Keywords
Induction - leukemia - pediatric - socioeconomic factors
Introduction
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy worldwide,
accounting for about 30% of all childhood malignancies.[1] According to the GLOBOCAN 2012 estimates (http://globocan.iarc.fr/), nearly 25,000
children in India are diagnosed with cancer each year, among which approximately 9000
children are diagnosed with acute leukemia. Although worldwide estimates for overall
5-year survival rate in ALL patients are more than 85%, exact data for the Indian
population are lacking in the present literature.[1],[2] A population-based cancer registry from Chennai and Bengaluru suggests a much lower
cure rate in India.
According to the WHO/United Nations Children's Fund (2015), approximately 2.9 billion
people worldwide have access to improved sanitary facilities or measures to sequester
human feces from the environment including pit latrines with slabs. A majority of
population, i.e., around 892 million, worldwide do not have access to sanitary facilities
whatsoever and practice open field defecation, rampant in rural and urban slums in
South and Southeast Asia as well as Sub-Saharan Africa. India is the largest contributor
of open field defecation in the world, practiced by nearly 600 million people. 844
million people worldwide lack a basic drinking water service. In India, 1.2 billion
people have access to drinking water from improved sources.[3]
Various factors are responsible for lower overall as well as event-free survival rate
in children with ALL in India such as delay in diagnosis, malnutrition, infections,
abandonment, limited resources, as well as limited access to adequate treatment. One
of the major causes of recurrent infections in Indian children is poor living conditions.
Although patients have access to sanitary latrines and filtered drinking water in
the hospital, they lack the same at home. Furthermore, few of the patients after being
discharged from hospital live in an overcrowded house made of mud, which results in
a cycle of infection, hospitalization, and undernutrition. This results in prolonged
hospitalization as well as delay in completion of treatment.
Previous studies have analyzed the effect of socioeconomic status (SES) of the child,
parental education, and time to reach hospital for chemotherapy on the event-free
as well as overall survival.[4],[5],[6] In our study, we tried to systematically evaluate the effect of sociodemographic
parameters on the duration of induction phase of chemotherapy.
Materials and Methods
After an ethical clearance from the institutional ethics committee, children with
ALL who underwent induction of remission from June 2015 to February 2018 were included
in the study.
A questionnaire was used to record the weight and immunization status of the child
and assess the type of house, source of drinking water, and sanitary facilities before
start of treatment. The following definitions were used in the questionnaire:
-
Type of house: (i) Brick house: House where the floor is paved, walls are stone or
brick-built, and roof is made of asbestos or concrete. (ii) Mud House: House in which
floor is packed earth, walls are made of dried mud or thatched, and roof is thatched
or comprises slate
-
Source of drinking water: (i) Filtered water: Drinking water obtained from reverse
osmosis purifier system installed in the household or bottled water. (ii) Nonfiltered
water: Drinking water obtained from hand pump, tap, submersible pump, and well
-
Sanitary facility (SF): (i) SF present: The presence of pit latrine with/without pour-flush
system. (ii) SF absent: Open field defecation.
Our patients received modified children's oncology group protocol. Children were stratified
into standard risk and high risk based on the National Cancer Institute/Rome criteria,
which include (i) age, (ii) total leukocyte count (TLC), (iii) immunophenotype, (iv)
cytogenetics, and (v) central nervous system (CNS) status. Children in the standard
risk group (age, 1–9 years, TLC, <50,000/mm3, pre-B cell ALL, favorable cytogenetics, i.e., t (12;21), hyperdiploidy, and CNS
status I) received 3-drug induction with vincristine, L-asparaginase, and intrathecal
methotrexate and those in the high-risk group (age >9 years, TLC, ≥50,000/mm3, T-cell ALL, unfavorable cytogenetics, i.e., t (9;22), t (1;19), mixed lineage leukemia
rearrangement, hypodiploidy, and CNS status II/III) received 4-drug induction with
vincristine, L-asparaginase, daunorubicin, and intrathecal methotrexate. For the induction
phase of chemotherapy, patients were admitted in the hospital for 10–14 days depending
on their counts and clinical status, following which they were discharged to attend
our day care chemotherapy clinic for further injections. Usually, it took 29 days
to achieve the end of induction phase of chemotherapy. Only those patients who did
not experience febrile illness during hospital stay and were stable at the time of
discharge were included. We hypothesized that the adverse sociodemographic parameters
result in episodes of infection causing reduction in counts and delay in completion
of induction chemotherapy. The duration of induction phase of chemotherapy was considered
delayed, if the patient received chemotherapy for more than 29 days. Those who died
during induction or abandoned the treatment were excluded from the study.
