Pediatric Oncology in the Arab World

Iyad Sultan

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Epidemiology and Cancer Registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Abandonment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Delayed Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Breaking Bad News . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Political Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Policy Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Improving Quality of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Success Stories in the Arab World . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Specific Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Leukemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Retinoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Special Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Multidisciplinary Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Bone Marrow Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Palliative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Survivorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

What Can Be Done in the Future? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

AbstractThe discipline of pediatric oncology has shortcomings that are similar to otherelements of health care in the Arab world. There are relatively few children with

I. Sultan (*)Department of Pediatrics, King Hussein Cancer Center, Al-Jubeiha, Jordane-mail: isultan@khcc.jo

© Springer Nature Switzerland AG 2020I. Laher (ed.), Handbook of Healthcare in the Arab World,https://doi.org/10.1007/978-3-319-74365-3_17-1

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cancer in the Arab world. It is estimated that there are more than 14,000 childrenbelow the age of 15 that are diagnosed with cancer every year in Arab countries.These patients require relatively more resources to be treated but they have animproved chance of cure in most of the cases. There are state-of-the-art centersthat were launched in different Arab countries. The best examples are those thatmobilized public support in the form of public awareness, volunteering, andgenerous financial donations and that established a clear mission and organizedleadership, where donors expect transparency and equality in care. On the otherhand, with the current instability affecting many Arab nations, there is a deteri-oration in the care of patients with cancer and the reemergence of communicablediseases as major causes of death in children. The priority in the Arab worldshould be having better cancer registries which provide accurate information,especially when linked with national survival records, and to secure sustainablefunding for essential drugs and facilities, as well as for training and retaininghealth workers.

KeywordsPediatric oncology · Cancer · Arab countries · Children · Leukemia

Introduction

Pediatric cancers are a group of malignancies that differ from adult cancers in theirtypes, management, and outcomes (Figs. 1 and 2) (Bray et al. 2018; Ferlay et al.2018). Leukemias, lymphomas, and brain tumors are the three most common groupsof tumors (representing 27%, 17%, and 13%, respectively) while the remainingtypes, most being solid tumors, represent 43% of all childhood cancers.

With the dramatic global reduction in child and adolescent mortality over the lasttwo decades, infectious diseases are no longer the leading cause of death in manycountries. As deaths by infectious diseases fell, mortality rates due to non-communicable diseases such as congenital anomalies, hemoglobinopathies, andcancer have risen, on relative terms, to the point where they are now the leadingcauses of death. Moreover, there is an increased interest in the impact of cancer andrelated therapies in affected patients (Kassebaum et al. 2017). This highlights theneed not only to cure pediatric patients with cancer but also to minimize the burdenof their illness and help provide therapy to avoid long-term disabilities.

Leukemia and brain tumors reign among the top ten causes of death in children5–14 years old in the Arab region (Table 1) (Kassebaum et al. 2017). It is clear thatpediatric cancer will negatively impact the survival of the young Arab population.Realigning resources to alleviate and cure childhood cancer is a challenging prep-osition as resources are limited in the majority of Arab countries. One has also tokeep in mind the burden of untreated patients on the health system as well as theunnecessary morbidity (e.g., enucleation, amputation, or organ damage) due toimproper or suboptimal treatment.

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Fig. 1 Types of pediatric cancers in Arab countries according to the GBD registry – accessed inAugust 2019 (GBD 2017 Childhood Cancer Collaborators 2019)

Fig. 2 Types of pediatric cancer seen in individual Arab countries presented in (a) frequencies and(b) percentages; all data present 2017 records per GDB portal (GBD 2017 Childhood CancerCollaborators 2019)

Pediatric Oncology in the Arab World 3

According to estimates from the International Agency for Research on Cancer(IARC), pediatric cancer claims annually the lives of around 100,000 children world-wide, with the majority (90%) being in low- and middle-income countries (Bray et al.2018). It is notable that the 5-year survival rates of children with cancer have improveddramatically from below 30% to 80% in high-income countries over the past fewdecades (Gupta et al. 2014). The same cannot be said about low- and middle-incomecountries where survival rates of children with cancer remain substandard.

The world-bank indicators suggest poverty rates of almost 50% of the populationin some Arab nations (Table 2). Anemia is prevalent in many Arab countries, ailingmore than 50% of the pediatric population in Somalia, Sudan and Yemen. Healthexpenditure and availability of resources are very heterogeneous among Arabcountries, to the point where even in the same country, some areas, typically nearthe larger cities, receive significantly better health-care. Six Arab countries, includ-ing Egypt which has the largest population in the region, spend less than 200 US$per capita on healthcare (World Bank 2018). Despite these challenges, state-of-the-art centers do exist in several Arab countries (Al-Nasser et al. 1996; El-Hayek et al.2003; Abdel-Rahman et al. 2008).

To put these numbers in perspective in comparison to the rest of the world, theaverage rates of anemia in Arab children below the age of 5 years (40%) andundernourishment (11%) are comparable to middle income countries (42% and10%, respectively). The average health expenditure per capita in the Arab world(356 in current US$) is comparable to middle-income countries as well (290 US$).This contrasts with the expenditure of low-income countries and high-incomecountries (37 and 5265 US$, respectively) (World Bank 2018).

