Potentially curative radiation treatment of children with brain tumors resulted from the introduction of megavoltage irradiation nearly 50 years ago, and initially carried out principally with cobalt gamma rays. Common childhood brain tumors are infrequently cured with radiation doses below 5,000 cGy in 180 cGy fractions. The practical level of radiation tolerance of the brain is 5,500 cGy. Megavoltage irradiation allowed such doses to be delivered without major short-term toxicity. Thus, adults may now be seen who were cured of a childhood brain tumor many years ago.
In practice, curative radiation treatment was introduced slowly, principally during the 1950s and '60s, so that it is still uncommon to see a survivor treated more than 30 years ago. However, enough years have passed that it is now possible to evaluate factors that are predictive of long-term survival in children with brain tumors and to estimate some of the risks associated with having a brain tumor eradicated by surgical and radiation treatment. This analysis updates and expands on a previous publication focusing on these issues .
A University of Toronto database exists for children who underwent irradiation for brain tumors diagnosed from 1958 to 1995. A total of 1,034 children up to and including the age of 16 years received radiation treatment for a brain tumor during that 38-year period.
With only rare exceptions, initial investigation and surgical management took place at the Hospital for Sick Children and subsequent radiation treatment was carried out at either the Princess Margaret Hospital (1958 to 1986) or Toronto-Sunnybrook Regional Cancer Centre (1986 to 1995). Long-term follow-up was provided at the Hospital for Sick Children until the children were 18 years of age and thereafter at either the Princess Margaret Hospital or Toronto-Sunnybrook Regional Cancer Centre. Radiation treatment was commonly administered postoperatively as a component of primary treatment (87%), rather than at the time of progression or relapse. This patient series is essentially population-based for the greater metropolitan Toronto region and northern Ontario.
The 5-, 10-, 20-, and 30-year survival rates for all 1,034 patients were 52%, 44%, 38%, and 30%, respectively (Figure 1). One in three of the patients who were alive at 10 years was dead at 30 years. Relapse- or progression-free survival rates at 5, 10, 20, and 30 years were 47%, 45%, 44%, and 44%, respectively.
Age and Gender
Age at diagnosis was not a prognostic factor. The 20-year survival rate was 36% for children less than 4 years old at diagnosis (N = 225), 39% for those 4 to 8 years old (N = 384), and 38% for those 8 to 16 years old (N = 419).
Also, there was no overall difference in survival by gender. As shown in Figure 2, the 20-year survival rate was 37% for boys (N = 582) and 40% for girls (N = 449). However, after 20 years, a greater number of deaths occurred in girls.
For the 607 patients for whom adequate surgical data were available, total resection (N = 143) resulted in a 20-year survival rate of 64% and less than total resection (N = 464), a rate of 36% (P < .0001; Figure 3).
The median radiation dose was 5,086 cGy, but the range was narrow. The 10th percentile was 4,000 cGy and the 90th percentile, 5,400 cGy. No significant survival difference was noted when patients who received a radiation dose above the median (5,086 cGy) were compared with those who received a lower dose (4,000 to 5,086 cGy). Respective 20-year survival rates for the two groups were 38% and 43%.
Year of Diagnosis
Overall, no significant improvement in survival occurred for patients treated in 1975 or afterward (N = 562), compared to those treated before 1975 (N = 464). The respective 20-year survival rates for the two groups were 42% and 36% (P = .11; Figure 4).
Table 1 summarizes 10- and 20-year survival rates by tumor histology. (Patients with brainstem tumors, optic nerve gliomas, and basal ganglia tumors include those with and without a tissue diagnosis.) The survival curves for patients with low- and high-grade astrocytomas are shown in Figure 5.
Second Malignant Tumors
The cumulative incidence of second malignant tumors was 13% at 20 years and 19% at 30 years (Figure 6). To date, 31 patients have developed a second malignant tumor and 2 patients, a third malignancy. The most common second malignant tumors were gliomas (9 patients), meningiomas (7), acute leukemia (5), sarcoma (3), and other tumors (7).
Survival from the date of diagnosis of a second malignant tumor was 58% at 5 years. None of the five patients who developed acute leukemia and only one of four patients who developed a high-grade astrocytoma survived. In contrast, all seven patients with a meningioma are currently alive. All meningiomas were included in this analysis, regardless of the degree of malignancy.
Cause of Death
Among the 546 patients who died, the cause of death was "disease" in 514 patients (94%), toxicity in 6 (1%), second malignant tumor in 12 (2%), and miscellaneous in 14 (3%). The classification "disease" was used when death was due to uncontrolled tumor, whether progressive or recurrent disease, and also for a very small number of patients who underwent prolonged hospitalization for irreversible neurologic damage and in whom no other cause of death was established.
The distribution of the cause of death varied with time (Table 2). In the first 5 years after diagnosis, disease was the cause of death in 97% of patients. After 20 years, disease was responsible for death in 30% of patients. A second malignant tumor became an increasingly important cause of death beyond 5 years after diagnosis.
At 10 years after diagnosis, 269 patients were alive, 69 of whom had previously suffered a relapse and 209 of whom were relapse free. Survival rates at 25 years (from diagnosis) in the relapsed and relapse-free patients were 49% and 94%, respectively (P < .0001).
Survival After Relapse
Survival, measured from the date of first relapse (or progression) for 533 relapsed patients was 22% at 5 years and 12% at 20 years.