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\begin{document}

\title{Moving the needle forward for low- and intermediate-risk pediatric
rhabdomyosarcoma in LMIC: outcomes from a cancer center in Pakistan}



\author[1]{Alina Sadaf}%
\author[1]{Sadia Anjum}%
\author[1]{Sana Rizvi B}%
\author[1]{Rabia Muhammad Wali}%
\affil[1]{Shaukat Khanum Memorial Cancer Hospital and Research Centre}%


\vspace{-1em}



  
  \date{May 25, 2024}


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





\selectlanguage{english}
\begin{abstract}
Background Pediatric rhabdomyosarcoma (RMS) is the most common soft
tissue sarcoma in children. In low- and middle-income countries (LMIC)
such as Pakistan, problems with delayed diagnosis, decreased access to
care, treatment abandonment and lack of multidisciplinary care may lead
to poor outcomes. Methods A retrospective chart review was conducted
from January 1, 2017, to January 1, 2022 to identify patients with low-
and intermediate-risk RMS at a tertiary cancer center in Pakistan.
Curative treatment was given per the standard arms of the Children's
Oncology Group (COG) studies ARST0331 and ARST1431. Results Forty-eight
patients were eligible for survival analysis. The most common tumor
region was parameningeal (31.3\%). The 3-year overall survival (OS) was
100\% for the 14 low-risk patients and 76.5\% for the 34
intermediate-risk patients. The worst performing tumor regions were
``other sites''. The 3-year event-free survival (EFS) for radiation
alone (55\%) as a local control modality was worse than for surgery
alone (66.7\%) or a combination of surgery and radiation (66.7\%).
One-third of the patient cohort had severe malnutrition (\textless{} 5th
percentile by weight) which was associated with lower 3-year OS of 75\%
vs 85.7\%. Eight patients (17\%) died (3 due to sepsis, 5 due to disease
progression), 11 (23\%) abandoned treatment and 15 (31\%) had
progressive disease. Conclusions There was a preponderance of
intermediate-risk RMS in this cohort, with 3-year OS approaching that of
high-income countries but with a lower PFS and EFS. Sepsis-related
deaths, treatment abandonment, and malnutrition remain significant
challenges.%
\end{abstract}%



\sloppy


Title: Moving the needle forward for low- and intermediate-risk
pediatric rhabdomyosarcoma in LMIC: outcomes from a cancer center in
Pakistan

Alina Sadaf\textsuperscript{1}, Sadia Anjum\textsuperscript{1}, Sana B
Rizvi\textsuperscript{1}, Rabia M Wali\textsuperscript{1}

\emph{\textsuperscript{1}Department of Pediatric Oncology, Shaukat
Khanum Memorial Cancer Hospital \& Research Centre (SKMCH\&RC),
Pakistan}

Corresponding author:

Alina Sadaf, MBBS

Consultant, Department of Pediatric Oncology

Shaukat Khanum Memorial Cancer Hospital \& Research Centre (SKMCH\&RC)

7-A Block R-3, Johar Town, Lahore, Pakistan

alinasadaf@skm.org.pk

Tel: (+92) 42 3590 5000

Abstract word count: 244

Main text word count: 1928

Number of tables: 2

Number of figures: 1

Short running title: Pediatric rhabdomyosarcoma outcomes in Pakistan

Keywords: rhabdomyosarcoma, outcomes research, soft tissue sarcoma\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviations} &\tabularnewline
\midrule
\endhead
ARMS & Alveolar rhabdomyosarcoma\tabularnewline
COG & Children's Oncology Group\tabularnewline
CSF & Cerebrospinal fluid\tabularnewline
DPE & Delayed primary excision\tabularnewline
EFS & Event-free survival\tabularnewline
ERMS & Embryonal rhabdomyosarcoma\tabularnewline
FFPE & Formalin fixed paraffin embedded\tabularnewline
FISH & Fluorescent in situ hybridization\tabularnewline
FN & Fusion negative\tabularnewline
FP & Fusion positive\tabularnewline
GCSF & Granulocyte colony stimulating factor\tabularnewline
LMIC & Low- and middle-income country\tabularnewline
MDT & Multidisciplinary tumor board\tabularnewline
OS & Overall survival\tabularnewline
PFS & Progression-free survival\tabularnewline
RMS & Rhabdomyosarcoma\tabularnewline
RT & Photon beam external radiation therapy\tabularnewline
\bottomrule
\end{longtable}