The immunization status of the patients was assessed keeping in view of the National
Immunization Schedule of India, which includes timely doses of bacillus Calmette–Guérin,
hepatitis B, diphtheria–pertussis–tetanus, and measles. The patients who received
the vaccines were considered immunized as per age.
Weight for age percentile of the child was determined using the WHO growth charts
to divide the patients into two groups, i.e., weight for age <10 percentile and weight
for age ≥10 percentile. The SES of patients was assessed using Kuppuswamy Scale which
includes education of the father, his occupation, and monthly income.
Apart from evaluating these parameters individually, a water-SF-housing (WaSH) score
was further devised and analyzed to predict the delay in the duration of induction
phase of chemotherapy. The WaSH score consisted of (i) source of drinking water (filtered
water = 1 and nonfiltered water = 0), (ii) SF (present = 1 and absent = 0), and (iii)
the type of house (mud house = 0 and brick house = 1), with a maximum score of 3 and
a minimum score of 0.
Statistical methods
Data management and statistical analysis was performed using SPSS version 16.0 (SPSS
Inc., Chicago, IL, USA). The data were presented as mean ± standard deviation for
continuous variables and as frequency and percentage for categorical variables. Independent
sample t-test was used to compare two groups with respect to normally distributed
numerical data. P < 0.05 was considered statistically significant.
Results
One hundred and ten children of pediatric ALL with a mean age 6.5 ± 3.5 years were
enrolled with a male-to-female ratio of 2.6:1. Demographic characteristics of the
sample population among the two groups are provided in [Table 1]. The duration of induction chemotherapy was delayed in 71 children with a total
duration of ≤36 days in 47 children, managed on an outpatient basis for an episode
of mild febrile neutropenia, and >36 days in 24 children, admitted in hospital for
severe febrile neutropenia. Among the children who were admitted for febrile neutropenia,
33% had acute gastroenteritis, 32% had lower respiratory tract infection, 29% had
skin and soft-tissue infections, and 6% had urinary tract infection. The most common
organism isolated was Staphylococcus aureus (46%), followed by Gram-negative organisms
(39%), i.e., Klebsiella pneumoniae, Escherichiacoli, and Pseudomonas. Fungal sepsis contributed 15% among the isolated organisms. The patients with respiratory
infections had more delay as compared to infection at other sites.
Table 1
Drugs used in various treatment protocols used to treat acute lymphoblastic leukemia
|
Characteristics
|
Results
|
|
SD – Standard deviation; SES – Socioeconomic status; SF – Sanitary facility
|
|
Age (years), mean±SD
|
6.5±3.5
|
|
Male:female
|
2.6:1
|
|
Nutrition, n (%)
|
|
Normal nutrition
|
89 (80.9)
|
|
Under nutrition
|
21 (19.1)
|
|
SF, n (%)
|
|
Yes
|
64 (58.2)
|
|
No
|
46 (41.8)
|
|
SES, n (%)
|
|
≤III
|
60 (55.5)
|
|
≥IV
|
50 (45.5)
|
|
Water supply, n (%)
|
|
Filtered
|
35 (31.8)
|
|
Nonfiltered
|
75 (68.2)
|
|
Type of house, n (%)
|
|
Brick house
|
70 (63.6)
|
|
Mud house
|
40 (36.4)
|
|
Immunization status, n (%)
|
|
Yes
|
76 (69.1)
|
|
No
|
34 (30.9)
|
|
Of all the patients enrolled, 34 (30.9%) were not immunized, 40 (36.4%) were residing
in mud house, 46 (41.8%) had no access to SF, and 75 (69.1%) were drinking nonfiltered
water. There was a statistically significant increase in duration of chemotherapy,
if the patient was unimmunized (P = 0.000), living in a mud house (P = 0.000), with no access to SF (P = 0.013), and drinking unfiltered water (P = 0.005) [Table 2].
