Discussion
In this retrospective study, we sought to understand the clinical
presentation, treatment, and outcomes for patients diagnosed with
medulloblastoma between the ages of three and fifteen years old in Peru,
a LMIC between 1997 and 2013, as well as the barriers affecting their
survival. Peru is a South American country with a population of over 30
million. Peru is an upper middle-income country that demonstrated large
economic growth over the last few years, but was defined as a LMIC
during our study period of 1997-2013 according to World Bank criteria
(www.worldbank.org). Data collected by the Pan American Health
Organization (PAHO) demonstrates that Peru is an example of how advances
in health care have decreased mortality due to communicable disease or
other preventable diseases while mortality due to malignancy remains
relatively unchanged (www.PAHO.org ; Supplemental Figure 1 ).
While the survival rates for average risk medulloblastoma are
approaching 80-90% in HIC, survival rates in our study, as well as
those in other LMIC suggest areas that can be addressed that will allow
for improvement in survival rates in pediatric medulloblastoma in Peru7, 8, 10, 21. Univariate analysis demonstrated that
histologic sub-type, presence of metastasis at diagnosis, and treatment
post-2008 all negatively affected outcomes in our study (Table
4 ). The incompleteness of data pre-2008 could adversely affect
comparisons between the two time periods and limited our ability to
perform multivariate analysis. The statistically significant decrease in
survival for patients with anaplastic subtype or metastasis at diagnosis
is consistent with other studies in HIC22, 23. Extent
of resection was not assessed pre-2008 and rates of GTR were lower in
the post-2008 cohort compared to rates of GTR in HIC studies. The extent
of resection was not found to be statistically associated with an
improved or worse survival outcome in this cohort, which is unexpected
given that extent of resection is a clinically important prognostic
variable in most HIC studies 15, 16, 18-20, 22. We
hypothesize that the large percentage of our cohort with residual tumor
> 1.5cm2 (50% post-2008) contributed to a decreased OS in
our cohort compared to studies performed in HIC and could be why gross
residual > 1.5cm2 was not associated with worse outcomes in
this study. There may be other several factors that contributed to
increased numbers of patients with large residuals in our patient
population: 1) lack of pediatric-trained neurosurgeons, 2) lack of
necessary equipment at facilities where the surgeries took place ie:
operative microscopes, or 3) delayed presentation leading to larger
primary tumor bulk at diagnosis. Indeed, even in HIC, it has been
suggested that higher rates of GTR are obtained when resection is
performed by a pediatric-trained neurosurgeon versus a general
neurosurgeon 24. Further analysis of neurosurgical
resources in LMIC such as Peru are warranted, however, we do recognize
that the prognostic significance of GTR in HIC studies has recently been
called into question once controlled for molecular subgrouping20, 25, 26. The etiology underlying worse outcomes
post-2008 remains unclear. A possible explanation could be the increase
of surgeries performed outside INEN and a subsequent delay in referral
for treatment leading to the patients presenting with large, difficult
to resect tumors and metastasis.
While resection is a critical aspect of medulloblastoma management,
having prompt access to radiation therapy planned and administered by
specialized radiation oncology facilities and subspecialists also affect
the outcome 27. Given that delays in initiating
radiation therapy have been demonstrated to lead to inferior outcomes in
medulloblastoma 23, 28, recent treatment protocols
state that radiation therapy should begin no later than 28-31 days after
surgery 16, 17. We found that 39 patients (40%) began
radiation therapy after 50 days (Table 3 ). Additionally,
limited or no access to pediatric trained neuro-oncologists and
chemotherapeutic agents may also negatively impact patient outcomes29. While pediatric oncologists at the time of this
analysis had no specific training in pediatric neuro-oncology, the
chemotherapy regimens used both pre- and post- 2008 were similar to
those used in HIC 17 and the chemotherapy agents were
available.
In addition to surgery, radiation, and chemotherapy, having prompt and
accurate MR imaging for pre-operative, and post-operative staging is
crucial for management of medulloblastoma. Indeed, in our study, timing
to MRI was a variable that may have affected our statistical analysis.
No patient had an MRI done within a 48-hour post-operative window used
in HIC to assess extent of resection more accurately. Furthermore, in
this cohort, post-operative imaging was only completed in 38/89
patients, all of them in the post-2008 treatment cohort. Even if
post-operative MRI could have been obtained quickly, neuro-radiologist
with expertise in pediatric neuro-oncology were not available during
this time period in Peru. As a testament to the importance of
neuro-radiographical assessment during medulloblastoma management, in
the landmark study which defined the current standard of care for
management of medulloblastoma, radiographical inaccessibility was one of
the statistically significant prognostic variables for EFS17.
As the range of diagnostic techniques broadens and treatment regimens
become increasingly designed based on the molecular landscape of
pediatric tumors, it is important to remember that approximately 80% of
the world’s children with cancer are not benefiting from these advances.
Given the recent consensus statement and World Health Organization (WHO)
guidelines incorporating molecular subtyping into risk stratification
for medulloblastoma 30, the inability to perform
molecular and signal transduction specific immunohistochemistry may
hamper the ability of oncologists in LMIC to accurately risk-stratify
their patients. Aside from adding prognostic data, molecular analysis of
CNS tumors has proven an important adjunct to arriving at the correct
diagnosis. Without the aid of molecular techniques, small round blue
tumors of the CNS can be misdiagnosed, resulting in skewing of survival
curves and response to treatment. A retrospective molecular analysis
from Children’s Oncology Group Trial ACNS 0332 of 31 patients with
institutionally diagnosed CNS primitive neuroectodermal tumors or
medulloblastomas found that 22 patients (71%) were actually other
disease entities such as high-grade glioma, atypical teratoid rhabdoid
tumors, or ependymomas 31.
Consortiums between LMIC and HIC could potentially aid in improving
outcomes for medulloblastomas at INEN. The Latin American Brain Tumor
Board (LATB) a weekly multi-disciplinary pediatric neuro
oncology-specific teleconference connects institutions from Latin
America with those in Canada, Spain, and the United States. The LATB is
an example of how collaborative efforts between HIC and LMIC can improve
care by giving real-time recommendations to oncologists in LMIC
institutions 32. In summary, outcomes for
medulloblastoma patients treated at the INEN from 1997-2013 were
inferior compared to outcomes obtained in HIC studies. Some of the
barriers identified in this study, which have impeded improved survival
at INEN, have been addressed since the conclusion of this study, future
analysis will be needed to evaluate the impact of these interventions on
patient survival. The challenge of improving survival for
Medulloblastomas at INEN is not based on more toxic treatments, but
received timely radiotherapy and chemotherapy after maximal safety
surgery, and creation on local multidisciplinary Pediatric Neuro
Oncology Team, the combination of international efforts such as the LATB
and the strengthening of networking and resource sharing among
neighboring countries as in Central America are good strategies, that
has been successfully demonstrated outstanding results in other Regions.4.