Presented as a poster ``Moving the needle forward for low- and
intermediate-risk pediatric rhabdomyosarcoma in LMIC: outcomes from a
cancer center in Pakistan'' at the The Pediatric Oncology East and
Mediterranean (POEM) Group 3\textsuperscript{rd} scientific meeting on
March 3-5, 2023. No online publication available.

Abstract

Background

Pediatric rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma
in children. In low- and middle-income countries (LMIC) such as
Pakistan, problems with delayed diagnosis, decreased access to care,
treatment abandonment and lack of multidisciplinary care may lead to
poor outcomes.

Methods

A retrospective chart review was conducted from January 1, 2017, to
January 1, 2022 to identify patients with low- and intermediate-risk RMS
at a tertiary cancer center in Pakistan. Curative treatment was given
per the standard arms of the Children's Oncology Group (COG) studies
ARST0331 and ARST1431.

Results

Forty-eight patients were eligible for survival analysis. The most
common tumor region was parameningeal (31.3\%). The 3-year overall
survival (OS) was 100\% for the 14 low-risk patients and 76.5\% for the
34 intermediate-risk patients. The worst performing tumor regions were
``other sites''. The 3-year event-free survival (EFS) for radiation
alone (55\%) as a local control modality was worse than for surgery
alone (66.7\%) or a combination of surgery and radiation (66.7\%).
One-third of the patient cohort had severe malnutrition (\textless{} 5th
percentile by weight) which was associated with lower 3-year OS of 75\%
vs 85.7\%. Eight patients (17\%) died (3 due to sepsis, 5 due to disease
progression), 11 (23\%) abandoned treatment and 15 (31\%) had
progressive disease.

Conclusions

There was a preponderance of intermediate-risk RMS in this cohort, with
3-year OS approaching that of high-income countries but with a lower PFS
and EFS. Sepsis-related deaths, treatment abandonment, and malnutrition
remain significant challenges.

Introduction

Pediatric rhabdomyosarcoma (RMS) is the most common childhood
sarcoma.\textsuperscript{1,2} Historically, RMS was classified as
alveolar (ARMS) or embryonal (ERMS) type based on histologic
features.\textsuperscript{3} The current risk stratification predicts
prognosis on modern treatment protocols and is based on multiple factors
including age, tumor site, modified TNM stage, surgicopathologic
findings (clinical group), and the presence or absence of
\emph{FOXO1}gene rearrangement which has replaced histologic
classification of RMS.\textsuperscript{4,5} Survival varies
significantly across the risk groups, ranging from an overall survival
(OS) of 20\% for high risk RMS to greater than 90\% for low risk
RMS.\textsuperscript{4} The treatment of RMS requires multimodal
therapies including chemotherapy, radiation and surgery. In low- and
middle-income countries (LMIC) such as Pakistan, there are significant
challenges faced by cancer patients including delayed diagnosis, reduced
access to specialized care, and treatment abandonment which may lead to
poor outcomes.\textsuperscript{6}

Methods

We conducted a retrospective chart review of the electronic medical
health record of patients who presented to a tertiary cancer center in
Pakistan from January 1, 2017, to January 1, 2022 including review of
patient notes, radiologic imaging, histopathology diagnosis, and
multidisciplinary tumor board (MDT) recommendations.

