Recurrent Progressive PLGG: Sequencing Targeted Therapies, Retreatment, and the Role of Radiation

In this segment, Dr. Abdelbaki, Dr. Margol, Dr. Chintagumpala, and Dr. Chi discusses treatment decision-making in the recurrent or progressive setting for pediatric low-grade glioma (PLGG), emphasizing that therapy selection depends heavily on prior treatment history, reason for progression, and individual patient factors.

A critical distinction is drawn between rebound regrowth, tumor regrowth after a drug holiday, and true on-treatment progression. When a child has tolerated and responded to a prior agent, rebound regrowth may warrant restarting the same therapy rather than automatically switching to a new one based solely on FDA approval status. Tovorafenib's rapid onset of tumor shrinkage makes it particularly appealing when stable disease alone is insufficient, such as when a tumor is growing in a functionally critical area, and its once-weekly dosing benefits patients with compliance challenges. However, decreased growth velocity remains a significant psychosocial barrier, particularly for tweens and adolescent athletes.

The panel agrees that no established optimal sequence exists among targeted agents. Tovorafenib, trametinib, and selumetinib are all options, with selection guided by the child's age, ability to swallow pills, and clinical situation. Retreatment with traditional chemotherapy is highlighted as a viable and sometimes overlooked option, as some tumors respond well to chemotherapy a second time. The broader toolkit also includes immune modulators, anti-angiogenic agents, and older chemotherapy regimens such as thioguanine/procarbazine/lomustine/vincristine (TPCV). The panel expresses appreciation for the expanded therapeutic armamentarium compared to prior decades, while stressing that no clinical data demonstrate superiority of one targeted agent over another.

Radiation therapy should also not be disregarded. In select cases, such as a teenager with rapid-onset quadriplegia from a progressive PLGG who had already received chemotherapy and targeted therapy, radiation can restore function when other options have been exhausted.

In the next episode, "Unmet Needs in PLGG: FGFR-Altered Tumors, Vision Preservation, and Long-Term Outcomes," the panel addresses the most pressing unmet needs in PLGG, including the challenge of treating FGFR-altered tumors, the ongoing struggle to preserve vision, and critical gaps in long-term outcome data.