Epidemiology and Cancer Registration

Nowadays, different tools are available to evaluate the statistics of cancer globally.Three resources should be highlighted: Global Cancer Data Registry (Globocan),Global Burden of Disease (GBD) Data (GBD 2017 Childhood Cancer Collaborators2019), and the global surveillance of trends in cancer survival (CONCORD) studiers

Table 1 Incidence and mortality of pediatric cancers in different regions according to Globocan

WHO East.Mediterranean High income

High-middleincome

Low-middleincome Low income

0–14 Mort. 0–14 Mort. 0–14 Mort. 0–14 Mort 0–14 Mort

Incidencea 10 4.3 16 2.4 12.2 2.4 8.5 4.4 8.4 4.4

Leukemia 3.1 1.6 5.3 0.75 4.7 0.66 2.8 1.8 1.5 1.8

Hodgkin 0.66 0.01 0.67 0 0.34 0.01 0.33 0.09 0.45 0.03

NHL 0.98 0.17 1.0 0.09 0.79 0.23 0.76 0.26 1.2 0.14

Brain 1.2 1.0 2.7 0.94 0.46 0.75 0.89 0.70 1.7 0.26

Kidney 0.71 0.16 0.93 0.06 0.55 0.12 0.53 0.15 0.99 0.14aExcluding nonmelanoma skin cancer; Mort. mortality, NHL non-Hodgkin lymphoma; dataobtained from Globocan 2018 site, accessed on 16 August 2019 (Bray et al. 2018)

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Table

2Pop

ulationandotherindicatorsof

health

status

inArabcoun

tries

Pop

ulation

Pediatric

popu

latio

n0–

14%

Pediatricto

who

lepo

pulatio

nPov

erty

(%)

Under-

nourishm

ent

(%)

Anemain

child

ren<5(%

)Health

expend

iture

per

capita(current

$)Hospital

beds

Nurses

per10

00

Algeria

40,606

,052

11,777

,882

295.5

4.6

3036

2–

–

Bahrain

1,42

5,17

128

9,18

920

3012

432.1

2.4

Djib

outi

942,33

329

7,47

932

23.0

12.8

4219

11.4

0.6

Egy

pt95

,688

,681

32,008

,916

3327

.84.5

3217

80.5

1.4

Iraq

37,202

,572

15,080

,527

4118

.927

.824

292

1.3

1.8

Jordan

9,45

5,80

23,38

3,35

336

14.4

4.2

3135

91.8

2.9

Lebanon

6,00

6,66

81,41

5,64

524

27.4

5.4

2556

93.5

2.6

Kuw

ait

4,05

2,58

485

0,16

621

2.5

2513

862.2

4.7

Libya

6,29

3,25

31,78

8,22

828

2937

23.7

6.9

Oman

4,42

4,76

297

4,96

822

6.2

3867

51.7

3.3

Morocco

35,276

,786

9,72

6,61

728

3.5

3419

00.9

0.9

Mauritania

4,30

1,01

81,72

4,90

540

31.0

5.3

6849

0.7

Palestin

e4,55

1,56

61,81

2,82

840

25.8

26

Qatar

2,56

9,80

435

6,73

614

2621

061.2

5.7

Saudi

Arabia

32,275

,687

8,24

1,75

626

4.4

381147

2.1

5.2

Som

alia

14,317

,996

6,66

3,51

847

560.1

Sud

an39

,578

,828

16,292

,154

4125

.657

130

0.8

1.2

Syria

18,430

,453

6,88

6,36

237

3566

1.5

2.3

Tun

isia

11,403

,248

2,72

6,43

324

15.2

5.0

2930

52.1

3.2

UAE

9,26

9,61

21,28

7,33

814

3.8

2716

111.1

3.1

Yem

en27

,584

,213

11,104

,607

4048

.628

.884

800.7

0.8

Total

(average)

405,65

7,08

913

4,68

9,60

733

11.0

4035

6

Dataextractedfrom

World

Bankwebsite,latestdatawereinclud

ed;em

ptycells

indicateno

data,accessedin

April20

18(W

orld

Bank20

18)

Pediatric Oncology in the Arab World 5

(Allemani et al. 2018). Extensive documentation of these resources are availableonline and a comprehensive review of their utility in registering pediatric cancerswas recently published (Bhakta et al. 2019). In general, these tools use national andsubnational cancer registries and mortality records along with different predictivetools to compensate for quality variations in data capturing, particularly in countrieswith low and middle income. Access to data and data visualization is availableonline and should be used to understand the scope of cancer in the Arab world.

Cancer statistics are typically presented with incidence rates calculated per100,000 individuals per year, and often age-stratified (0–4, 5–9, etc.) and thenstandardized, i.e., recalculated using a standard population structure to make itsuitable for international comparisons. Due to using different sources and methods,the two international registries we used to evaluate the incidence of childhood cancershowed some differences (Fig. 3). However, most Arab countries had annualincidence rates just above 10 per 100,000 (standardized to world population).

Survival estimates are often presented of 5- and 10-year survival estimates,typically constructed using the Kaplan-Meier method. While informative, thesesurvival estimates require meticulous registration of survival time (time from diag-nosis to last follow up or mortality), information which is often lacking in manyregistries. A new way to present these data is the mortality to incidence ratio (MIR),which is the ratio of cause-specific-mortality to disease incidence. This is anattractive method that can be used by most registries where data from verbal

Fig. 3 Incidence rates of childhood cancer in Arab countries as depicted by (a) GDB portal and (b)Globocan; data presented age-adjusted and standardized per 100,000 individuals as per 2017(GDB) and 2018 (Globocan) (Bray et al. 2018; GBD 2017 Childhood Cancer Collaborators 2019)

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autopsies can be extracted, and this metric is the standard way of presenting survivalestimates in the GBD study. Again, the two registries showed noticeable differencesin recording MIRs in different Arab countries. Larger differences were noticed incountries with active movement of refugees (e.g., Jordan, Lebanon) and in countrieswith poor national records, highlighting some of the challenges that are faced whenevaluating cancer statistics in the region (Fig. 4).

