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.