Discussion
Our study sought to describe the epidemiological characteristics and
provide survival outcome data of children with medulloblastoma, age 3-18
years in a single, public tertiary-care referral center located in Rio
de Janeiro/Brazil.
Five-year event-free survival of this cohort was 58.4% and the overall
survival was 59.1%, for patients >3-18 years at diagnosis,
and 5-year OS 69.4% for SR and 53,8% for HR patients. In a
retrospective study from 1983 to 2001 at the same institution with 101
patients under 18 years, the 5-year OS was 53% and the 5-year Disease
Free Survival (DFS) rate was 40%(21). According to staging, our cohort
had 5-year OS of 52.9% for M+ and 71.0% for M0 (p=0.019). In previous
Brazilian studies, patients M+ had 5-year OS of 43.7% and M0 had 5-year
OS of 73.8%(21) and 5-year OS 59% for SR patients and 5-year OS 24%
for HR (22).
High-income countries generally have better survival outcomes compared
to lower income countries. The COGA9961 trial, conducted in the United
States, had 5-year EFS of 81% and OS 87% for standard-risk
patients(20). Other reports from Canada(23) (OS: 69.2%) and United
Kingdom(24) (OS: 73.4%) show similar survival outcomes. However, some
high-income countries show lower survival rates, such as Spain(25,26)
with reported 5-year OS of 55% and EFS of 46%, Singapore(27) with
5-year OS of 51.5% and EFS of 44.5%, and Norway(28) with 5-year OS of
62%. Some upper middle-income countries have reported variable
outcomes, such as Taiwan(29) where 5-year OS has been reported 65.9% in
one institution and 50% in another institution(30).
The difference in survival among high income (HIC) and low-middle income
countries (LMIC) is multifactorial. Late diagnosis with advanced disease
presentation, coexisting debilitating conditions (such as malnutrition),
treatment abandonment, and inefficient health care systems are some of
the barriers of care in pediatric cancer in LMIC(31).
Treatment abandonment has been considered one of the most important
causes of cancer treatment failure in LMIC(38) and is defined as the
failure to start or complete medically-indicated, possibly curative
treatment causing unnecessary mortality and morbidity(39). The causes of
treatment abandonment are multifactorial – financial, social,
political, health care availability – and are frequently beyond the
family’s possibility to control. The duration to define abandonment is
≥4 consecutive weeks of missed therapy. Since patient refusals of
treatment without resuming therapy are not always recorded, treatment
abandonment has been historically underreported and misclassified and
the reported rates are variable, ranging from 0 to 74.5%. At INCA, the
report from 1139 patients between 2012-2017 was 1.66% for all pediatric
solid tumors and 0.7% for pediatric brain tumors(20). The main reasons
for abandonment were lack of understanding the need for therapy,
followed by transportation and financial difficulties. In this present
study there was 2 cases of abandonment of treatment after radiation
therapy (1.6%). Both patients are alive and resumed the follow-up
without chemotherapy, confirming their result that abandonment was not
associated with increased mortality.
Survival was also assessed by the distance from home to the tertiary
cancer center. Patients who lived more than 40km from INCA fared better
than those who lived closer, (5-year OS: 68,2% vs 52%; p=0.032). This
counterintutive conclusion can be possibly explained by socioeconomic
conditions that Brazilian patients face during their treatment. Patients
who live far from INCA can stay at housing provided by Ronald McDonald
House Charities, which is near the hospital and has transportation at
any time of the day and in case of emergencies (such as fever). So even
the poorest patients hosted there can access the hospital promptly when
needed, reducing the time to get medical support or diminishing
absenteeism. Patients often complain about lack of transportation to
acess the hospital for outpatient consultations or for emergencies, and
while the government provides some resources for patient transportation,
it is not widely distributed or utilized.
The use of initial chemotherapy after surgery and delayed radiation
therapy has shown worse outcomes when compared to upfront radiation
therapy(32). In this cohort, a group of patients (n=12) received pre-
irradiation chemotherapy by week 15. Eighty-three patients received
upfront radiation therapy post surgery according to the COGA9961
protocol; this group had increased OS when compared to the chemotherapy
pre irradiation protocol (70.6% vs 41.7%), which was used until the
early 1990s when it was replaced by the COGA9661. Current strategies
recommend risk-adapted CSI and adjuvant chemotherapy in children above
3-5 years(1), while infants should receive treatment with either
high-dose chemotherapy and stem cell transplant(32) or intraventricular
chemotherapy(33), in order to avoid or delay the use of radiation
therapy.
The epidemiological characteristics of this series possibly explain the
differences in survival that medulloblastoma patients have in Brazil.
Issues related to limited health care resources, poverty, delayed
diagnosis, treatment abandonment, and malnutrition are reflected in
inferior survival outcomes when compared to high-income
countries(34).There is a difference in survival between high-income
countries treating their patients per COGA9661, with a reported 5-year
OS of 87%(20) and the present study where the overall survival was
69.4% for SR patients. Despite the difficulties encountered in an
upper-middle income country, it was possible to deliver treatment with
good results. Nevertheless many initiatives can hopefully be explored to
aid in improving the results and reducing these differences.
The limitations of the study are primarily due to its retrospective
nature and the limitations of chart information, with missing data.
Patients being operated in other institutions pose also difficulties,
because of lack of information. The strengths of the study are the
relatively large number of patients with medulloblastoma from a single
institution, and the homogeneous treatment that most patients received.
INCA as public reference hospital for cancer pediatric patients
registers the vast majority of medulloblastoma patients in the state.
Thus, this study is possibly a proxy of the medulloblastoma scenario in
Rio de Janeiro.