Another recently introduced concept is the Disability Adjusted Life Years (DALYs),which is the sum of life years lost to disease and/or disability. This metric can be used tocompare the impact of different diseases under different situations, and supposedlyworks well in understanding the burden of childhood cancer on a global scale (Bhaktaet al. 2019; GBD 2017 Childhood Cancer Collaborators 2019). It is estimated thatchildhood cancer ranks sixth among all types of cancers (including adult cancers) in itsglobal impact, with 11.5 million DALYs in 2017. Childhood cancers ranks ninth amongchildhood illnesses, with more profound impact in middle income countries (GBD 2017Childhood Cancer Collaborators 2019). The DALYs for childhood cancers in Arabcountries is shown in Fig. 5. More DALYs were recorded for children diagnosed beforetheir fifth birthday and in Arab countries with lower incomes.

The Arab world has a population of more than 400 million, with a pediatricpopulation (0–14-years-old) of more than 130 million; or in other words, roughlyone-third of the population of the Arab world is under 15 years old. According toGlobocan, 13,720 pediatric cancer cases are diagnosed annually in Arab countries

Fig. 4 Morality-incidence ratio (MIR) of childhood cancer in Arab countries as depicted by (a)GDB and (b) Globocan. MIR was calculated by dividing the number of children who died due tocancer in each country by the number of children diagnosed with cancer in 2017 (GDB) and 2018(Globocan) (Bray et al. 2018; GBD 2017 Childhood Cancer Collaborators 2019)

Pediatric Oncology in the Arab World 7

(Table 3). The average incidence of cancer is 11.4 per 100,000 children, but with awide variation (Fig. 2). While genetic factors can play a role in the development ofpediatric cancers, less than 10% of children with cancer actually harbor germlinemutations, making genetics less likely involved in variations in childhood cancersincidence. Similarly, environmental factors do not seem to play a major role in thedevelopmental of childhood cancers. It is assumed that true variations in incidencereflects differences in data registration (GBD 2017 Childhood Cancer Collaborators2019). While Globocan previously presented some data on survival estimates, theseestimates did not parallel published reports. As stated above, mortality to incidenceratio (MIR) is a more robust measure for survival estimates, but with a caveat: poorregistration of cancer can result in a falsely elevated MIR. Nevertheless, MIRs ofchildhood cancers in Arab countries as obtained from the GBD portal are in line withmiddle-income countries and show some wide heterogeneity (Fig. 6) (Ribeiro et al.2008).

Reporting childhood cancer has inherent challenges. Just as adult cancer regis-tration typically follows an anatomical location, childhood cancers should berecorded according to histology. This is very important due to the rarity of childhoodtumors and the fact that anatomical locations hardly correlate with pathology. Forthese reasons, the International Classification of Childhood Cancer (ICCC)(Steliarova-Foucher et al. 2005) was established; this system should preferably beused by all registries capturing pediatric malignancies. Additionally, while the TNMstaging method (T refers to size of main tumor, N refers to the number of nearbylymph nodes with cancer, M refers to whether the cancer is metastasized) is usually

Fig. 5 Disability adjusted lost years (DALYs) for children with cancer in Arab countries presentedin rates per 100,000 individuals (GBD 2017 Childhood Cancer Collaborators 2019)

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reserved for adult cancers, the same system cannot be applied to pediatric cancers,thus alternative methods should be sought (Gupta et al. 2016). The Toronto Child-hood Cancer Staging Guidelines are available online and endorsed by many socie-ties. Cancer registries in the Arab world face many other challenges. Among thesechallenges are duplication, poor registration, and lack of trained registry profes-sionals which make captured data challenging to use and analyze (Jawass et al. 2016;Missaoui et al. 2011). However, improvement over time is anticipated. When linkedto survival data, available typically through national records, these registries canbecome invaluable tools for health policy makers (Khoshnaw et al. 2015). On theother hand, when the link between cancer registries and survival records is poorlystructured, inaccurate survival rates can unfortunately cloud factual data (Allemaniet al. 2018).

Table 3 Number, incidence, and mortality of children with cancer in Arab countries according toGlobocan

Country Number of children with cancer Incidence Mortality MIR (%)

Algeria 1399 11.3 5.3 47

Bahrain 26 8.8 2 23

Djibouti 21 7.2 1.7 24

Egypt 4180 12.6 5.8 46

Iraq 207 10.5 2.8 27

Jordan 1581 10 3.4 34

Kuwait 390 11.3 3.4 30

Lebanon 96 10.9 3 28

Libya 183 13.4 4.4 33

Mauritania 185 10.4 4.8 45

Morocco 97 5.4 0.89 16

Oman 1137 11.7 4.7 39

Qatar 118 11.3 3.7 33

Saudi Arabia 29 7.9 3.5 45

Somalia 989 12 3.9 33

State of Palestine 689 9.8 2.5 25

Sudan 1620 9.7 3.9 40

Syria 710 11.3 4.3 39

Tunisia 309 11.1 4.7 42

UAE 158 12.3 2.8 23

Yemen 1149 10.1 3.3 33

All 21 states 15,273 11.4 7.5 34

Globocan accessed in August 2019; rates are projected to 2018; not all data reflects actualregistration and national mortality was estimated by modeling in many countries; not all data isage-adjusted; incidence and mortality are presented per 100,000 children 0–14 years old; MIR,mortality-to-incidence ratio was calculated using this formula (number of children who died ofcancer/number of patients registered to have cancer in the same year). UAE United Arab Emirates(World Bank 2018)