Patients who were accepted for treatment at the cancer center were
required to have a confirmed histologic diagnosis of RMS based on
morphology and detection of myo D1, myogenin and desmin on
immunohistochemical staining. Testing for \emph{FOXO1} gene
rearrangement was performed using fluorescent in situ hybridization
(FISH) on formalin fixed paraffin embedded (FFPE) tissue with
commercially available Vysis \emph{FOXO1} Break Apart Fish Probe kit
(Abbott, Illinois, USA) using Fluorescent Microscope (Olympus\selectlanguage{ngerman}®, Tokyo,
Japan) to enumerate the signals.

All patients with RMS underwent staging evaluation with computed
tomography (CT) chest, technetium-99 bone scan and dedicated magnetic
resonance (MR) imaging of primary tumor site and regional lymph nodes.
Patients with ERMS without nodal or lung metastases did not undergo bone
marrow evaluation due to very low likelihood of bone marrow
involvement.\textsuperscript{7} Cerebrospinal fluid (CSF) cytology was
performed for all patients with parameningeal RMS.

Patients classified as low-risk RMS fulfilled the following criteria:
ERMS (or FN) with either (i) group I, II and stage 1,2 or (ii) group
III, stage 1 orbit. Intermediate- risk RMS included: FP RMS with group
I-III disease with stage 1-3 or ERMS (or FN) RMS with either (i) group
I/II, stage 3 disease, (ii) group III with any stage disease (except
orbit) or, (iii) group IV, stage 4 disease with age \textless{} 10
years. High-risk RMS patients were excluded from the analysis as they
were not offered curative therapy due to resource limitations. These
included FN-RMS with age \textgreater{} 10 years and group IV, stage 4
disease, or FP-RMS of any age with group IV, stage 4 disease.

Institutional practice was to treat patients with low-risk RMS per
regimen A of the Children's Oncology Group (COG) study ARST0331
(NCT00075582) and intermediate-risk RMS per regimen A of the COG study
ARST1431 (NCT02567435) without maintenance chemotherapy. Growth factor
support with granulocyte colony stimulating factor (GCSF) was not
routinely used.

Data analysis was performed using SPSS version 27 (IBM Corporation).
Comparison of categorical participant characteristics between the groups
was conducted using Fisher's exact test. Kaplan Meier curves were
generated in SPSS. Overall survival (OS) was defined as the time from
diagnosis to death or last follow up. Progression-free survival (PFS)
was defined as time from diagnosis to death, progression or last follow
up. Event-free survival (EFS) was defined as time from diagnosis to
death, progression, relapse, treatment abandonment or last follow up.

Results

Sixty-three patients with pediatric RMS were identified in the chart
review but 48 were eligible for survival analysis. Details of excluded
patients are as follows: 6 high-risk RMS, 3 patients were treated at an
outside facility, 2 died during staging workup, and 4 absconded before
starting treatment (attributed to treatment refusal).

Of the 48 cases analyzed, 22 (45.8\%) were female. The average age was
5.8 years (median 5.9 years, range 10 months -- 16.8 years). Most
patients (62.5\%) presented with a large tumor volume (\textgreater{} 5
cm). Of the 48 patients, 14 (29.1\%) were severely malnourished at
presentation (\textless{} 3\textsuperscript{rd} percentile by
weight-for-age). Baseline patient and disease characteristics are
summarized in Table 1.

There were 14 patients (29\%) with low-risk and 34 (71\%) with
intermediate-risk RMS. Among the 34 patients in the intermediate-risk
group, 24 patients (71\%) had ERMS, 7 (21\%) had ARMS, and 3 had spindle
cell histology. \emph{FOXO1} gene rearrangement was detected in 7 (15\%)
of the 48 cases analyzed, negative in 26 (54\%), not checked in 15
(31\%) patients due to failed assay or insufficient tissue specimen. Of
the 15 patients with no available \emph{FOXO1} testing, 12 were ERMS and
2 had spindle cell histology. The most common tumor region was
parameningeal (31.3\%) followed by head and neck (20.8\%) (Table 1).

