Temporal Changes in Treatment and Late Mortality and Morbidity in Adult Survivors of Childhood Glioma: A Report from the Childhood Cancer Survivor Study

This is a long-term outcome study on survivors of pediatric glioma. The main purpose of the study was to evaluate the impact of changes in treatment approaches for pediatric glioma over the past few decades on long-term mortality, chronic health conditions, and subsequent tumor risk among survivors.

Background:

In the past, treatment for pediatric low-grade glioma (PLGG) typically included surgical resection, whole-brain radiotherapy, and conventional cytotoxic chemotherapy. However, whole-brain radiotherapy increases the risk of long-term complications such as subsequent tumors and cognitive impairment. Since the 1980s, chemotherapy has been gradually used to delay or avoid the use of whole-brain radiotherapy, especially for younger patients. In the 1990s, platinum-based regimens became the first-line treatment choice after surgery. This study aimed to evaluate the impact of this change in treatment strategy on long-term outcomes for survivors.

Study Population:

The study was based on the Childhood Cancer Survivor Study (CCSS) cohort, including 2,501 5-year survivors of pediatric glioma diagnosed between 1970 and 1999 in the United States and Canada.

Main Research Methods:

1) Patients were divided into three groups based on the decade of diagnosis (1970s, 1980s, and 1990s), and the treatment approaches and long-term outcomes were compared across groups;

2) Patients were also categorized into surgery only, chemotherapy (± surgery), and whole-brain radiotherapy (± chemotherapy/surgery) groups, and long-term outcomes were compared;

3) Multivariable models were used to analyze whether the impact of changes in treatment approach on outcomes was independent of the decade effect;

4) The main outcome measures included long-term mortality (overall mortality, recurrence/progression mortality, non-tumor mortality), incidence of grade 3-5 chronic health conditions, and subsequent tumor risk.

Key Findings:

1) The use of whole-brain radiotherapy gradually decreased over time (62.6% in the 1970s, 49.9% in the 1980s, and 26.0% in the 1990s), while the use of chemotherapy increased.

2) Patients diagnosed in later decades had lower risks of long-term mortality, grade 3-5 chronic health conditions, and subsequent tumors compared to those diagnosed earlier. For example, the 15-year cumulative incidence of grade 3-5 chronic conditions was 18.7% in the 1970s, 17.2% in the 1980s, and 13.2% in the 1990s.

3) After adjusting for treatment approach, most of the outcome differences across decades were attenuated or disappeared, suggesting that the improved outcomes were primarily due to changes in treatment strategy.

4) Compared to surgery alone, the whole-brain radiotherapy group had the highest risk of adverse long-term outcomes, while the chemotherapy group had an intermediate risk. For example: - Overall mortality risk: surgery 2.0%, chemotherapy 6.9%, whole-brain radiotherapy 11.3%; - Grade 3-5 chronic conditions: surgery 8.3%, chemotherapy 14.0%, whole-brain 24.5%; - Subsequent tumors: surgery 0.9%, chemotherapy 1.7%, whole-brain 3.0%.

5) Whole-brain radiotherapy was more likely to lead to declines in quality of life, such as cognitive/learning impairment, employment difficulties, and lower personal income, compared to chemotherapy.

6) Delaying whole-brain radiotherapy for more than one year had a similar impact on long-term complications as immediate radiotherapy.

This study validated that the adjustment in treatment strategies for pediatric PLGG over the past few decades (reduction in whole-brain radiotherapy and increased use of chemotherapy) has improved long-term survival quality for patients, providing strong support for clinical practice. While whole-brain radiotherapy is more effective in tumor control, it also has the highest long-term toxicity; therefore, the benefits and risks need to be weighed when selecting treatment strategies. The researchers suggest further exploration of emerging treatment approaches to avoid radiotherapy, in order to further improve the long-term survival quality for PLGG patients.