Pediatric Oncology in the Arab World 9

One easy way to check for the reliability of cancer registry data is to look fordiseases with dismal outcomes (e.g., diffuse pontine glioma, expected 2-year sur-vival of <10%) vs. diseases with a better outcome (e.g., Hodgkin lymphoma,expected 2-year survival of>80%). In addition, survival curves should be contrastedwith published reports from other countries to check the accuracy of the varioussurvival registrations. Worsened survival rates can be anticipated if there is biasedregistration where patients who die from cancer are more likely to be entered into thecancer registry, whereas better survival in cancer registries is anticipated where thereis poor link between records and death registration. In many cases, the cause of deathis commonly reported to be cardiopulmonary arrest, even for cancer patients. Thismakes calculations pertaining to cancer-specific survival rates quite inaccurate.Training and partaking in repetitive auditing with robust quality control can domuch to improve the situation over time.

Fig. 6 Scatter plot of HDI (Human Development Index) vs. MIR (Mortality Incidence Ratio) of allcountries (red) vs. Arab countries (blue); regression lines are shown as well as some names of Arabcountries as space allowed. Data were obtained for year 2017 (a, GDB data) and year 2018(b, Globocan data) (Bray et al. 2018; GBD 2017 Childhood Cancer Collaborators 2019)

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Challenges

Abandonment

Among the unique problems that face pediatric oncologists are “treatment refusal,”where families refuse treatment, or “abandonment,” where treatment is delayed for asignificant period. Abandonment is prevalent in low-income countries (Weaver et al.2015; Alvarez et al. 2017). One study surveyed 602 respondents from 101 countries andestimated abandonment rates at 15% of children with cancer, with the vast majority ofthem living in low- and middle-income countries (Friedrich et al. 2016). There is ascarcity of data from Arab countries regarding abandonment. It is possible that the ratesare low, but the strong belief in alternative medicine and the lack of adequate transpor-tation in some areas may add to this problem. Added to this is the influence of theextended family and the community surrounding the patients who sometimes encourageabandonment in favor of traditional and alternative therapies (Mostert et al. 2014).

The most accurate estimates of abandonment were reported in Morocco, where arate of 12–37% was reported and was considered among the top challenges that facepediatric oncology in the country (Hessissen et al. 2010, 2013; Hessissen andMadani 2012). Addressing this complex problem requires a thorough understandingof its causes, including family dynamics, perceptions, public awareness, and gov-ernmental healthcare financing (Friedrich et al. 2016). Financial support can help toresolve this problem (Srinivasan et al. 2015).

Another related problem is noncompliance. This is particularly important inpatients receiving prolonged courses of oral medications, which occurs in allcases. A report from Egypt showed that noncompliance occurred in half of the129 patients surveyed, as confirmed by serum drug levels. This was more commonin patients with large families, poor levels of education, and low socioeconomicstandards (Khalek et al. 2015).

Delayed Diagnosis

Delay in diagnosis of pediatric cancer is common in the Arab countries. Surprisingly,physicians contribute to more delays than do parents. A recent study from Egyptanalyzed the causes of delays in diagnosis of children with cancer and reported thatphysicians-related issues outweighed issues related to parental delays by ten times(28 vs. 3 days). The same study found that the parent’s level of education orsocioeconomic status had no influence on diagnostic delays (Abdelmabood et al.2017), highlighting again the role of physicians in postponing diagnosis.

Programs attempting to provide solutions should focus on physicians. Mostpediatricians will encounter only a handful of cases during their careers. Thisinexperience is compounded with the fact that pediatric cancer can be asymptomaticor be present with nonspecific symptoms for a long time, e.g., back pain, nonspecificabdominal pain that may mimic constipation, intermittent fever, limping or jointswelling, etc. Among patients who experience the highest number of delays are those

Pediatric Oncology in the Arab World 11

with bone tumors. Our clinic treated cancer patients who were initially treated for“fractures” or “knee joint problems” for 6–12 months prior to referral to an oncol-ogist. Some patients had improper interventions or biopsies that rendered theaffected limb unsalvageable. Diagnosis of retinoblastoma can also be delayed ifproper examination under anesthesia is delayed. This diagnosis can be missed whenyoung children are examined with an ophthalmoscope without proper preparationand sedation.

Breaking Bad News

“Breaking the bad news” of cancer diagnosis to families is particularly challengingin all cultures. It is not uncommon for Arab families to exhibit an overwhelmingfeeling of guilt; this is further complicated by the rampant mistrust of medicalpersonnel and facilities in the region (Otmani and Khattab 2016; El Malla 2017).Added to that is the fear of fully disclosing facts to the patients and families at timesof diagnosis or relapse (El Malla et al. 2017), and the challenges that face parentswho may already be suffering from other socioeconomic challenges (Pelletier andBona 2015; El Malla 2017). In many cases, facing the challenge of having a childwith cancer exposes family to additional stress that can lead to marital problems andother professional or personal hardships (Arabiat et al. 2013).

Loss of workdays or outright abandoning work as well as newfound financialburdens can further complicate the situation. These issues need to be addressed earlyon. Social workers need to work closely with the rest of the hospital team to identifysocial problems and openly discuss them. It is essential to encourage parents toresume a normal life as soon as possible. Leaving work or having both parents in thehospice alongside the patient at all times should be discouraged. Allowing parents toleave and having a somewhat normal social life is important, as parents commonlylose interest in eating and sleep due to their distress. Anger, denial, and bargainingare all expected phases of bereavement, and are commonly witnessed and should beanticipated and discussed. Caring for siblings is also an important issue to discuss, asit is crucial to maintain correct treatment of the affected child while upholdingnormal relationships with their siblings.