Local control was with surgery alone for 5 patients, photon beam
radiation therapy (RT) alone for 20 (42\%), and a combination of surgery
and RT for 15 (31\%). Orbital RMS was treated with radical RT, except
for one patient who underwent orbital exenteration. Lymph node sampling
was performed for 6 patients. Thirteen patients had upfront tumor
excision; 8 of these were performed at an outside institution prior to
presentation to our cancer center. Eight patients had delayed primary
excision (DPE), of which 6 had a reduction in radiation dose (1 refused
RT and 1 patient had an amputation of an extremity RMS). Among the 8
patients with DPE, 3 were in the abdomen or pelvis, and one each was in
the parameningeal, head \& neck, extremity, and orbital regions.

Of the 48 patients, 15 (31\%) had disease progression, 8 (17\%) died (3
from sepsis, 5 due to disease progression) and 11 (22.9\%) abandoned
treatment (3 during active curative therapy, 8 after disease
progression). The 3-year OS for the entire cohort was 83\%, PFS was 58\%
and EFS was 52\% (Table 2, Figure 1A). OS varied significantly by risk
group, tumor region, and tumor size, but not by nutritional status
(Figure 1A-D).

Discussion

Age at presentation and gender distribution were similar to those
reported for the COG studies.\textsuperscript{8} The median duration of
symptoms at presentation was 90 days (range 30 -- 450 days) and for
those with symptoms for \selectlanguage{english}[?] 90 vs \textgreater{} 90 days there was no
difference in 3-year OS (p=0.81). This delay in diagnosis far outstrips
the median diagnostic interval (DI) of 16.5 days reported for a Canadian
cohort of RMS which also did not appear to affect patient
survival\textsuperscript{9} as well as the median symptom interval of 2
months for an Indian cohort.\textsuperscript{10} Tumor volume and
patient weight have been previously shown to predict outcomes in
children with intermediate-risk RMS.\textsuperscript{11} In our cohort,
patients with tumor size \selectlanguage{english}[?] 5 cm at diagnosis had a 3-year OS of 100\%
compared to 73.3\% in those with tumor size \textgreater{} 5 cm
(p=0.01). Fourteen patients (29.1\%) were severely malnourished, but
this did not significantly affect their survival.

Bhurgri et al reported outcomes of pediatric RMS in Karachi from
1998-2002, stating a 3-year OS of 30\% for
all-comers.\textsuperscript{12} The survival data from our cohort shows
an improvement compared to the historical control and fairs better than
contemporary outcomes reported in other LMIC such as neighboring
India\textsuperscript{10} and Central America\textsuperscript{13} but
more ground needs to be covered to approach outcomes of high-income
countries (HIC). Most patients in this cohort had intermediate-risk RMS,
with a 3-year OS approaching that of HIC but with a lower EFS. Our
institutional preference is to treat RMS according to North American COG
protocols due to the ease of administering vincristine-actinomycin
D-cyclophosphamide (VAC) and vincristine-irinotecan (VI) chemotherapy in
the outpatient setting which is the preferred approach in LMIC and has
evidence of comparable survivable to European protocols that use the
inpatient chemotherapy protocol ifosfamide-vincristine-actinomycin D
(IVA).\textsuperscript{14,15} Results from ARST0531 (forming the basis
of the standard arm of ARST1431) showed a 4-year OS of 72\% similar to
our 3-year OS of 76.5\% but the 4-year EFS of 59\% compares poorly to
our 3-year EFS of 38\%.\textsuperscript{8} This is attributed to poor
local control with 7 patients (20.6\%) who had no local control (3 died,
3 progressed on neoadjuvant therapy and 1 absconded). For the 11
patients who had surgery included in their local control strategy, 5
underwent upfront resection (2 of these patients had local failures),
while 6 underwent DPE (54.5\%) all of whom had a reduction in the RT
dose. Upfront resection is discouraged in LMIC\textsuperscript{14}partly
because it is performed at local hospitals without the appropriated
surgical oncology expertise and an R0 resection is difficult to achieve
in these cases. Sixteen (47.15\%) patients were treated with radiation
alone as local control strategy.