Table 2
Effect of various parameters on the duration of induction phase of chemotherapy
|
Duration of induction
|
P
|
|
SES – Socioeconomic status
|
|
SES
|
|
|
|
Lower (n=50)
|
33.32±5.7
|
0.832
|
|
Middle (n=60)
|
33.42±6.72
|
|
|
House
|
|
|
|
Mud house (n=40)
|
37.58±7.78
|
0.000
|
|
Brick house (n=70)
|
30.97±3.439
|
|
|
Sanitary latrine
|
|
|
|
Absent (n=46)
|
35.11±7.87
|
0.013
|
|
Present (n=64)
|
32.13±4.47
|
|
|
Water supply
|
|
|
|
Nonfiltered water (n=75)
|
34.5±6.89
|
0.005
|
|
Filtered water (n=35)
|
30.94±3.74
|
|
|
Immunization status
|
|
|
|
No (n=34)
|
38.85±7.782
|
0.000
|
|
Yes (n=76)
|
30.92±3.298
|
|
|
Weight
|
|
|
|
<10 percentile (n=58)
|
32.38±5.57
|
0.079
|
|
≥10 percentile (n=52)
|
34.48±6.86
|
|
The children belonging to lower (n = 50) and middle (n = 60) SES showed no significant
effect on the duration of induction phase of chemotherapy (P = 0.832). Although the delay in induction phase of chemotherapy was noted in the
group with weight age percentile ≥10 (P = 0.079), it was not significant statistically [Table 2].
A WaSH score of 0 or 1 was significantly associated with delay in duration of induction
phase of chemotherapy (P = 0.000) [Table 3].
Table 3
Water, sanitation, house score
|
Score
|
Duration of induction(days)
|
P
|
|
<2 (n=50)
|
35.98±7.71
|
0.000
|
|
≥2 (n=60)
|
31.20±3.56
|
Discussion
Survival rates are poor in developing countries due to high treatment-related mortality
(TRM) attributed partly to high prevalence of malnutrition[7] and infection. Infection is the most common cause of TRM even in developed countries.
The incidence of TRM on contemporary trials in ALL is 2%–4%.[8],[9] It has been postulated that malnutrition results in immune dysfunction causing poor
tolerance to infections and altered drug metabolism leading to higher drug toxicity
and adverse clinical outcomes.[9],[10]
Several studies in developed countries have evaluated the effect of undernutrition
on prognosis and survival of patients with acute leukemia. Interestingly, both undernutrition
and obesity are associated with an inferior event free-survival as reported by Orgel
et al.[11] A study from India by Roy et al. stated that undernourished children experience more episodes of febrile neutropenia
resulting in poor outcome.[12],[13] Thus, nutritional status of the child at the start of treatment correlates with
outcome. In our study, however, the duration of induction was not significantly affected
by the nutritional status of the child (P = 0.079).
Apart from nutritional status, our study also focused on the influence of immunization
status of the child and SES along with associated demographic factors on the duration
of induction phase of chemotherapy. Many studies have assessed the effect of SES on
the incidence of ALL as well as its effect on overall survival and relapse, with only
few studies from developing countries including India.[14],[15],[16]
In our study, children with poor living conditions, i.e., children residing in a mud
house with no access to SF and filtered drinking water, had a delay in the duration
of induction phase of chemotherapy. Furthermore, the delay in induction was experienced
by those who were not immunized before start of induction chemotherapy (P < 0.001). The delay was mostly due to unprecedented infections during the treatment
when patients were discharged home to come for chemotherapy, resulting in deterioration
of patient's general condition, requiring hospitalization and thus prolonging the
duration of induction phase of chemotherapy. We hypothesize that delay in the unimmunized
group may be due to associated adverse sociodemographic parameters rather than immunization
alone as most of these children belonged to SES IV and V with unhygienic living conditions.
Conclusion
Disease as well as chemotherapy weakens the immune system, predisposing patients with
cancer to innumerable infections resulting in multiple hospitalizations, increasing
the incidence of relapses as well as patient succumbing to fatal infections. It is
already known that the delay in early phase of chemotherapy can affect overall survival.
Thus, to curb delay in chemotherapy due to infectious causes and thereby improve outcome,
an improvement in living conditions can play an important role. This study subjectively
evaluates the living condition of patients and its effect on the duration of chemotherapy.
The authors of this study feel that interruptions during induction chemotherapy due
to infections results in dose reduction/stoppage of chemotherapeutic agents during
the febrile episode, causing delay in completion of induction chemotherapy. This may
have an adverse effect on overall and event-free survival of patients with acute leukemia.
More studies are needed to support the effect of interruption during induction chemotherapy
on overall/event-free survival in patients with acute leukemia.