Informing a child that he/she has cancer is challenging. Two rules apply: First, thechild’s level of understanding should be evaluated before discussing this informationwith him/her; and second, one should not provide misleading information. Loss oftrust impacts the pediatrician-patient relationship and can also affect the efficacy ofthe treatment the child is receiving. Adolescent girls in particular exhibit a height-ened concern regarding body image and hair loss. This has to be openly and honestlydiscussed and explained. Photos showing children regaining hair after finishingtreatment can help in alleviating distress under these circumstances.

Once the diagnosis is made and information is disclosed, the use of alternativemedicines should be discussed. The treating physician should assume that manyfamilies will explore herbal and other modalities of alternative medicine shortly afterdiagnosis (Naja et al. 2011). Honest and open discussion can help parents to be

12 I. Sultan

partners in choosing the best treatment plans and prevent unforeseen drug interac-tions related to alternative treatment plans.

Political Instability

There has been political uproar in the Arab world, as shown by the recent period ofcivil unrest with the eruptions of protests in the region. The historic improvement inlife expectancy in the region ceased, and a reversal leading to an actual decline in lifeexpectancy has occurred in Egypt, Yemen, Libya, and Syria (Mokdad et al. 2016).Children suffered significantly during this period, particularly in Syria, wheredeclining infant mortality rates saw notable increases from 2010 to 2013; this isnow at levels equal or below that in several impoverished sub-Saharan Africancountries (Mokdad et al. 2016). An accurate assessment of childhood cancers inrefugees is not currently available. While nongovernmental organizations and gov-ernmental assistance have made some efforts in this regard, additional efforts areneeded (Kebudi et al. 2016; Silbermann et al. 2016; Saab et al. 2018).

Policy Changes

Pediatric oncology is frequently disregarded in the national cancer control agenda.Moreover, pediatric oncologists are often not aware of the existence of cancercontrol plans (Weaver et al. 2017a). Ideally, children with hematologic disorders,particularly those needing bone marrow transplantation, should be included in thenational cancer control plans to reduce programmatic redundancies in resource-limited settings (Weaver et al. 2017b).

Policy makers need to understand that pediatric oncology is a surrogate forachievements of the health care system. Ribeiro et al. very elegantly showed thatthe survival of children with cancer correlates with annual government spending onhealth care (Ribeiro et al. 2008). To make the best use of financial resources, policymakers need to negotiate better pricing with pharmaceutical companies. Chemother-apy shortages and fluctuating prices can be avoided when governments understandthe dynamics of this industry. An emerging concern is the rapidly increasing pricesof new therapeutics, e.g., immunotherapy for children with neuroblastoma (Capitiniet al. 2014). International collaboration between governments should attempt to endthis unjustified increase of drugs prices. Additionally, policy makers need to under-stand the flow of work in pediatric oncology. Adding a palliative care service withhome visits might seem like an extra financial burden, while in reality this serviceminimizes hospital stays and decreases the cost of caring for terminally ill patients(Conte et al. 2015).

Oncologists should provide details of childhood cancer and its management topolicy makers. A clear example was the low survival reported in Denmark in manypublications. This led to a national awareness program where cancer was consideredto be an acute illness and received much attention. Hospitals were required to

Pediatric Oncology in the Arab World 13

diagnose and refer patients acutely, and the process was closely monitored. This ledto an observable improvement in the outcomes of patients with cancer (Madsen andFrolund 2008; Allemani et al. 2018).

In the opinion of the author, hospital administrations need to improve the trainingand retention of nurses as a priority in pediatric oncology, and for cancer care ingeneral. Providing nurses with adequate training and checking their competencies isessential in establishing pediatric oncology units (Day et al. 2012). A useful examplewas pioneered at the King Hussein Cancer Centre, where clinical nurse coordinatorsreached new levels of health care competencies that were similar to physicianassistants in other parts of the world. This helped in providing improved care eventhough fewer trained oncologists were available (Al-Qudimat et al. 2009).

Improving Quality of Care

A recent computational analysis created simulation models of 200 countries cali-brated using CONCORD-3 study results (Ward et al. 2019). The estimated net global5-year survival of childhood cancer is 37.4%, in comparison with 83% in NorthAmerica. The model predicts that improving access to services (chemotherapy,radiation, ophthalmic surgery, neurosurgery, etc.) can only modestly improve canceroutcomes in children. More impact can be expected only when these services areprovided in a comprehensive way (i.e., multidisciplinary teams) and when levels ofservices are improved in related services (e.g., infection control and nutritionalsupport). For that reason, adopting a holistic approach is preferred when addressingthe poor cure rates of children with cancer, instead of using the current fragmentedapproaches (e.g., abandonment, access to chemotherapy).

Success Stories in the Arab World

Obstacles related to chemotherapy availability and pain management have beenlargely overcome in Morocco (McCarthy et al. 2004; Hessissen and Madani2012). A Moroccan NGO (ALSC) was established with a mission to providechemotherapy at no cost to all government-run oncology units, where the majorityof children with cancer are treated. This solved a major hurdle for pediatric oncol-ogists. Identifying simple achievable goals with programs that focus on sustainabil-ity has dramatically changed pediatric oncology in Morocco (Hessissen and Madani2012). The program later expanded by partnering with regional authorities onmanaging Wilms tumors and brain tumors.

