Investigators must remember that patients are exposed to treatment regimens that are often different for adults when compared to children. Children and adults differ in their ability to withstand different treatment protocols. Greenberg et al. 2001 and Packer et al. 1994 found that 44 % of children were able to complete a multi-agent CDP protocol (to the 8th cycle), while no adult patients in Greenberg et al.’s study were able to complete the CDP protocol (Greenberg et al. 2001; Packer et al. 1994). While the inability to complete therapy may have something to do with the differences in survival, perhaps a more complex mechanism is at work. Adults are typically offered the same post-operative adjuvant therapy protocols as children, but because they are more likely to have SHH-driven tumors, the effect of chemotherapy is less, because SHH-driven tumors may not have the same response as WNT, group 3, and group 4 tumor subtypes. Thus, while we suspect that WNT tumors respond well to typical adjuvant therapies because of their impressive survival rates, the interaction between the latest radiochemotherapy protocols and MB subtypes is unclear when survival or progression-free survival is the measured outcome.

It is well known that adults get more MBs in the cerebellar hemispheres, while children are more likely to have tumors located in the cerebellar vermis. While it is often thought that it is easier to obtain gross-total resection in hemispherically located tumors, there is little evidence that location is associated with survival (Greenberg et al. 2001). Lastly, the effect of anatomical location on survival is probably a relationship confounded by gross-total resection rates or genetic factors.

To briefly recap: confounding is considered to be the situation in which the study exposure groups (in this case, age-categories) differ in their hazard rates or in relative survival-excess hazard rates for reasons other than the effects of the exposure group variable (Greenland et al. 1999). To relate this to the ideas presented here, if anatomical location was known to have an impact on excess hazard rates, when gross-total resection rates are taken into account (controlled for), the effect of anatomical location on excess hazard rates may disappear. In other words, the anatomical location has a relationship with survival, only because it affects the surgeons ability to achieve a gross-total resection at surgery.

Incidence of late relapse appears to be greater in adults, with relapses in children tending to occur before 3 years post-diagnosis. Khalil (2008) presents a series of 51 pediatric MBs in which all patients that relapsed (10, or 20 %) relapsed before 2 years. Brandes et al. 2007 demonstrated 17 relapses in 36 adult patients (47 %), with a median recurrence time of 3 years post-diagnosis (Brandes et al. 2007). In addition, when one reviews the progression-free curves of various studies including children, plateaus are noted to start at or before 4 years for children (Allen et al. 2009; Evans et al. 1990; Rutkowski et al. 2010; Zeltzer et al. 1999). When compared to adults the progression-free curve of adults continues to decrease and reaches a plateau at 10 years (Padovani et al. 2007). While these progression-free curves are consistent with the finding of survival differences between adults and children (because adults appear to progress later than children), although it may seem logical, but we are as yet unclear if later progressions explain the survival difference seen after 4 years.

To measure survival differences between adults and children, investigators must take into account that adults, and especially elderly people in the general population are already more likely to die than children. The mortality rate of the general population is called the expected mortality rate. Subtracting the expected mortality rate from the hazard rate in a population of cancer patients gives us a measure known as the excess hazard rate, and when transformed into the survival scale this gives us the measure known as relative survival (RS). RS is considered to be the gold standard of cause-specific survival estimation because of its robustness and non-reliance on death certificates for correct descriptions of the cause of death.

When one compares the survival rates of children to those of adults, the relationship between the categories changes during follow-up (at least in population-based studies). As mentioned previously, survival rates are virtually identical before 4 years. After 4 years the survival rates begin to differ, with adults faring worse. This concept is known as non-proportional hazards, and is key to understanding changing relationships between two groups. As a brief recap, hazard rates are what underpin survival rates. A hazard rate is the instantaneous event per unit of time. In other words, it is the amount of deaths per smallest unit of time. Some might call this the “speed of death” or “speed of mortality”. Regression models that present hazard ratios generally present a ratio of two hazard rates. For example, if during a particular month 5 children per 100 children died, and this was compared with 10 adults per 100 died, a hazard ratio of 2 would be present.