For the 14 patients with low-risk RMS, the 3-year OS of 100\% and EFS of
86\% was comparable to results of ARST0331 where 3-year OS was 98\% and
failure-free survival was 89\%.\textsuperscript{16} Ten of the low-risk
RMS patients (71\%) had surgery as part of their local control strategy.
Of the two patients who progressed, one patient had 4 subsequent
surgeries for local failures and another patient had radiation therapy
for local failure indicating that low-risk RMS can be salvaged after
progression.

Since there were several surgeries performed at local hospitals prior to
presentation to our center, we could not acquire adequate specimens to
perform \emph{FOXO1} testing in 31\% of the patients. However, this
would not have changed the risk-stratification for any of these patients
due to their age, stage, and clinical group and all patients with
alveolar histology RMS, were noted to be \emph{FOXO1} -rearranged. A
recent review recommends focused \emph{FOXO1} testing in LMIC in
alveolar, mixed, or unspecified RMS histologies due to
resource-limitations.\textsuperscript{14}

Three patients with intermediate-risk RMS died due to sepsis, while
there were no sepsis-related deaths reported in ARST0331 and
ARST0531.\textsuperscript{8,16} Undernutrition may have contricuted to
sepsis-related death in one patient who was severely malnourished.
Undernutrition may alter the pharmacokinetics (PK) of chemotherapeutic
agents in children with cancer leading to decreased clearance and
prolonged exposure to drugs.\textsuperscript{17} The higher
treatment-related mortality may indicate the prophylactic use of GCSF in
our setting\textsuperscript{14}. On the other hand, grade \selectlanguage{english}[?] 3 diarrhea
did not occur in any patient in the intermediate-risk cohort while the
rates of irinotecan-related diarrhea reported in ARST0531 (forming the
basis of the standard arm of ARST1431) were
\textgreater{}10\%\textsuperscript{8} which may be explained by a lower
predicted incidence of \emph{UGT1A1} genetic polymorphisms that affect
irinotecan metabolism in Asians compared to Caucasians and
African-Americans.\textsuperscript{18}

This study demonstrated a high rate of treatment refusal and
abandonment; 4 patients refused treatment (excluded from analysis) while
11 patients abandoned active treatment (23\%). This may be attributed to
the high financial toxicity of cancer treatment in
LMIC.\textsuperscript{19} Although cancer treatment is fully funded by
our hospital through charity, families still experience hardship due to
the cost of relocation and loss of income during the treatment period.
Abandonment of active treatment was considered an ``event'' in EFS
analysis as recommended by the International Society of Pediatric
Oncology Abandonment Working Group.\textsuperscript{20} High risk RMS
was not studied as these patients are not offered curative therapy at
our institute due to a limitation of resources. Therefore, there was
only 1 patient with stage 4 disease in our study. In addition,
under-representation of bladder RMS is explained by lack of pediatric
urologic services at our center including lack of access to
post-operative vesicostomy care.

Our study highlights the need for addressing barriers to pediatric RMS
care in Pakistan including development of a cancer referral network and
specialized pediatric surgical oncology services, access to financial
support for families during cancer treatment, and aggressive nutritional
rehabilitation of children with cancer.

Acknowledgements

None

Conflict of Interest Statement

None of the authors have any conflicts of interest to disclose.

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Figure 1. 3-year overall survival Kaplan-Meier curves for low- and
intermediate-risk rhabdomyosarcoma by (A) risk group, (B) tumor region,
(C) tumor size at presentation, and (D) nutritional status at
presentation. P \textless{} 0.5 for risk group, tumor region, and tumor
size, but not for nutritional status.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
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