Another success story is the progress at the King Hussein Cancer Center inJordan (KHCC), which started as a poorly equipped center that was establishedthrough charity, and that was transformed shortly after the death of Jordan’s KingHussein bin Talal following a battle with cancer in 1999. The center was renamedas the KHCC, highlighting its role as a cancer treatment center – and not merely asa center of hope as it was previously called. Dramatic changes incorporating

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inspirational motivation as well as standardization of policies and procedurecontributed to a major transformation in the leadership, structure, mission, andquality control of the center. This led to it being the first joint commissioninternationally accredited hospital in Jordan. KHCC continues to be a source ofpride to Jordanians and serves as an example of a successful nonprofit organizationin the Arab world (Moe et al. 2007).

The inception of the Children’s Cancer Hospital in Egypt (CCHE, also known as57,357 hospital) in 2007 occurred through an initiative of a group of pediatriconcologists and policy makers who started an unprecedented campaign in theArab world. The dream of having underprivileged children with cancer receivethe highest level of care motivated the public to donate generously to theproject. Maintaining the CCHE, expanding its facilities, and supporting itsgrowing research activities were all coupled with a sustainable program ofpublic awareness and motivational TV ads that were aired around the Arab world(Zaghloul 2009).

In Lebanon, the American University of Beirut Medical Center (AUBMC) andthe Children’s Cancer Center of Lebanon (CCCL) collaborated with St. Jude Chil-dren’s Research Hospital (SJCRH) in Memphis (USA) and the American LebaneseSyrian Associated Charities (ALSAC) to establish and maintain a state-of-the-artnew facility. This center is a hub for training and for intense research in pediatrichematology and oncology. The center also provides healthcare for the Syrianrefugees residing in Lebanon. This humanitarian role highlights the important andunanticipated roles that pediatric oncology units play in the Arab world (Saab et al.2018).

It is through the many sacrifices of pediatric oncologists in Iraq that children withcancer continue to receive care in extremely challenging times. There are manyoccasions when two or three patients occupy a single bed in heavily crowdedhospitals. Infection control becomes a less important issue when oncologists neededto make life-saving decisions (Al-Hadad and Al-Jadiry 2012). Despite these diffi-culties and a high rate of treatment abandonment, more than half of patients withhigh grade B-cell non-Hodgkin lymphoma were cured; this is truly a remarkableachievement considering the circumstances (Moleti et al. 2011). Similarly, inductionmortality in acute lymphoblastic leukemia dropped from 24% in 2007 to 10% in2010; another indicator of the great efforts of all the care givers in the country(Al-Hadad et al. 2011). Furthermore, twinning with a cancer center in Romeimproved the outlook of children with cancer in Baghdad, particularly those withacute promyelocytic leukemia (Testi et al. 2006).

Pediatric Oncology in the Arab World 15

Specific Cancers

Leukemias

Acute lymphoblastic leukemia (ALL) is the most common cancer type in children.Due in large part to the historic work of collaborative groups and many studies, mostpatients with ALL are cured. Pillars of treatment include intensive courses ofagents such as asparaginase, vincristine, steroids and anthracyclines, high dosemethotrexate, intensive intrathecal chemotherapy to treat or prevent CNSdisease, and prolonged course of up to 2–3 years of maintenance regimen oforal chemotherapeutic agents. These treatments have resulted in more than 90%of patients with ALL being cured – defined as being in remission at 4-yearspost treatment (Pui et al. 2014).

Delivering adequate therapy to children with ALL requires multiple levels ofsupportive care to manage tumor lysis, infections, mediastinal masses, blood prod-ucts support, and palliative care (Hunger et al. 2009; Ceppi et al. 2015). A balancebetween more toxic regimens that need robust supportive care, such as the St. Judetotal protocol, and a less intensive regimen that can cure many patients with minimaltoxicity, should be carefully selected. The use of intensive regimens has beensuccessfully implemented in many centers in the Arab world (Rahman Sayed et al.2016), while others elected to choose less-intensive and more cost-effective regi-mens despite lower cure rates (Tantawy et al. 2013). Impressive survival rates ofpatients with ALL was reported by the CONCORD-3 study in Jordan, Qatar, andKuwait, bearing in mind the many challenges related to the quality of data onsurvival outcomes (Table 4) (Allemani et al. 2018).

A large collaborative study by the Middle East Childhood Cancer Alliance(MECCA) group reported data on 1171 patients with ALL. The mean age of patientswas 6.1 years and 59% were males. T-cell acute lymphoblastic leukemia and B-cellprecursor ALL represented 15% and 85% of the cohort, respectively. Interestingly,there was a lower percentage of ETV6-RUNX1 translocation (15%) reported in thisstudy compared to reports fromWestern countries, where around 25% of Pre-B ALLcases are frequently reported (Greaves 2006). The study reported excellent responses

Table 4 Last reported survival on CONCORD-3 studya

Brain ALL Lymphoma

Algeria 54.1 (39.2–69.0) 30.9 (10.1–51.6) 77.5 (65.4–89.7)

Jordan 57.3 (49.9–64.8) 88.0 (83.1–92.8) 87.0 (81.4–92.6)

Kuwait 59.2 (39.2–79.1) 88.4 (80.6–96.2) 96.3 (91.4–100.0)

Qatar 65.5 (34.5–96.5) 82.6 (61.2–100.0) 95.3 (87.3–100.0)aNot all data were age-standardized, and in many occasions, survival estimates were consideredunreliable for different reasons; 100% survival was not listed and a previous reported survival waschosen to give better representation; latest data available were used in this table (Allemani et al.2018)

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to induction chemotherapy, with 96% of patients achieving complete remission(Al-Mulla et al. 2014).

