costs of families during treatment. Since these required
interventions are so different, it is key to distinguish between the
different causes of treatment failure. This is often challenging,
especially in LIC.

Traditionally, cancer outcomes in HIC are reported as EFS,
progression-free survival, relapse-free survival and OS depending on the
specific cancer type, often summarised as 2- and 5-year survival
estimates. These survival methods account for different lengths of
follow-up and censoring.\textsuperscript{9} They also can consider
competing events. Typically, the probability of survival, or the
cumulative incidence of disease relapse are reported as some time point.
That time point will depend on the prognosis and natural history of a
specific cancer cohort. For example, if events are expected to occur
late, reporting survival at an early time point will be less
useful.\textsuperscript{10} Reporting of these statistics require the
ability to identify when a patient was last seen in the healthcare
system (to inform censoring) as well as the ability to monitor for
events such as relapse or death during the window in which these events
are relevant (for example, 5 years).

The Collaborative African Network of Childhood Cancer Care and Research
(CANCaRe Africa) have reported on the end-of-treatment outcome of
patients.\textsuperscript{11,12} This approach describes outcomes at the
end of the planned first line treatment protocol. This time point is
usually not included in traditional reporting of cancer outcomes in HIC.
It can also indicate the moment of switch from first line treatment
protocol to either a rescue protocol or palliative care. End of
treatment outcomes in abovementioned studies were categorised as
follows: (1) Alive, no evidence of disease; (2) Treatment abandonment;
(3) Persistent disease (evidence of disease), including relapse or
progression of disease during treatment; (4) Death before the start of
treatment and (5) Death during treatment.\textsuperscript{11,12} Death
during treatment can be divided into treatment related mortality (TRM)
and disease related mortality (DRM) if the required information is
available.\textsuperscript{8} Death before treatment is DRM. A
misdiagnosis becoming apparent during treatment needs to be classified
if relevant for the study and managed accordingly, e.g. by excluding the
patient.

This approach can be used as a starting point to create a feasible and
uniform way to categorise the outcomes at the end of treatment in LIC.
We will need a system in which the different different domains at the
end of treatment are sliced according to causes of treatment failure and
are mutually exclusive. It may be useful to have the preferred
categorisation and terminology decided upon by consensus and a modified
Delphi approach by a group of representative stakeholders to create
uniformity in reporting. This has recently been done for similar topics
in relation to the Global Initiative for Childhood Cancer
(GICC).\textsuperscript{13}

The advantage of reporting outcomes at the end of treatment is that it
requires no follow up and is thus easier to collect. Follow up is often
challenging in LIC due to limited resources to obtain patient status at
regular intervals following treatment completion. Families have other
priorities than to return with a well child to clinic for follow up.
Active follow-up, initiated by the health team, is challenged by long
distances, bad roads, lack of addresses, lack of phones and lack of
funding.

End-of-treatment outcome provides complete information on the proportion
of patients with treatment abandonment. It also captures most patients
with TRM, although will miss patients who die from late toxicities such
as cardiotoxicity.

As an illustration of the potential value of reporting on
end-of-treatment outcome, a retrospective study described
end-of-treatment outcomes of children with newly diagnosed common and
curable childhood cancer types in Malawi. The study found 53\% of
patients alive without evidence of disease, 19\% with treatment
abandonment and 23\% with death during treatment.\textsuperscript{12}The
study concluded that interventions to enable patients to complete
treatment and improve supportive care require prioritization to improve
survival. These data justified a pilot study to prevent treatment
abandonment by supporting families with out-of-pocket costs. Using the
abovementioned study as a baseline, the intervention was associated with
a decrease in treatment abandonment from 19\% (49 of 264) to 7\% (10 of
150) (p\textless{}0.001). The proportion of patients alive and without
evidence of disease at the end of treatment non-significantly increased
from 53\% (139 of 264) to 61\% (91 of 150) (p =
0.1).\textsuperscript{14}

Documenting end of treatment outcome has limitations. It does not allow
us to properly consider when events occur or incorporate competing
events (such as death due to malaria). Comparisons across centres using
protocols of different lengths for a given disease are more challenging,
even for treatment abandonment and death during treatment. For example,
if a protocol for acute lymphoblastic leukaemia is 1 year in one centre
and 3 years in a second centre, the abandonment rates will almost
certainly be higher in the latter scenario, but may not translate into
differences in OS. End-of-treatment outcomes can only estimate the
maximum EFS and OS -- but these estimates may decline considerably with
follow-up depending on the disease.

In conclusion, local evidence is key to prioritise and evaluate impact
of interventions to increase care and survival of children with cancer
in low-income countries. Information on outcome of patients and causes
of treatment failure is essential. Documentation of end-of-treatment
outcome is a relatively simple method providing data most relevant to
the LIC setting while LIC capacity improves to enable reporting of
traditional survival metrics.

\textbf{Conflict of interest Statement} None declared.

References

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Children With Cancer in Low- and Middle-Income Countries--a SIOP PODC
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