Unlike ALL, acute myeloid leukemia is more challenging to treat. A recipe ofintensive chemotherapy, antibiotic prophylaxis, intensive care unit support, nutri-tional support, and bone marrow transplantation of selected patients is needed foroptimal care of these patients. Reported survival results remain below those indeveloped countries (59% vs. 70%), making treatment of acute myeloid leukemiaa unique challenge in the region (Jastaniah et al. 2016).

Acute promyelocytic leukemia represents a unique group of acute myeloidleukemias. These patients benefit from cytarabine-containing protocol and the useof all-trans-retinoic acid and/or arsenic trioxide to induce differentiation of malig-nant blasts. Delays in diagnosis and initiation of therapy can lead to loss of life.Successful treatment of these patients has been reported in a multicenter study inSaudi Arabia, despite mildly inferior outcomes compared to developed countries(Jastaniah et al. 2017).

Lymphomas

Many centers in the Arab world report outstanding results in treating children withHodgkin lymphomas (Sherief et al. 2015a). The current challenge is to maintain thishigh cure rate while minimizing the burden of treatment, e.g., avoiding procarbazine inmales and radiation in females due to the risk of infertility and breast cancer, respectively.

Burkitt lymphoma is the most common type of non-Hodgkin lymphoma in chil-dren. Successful treatment protocols were established in developed countries (Sheriefet al. 2015b). The high toxicity of these protocols can be balanced by positiveoutcomes. Nevertheless, these regimens cannot be undertaken in areas where malnu-trition and lack of supportive care are common. Alternatively, less toxic regimens exist,such as the Malawi protocol (28-day treatment with four doses of cyclophosphamideand intrathecal chemotherapy) which cures half of treated patients at an extremely lowcost of less than 50 US$ (Depani et al. 2015). While this approach might be extreme,tailoring treatment to available resources is crucial to improving outcomes and mini-mizing toxicity (sometimes lethal) and abandonment.

Brain Tumors

Children with brain tumors represent a unique concern. While the spectrum of tumorsis similar to developed countries (Ezzat et al. 2016), oncologists in the Arab world faceconcerns similar to those in low-income countries. Delay in diagnosis is a serious issuethat often can compromise the survival and neurologic outcomes of children. Reluc-tance of surgeons to perform complete resection, either because of fear of neurologicsequelae or lack of experience, jeopardizes the survival outcome of these patients(Abdalla et al. 2018). Using radiotherapy improves survival but at the cost of reducedcognitive function due to harm to the developing brain. The outcome of these patients

Pediatric Oncology in the Arab World 17

cannot be measured by “overall survival” data, as tests to determine their IQ, schoolperformance, and quality of life are equally important.

Retinoblastoma

Retinoblastoma is the most common primary malignant eye tumor in children andrepresents 3–5% of all childhood malignancies. The disease represents a classicalexample of the two-hit-theory, where a mutation of the Rb-gene on chromosome13 can lead to an autosomal dominant disease that typically affect both eyes at ayoung age; other cases are sporadic and typically presents in one eye after the first yearof life. Successful treatment of retinoblastoma does not imply only saving lives but alsosaving eyes and retaining vision. This requires the work of a multidisciplinary team ofdedicated ophthalmologists, aided by functional equipment. As most patients hadenucleation and many died of metastatic diseases in the past (Senft et al. 1988), thesuccess of the King Hussein Cancer Center in rapidly establishing a successful unit hasbeen historical. Due to continuous training of staff, results of eye salvage and survivalrates equal those seen in the best medical centers in the world (Al-Nawaiseh et al.2014). A recent genetic study confirmed a very high rate of germline disease (72%)that was observed in all patients with bilateral retinoblastoma and in approximatelyone-third (30%) of patients with unilateral disease; half of all germline mutations wereinherited from one of the parents (Yousef et al. 2017).

Special Services

Radiation

Radiation therapy is critically needed when treating half of the children diagnosedwith cancer; this is often the most challenging aspect of delivering optimal care, dueto poor availability of this service in many Arab nations. There are several reasonsfor this: first, machines are not always available. The number of radiation machinesper million population is an important indicator of cancer care. In upper middle-income countries, there is an average of 1.4 machines per million population. Half ofthe Arab countries have less than 1 machine per million population; moreover,approximately one fifth of available machines (60 out of 332) are cobalt machines(Table 5). These machines, while cheaper and needing less maintenance and have alower need for stable electrical current and water supplies, still pose an increased riskof radiation leak. Cobalt machines deliver poorer quality radiation, with higher dosesdelivered to the skin and a larger beam, which also can irradiate critical structures(DDoRChdioAA 2018).

Optimal delivery of radiation requires well-trained radiation oncologists, medicalphysicists, the use of masks and other fixation equipment to minimize movementduring radiation, as well as proper sedation of young children. Proper planning startswith a multidisciplinary team, where the need for radiation and the proper dose and

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volume are reviewed. It is essential to use this modality judiciously to avoidsubsequent toxicities. While some poorly equipped centers use 2-D planning, mostchildren benefit from better planning using CT-planning to deliver 3-D conformalradiation. For selected tumors (e.g., head and neck cancers), intensity modulatedradiotherapy, or volumetric intensity modulated arc therapy can help by avoidingapplying radiation to nearby critical structures. More recently, proton therapy hasbeen used to deliver radiation at higher precision than possible with classical photonradiation (Parkes et al. 2017). Such units will be operational in Riyadh and Cairo inthe coming years.

Table 5 Number of radiotherapy centers and radiotherapy machines present in Arab countriesaccording to Directory of Radiotherapy Centers website

CountriesRadiotherapycenters

Clinicalaccelerator

Co-60

Total number ofmachines

Machines permillion populationa

Algeria 15 34 4 38 1.0

Bahrain 2 4 0 4 2.9

Djibouti – – – – –

Egypt 70 92 24 116 1.3

Iraq 22 17 1 18 0.5

Jordan 5 12 1 13 1.7

Kuwait 1 3 0 3 0.8

Lebanon 11 16 3 19 3.2

Libya 3 0 2 2 0.3

Morocco 20 35 2 37 1.1

Mauritania 1 1 0 1 0.3

Oman 1 2 0 2 0.4

Qatar 1 3 0 3 1.3

Saudi Arabia 15 35 1 36 1.1

Somalia – – – – –

State ofPalestine

– – – – –

Sudan 3 2 5 7 0.2

Syria 3 2 5 7 0.4

Tunisia 11 11 10 21 1.9

United ArabEmirates

2 4 0 4 0.4

Yemen 1 0 2 2 0.1aMachine per million population were calculated using last population reported on the World HealthOrganization website accessed in April 2018; data obtained from DIRAC (Directory of Radiother-apy Centers). https://dirac.iaea.org/. Accessed April 2018

Pediatric Oncology in the Arab World 19

Multidisciplinary Team

While many centers achieved promising results in treating ALL and lymphomas, thesuccess in treating solid tumors is still lagging. In particular, bone sarcomas and softtissue sarcomas have inferior outcomes compared to treatments in developed coun-tries. Centers that reported excellent outcomes are those that have regular multi-disciplinary team meetings (Cantrell and Ruble 2011; Salman et al. 2012;Al-Jumaily et al. 2013; Hessissen et al. 2013; Abdel-Baki et al. 2015; Elzomoret al. 2017). Beyond sharing notes and medical reports, oncologists, surgeons,pathologists, and radiation oncologists discuss cases directly with each other. Plan-ning surgery and interpreting pathology reports require all these disciplines to meetregularly and engage in structured discussions.

Bone Marrow Transplantation

Attempts at better regional collaboration led to the establishment of an EasternMediterranean blood and marrow transplantation group, consisting of eight coun-tries (Egypt, Iran, Jordan, Lebanon, Oman, Pakistan, Saudi Arabia, and Tunisia).The group recently published its first report of pediatric transplantation. A total of5187 transplants were performed, with the majority (87%) being allogeneic. Morethan one third (39%) were for malignant indications, while the rest (61%) were basedon other nonmalignant indications, mostly hemoglobinopathies and bone marrowfailure. Due to the relatively large family sizes in the Arab world, approximately95% of the matched donors were related (Hussein et al. 2017).

Palliative Care

Providing palliative care is an integral part of cancer management. Having plans todeal with symptoms of diagnosis or managing terminally ill children with cancer isessential. However, there are many obstacles for delivering adequate palliative carein the Arab world. In many cases, policy makers assign financial resources tocurative care. There is a lack of well-trained professionals able to treat terminallyill patients, and morphine and other narcotics are often unavailable (Mojen et al.2017). Moreover, the laws that regulate the end-of-life care are confusing and notwell established in many Arab countries. As in other low- and middle-incomecountries, shortcomings in delivering palliative care in the Arab world are relatedto lack of national health support systems, specialized education, and adequateaccess to opioids (Caruso Brown et al. 2014). Burn-out is a common problem facinghealth workers, particularly in those interacting with dying children. Professionalsshould provide support to each other, to reduce the stresses associated with thesechallenging events.

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Survivorship

A growing population of patients with special needs exist as more children withcancer survive after treatment. Poor vaccination rates, obesity, and hepatitis C virusinfection are common in these patients in the Arab world (El-Rashedy et al. 2017;Fayea et al. 2017). Survivors of cancer in the Arab world are not well studied. Thesepatients face challenges in education, employment, and marriage opportunities.Counseling regarding reproductive life as well as back-to-school programs couldbetter prepare them for life after treatment. Programs that are familiar with medicalproblems of survivors of pediatric cancers can assist in detecting late relapses,secondary cancers (e.g., thyroid cancer), growth delays, and cardiac dysfunction.

What Can Be Done in the Future?

• Improving data registration, in particular, rates of abandonment and survival• Partnering with more advanced programs• Encouraging collaboration between centers in the same country and between

different countries in the Arab world• Encouraging research activities related to regional needs• Establishing training programs to train physicians and nurses• Creating strategies to reduce burnout in health care providers (and increase

resilience)• Identifying alternative resources for funding• Improving communications with policy makers and providing them with accurate

information• Establishing palliative care centers and survivorship programs• Improving health infrastructure and access to care

Conclusion

Pediatric cancer poses an important problem in Arab countries. Despite manysimilarities, huge gaps exist. Closing these gaps requires collaboration, twinning,and following the many successful examples that exist already. The future of Arabchildren with cancer depends on offering trained personnel to offer the optimal levelof care needed, investing in radiation facilities, offering basic chemotherapeuticdrugs, and facilitating the integration of children with cancer in their communities.The challenge of the ongoing unrest and wars in many Arab countries should notjeopardize the care of these most-vulnerable patients.

Pediatric Oncology in the Arab World 21

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