Proton Therapy May Improve Cognitive Outcomes in Craniopharyngioma


A phase 2 trial indicates that limited surgery and post-operative proton therapy result in a high rate of tumor control and less severe complications in young patients with craniopharyngioma.

The use of proton therapy did not improve survival outcomes vs a historical cohort, and resulted in a lower severity of cognitive impairment compared with photon therapy in pediatric and adolescent patients with craniopharyngioma, according to data from a phase 2 clinical trial (NCT01419067) published recently in the Lancet Oncology.

Proton Therapy May Improve Cognitive Outcomes in Craniopharyngioma | Image Credit: © Dr_Microbe -

"A reduction in the volume of healthy brain exposed to radiation seems to reduce the cognitive effects of irradiation," according to the study authors.

Three-year progression-free survival (PFS) was 96.8% (95% CI, 90.4%-99.0%) among patients treated with proton therapy, with investigators reporting 3 instances of progression; the corresponding value was 96.0% (95% CI, 89.7%-98.5%) among those treated with photon therapy, with 4 progression events (P = .89). Three-year overall survival (OS) was 100% in both groups.

Five-year PFS was 93.6% (95% CI, 86.3%-97.1%) in the proton therapy cohort vs 90.0% (95% CI, 82.2%-94.5%) in the photon therapy cohort, with 6 and 10 progression events, respectively (Hazard ratio, 0.54; 95% CI, 0.24-1.19).

At the same time, investigators reported significant differences between the 2 cohorts in certain longitudinal scores; patients treated with photon therapy experienced decreasing values for intelligence quotient (-1.09 points per year; P = .0070) and adaptive behavior (-1.48 points per year; P = .030) vs those treated with proton therapy.

“The potential benefit of proton therapy in the treatment of craniopharyngioma is to reduce the volume of healthy brain exposed to low doses,” the investigators wrote. “This is most relevant to crucial structures not adjacent to the targeted volume. A reduction in the volume of healthy brain exposed to radiation seems to reduce the cognitive effects of irradiation.”

Investigators of this single-arm, phase 2trialenrolled 94 patients into the proton therapy cohort from August 22, 2011 to January 19, 2016. Outcomes among these patients were compared with those among a historical cohort of 101 patients treated with surgery plus photon therapy.

Overall, 52% of patients in the experimental cohort were female. Additionally, 66% were White, with a further 17% identifying as Black, 2% as Asian, and 15% as other races. The median age was 9.39 years (interquartile range [IQR], 6.39-13.38).

Patients in the experimental cohort received conformal proton therapy using passive scattering methods with apertures and compensators. The clinical target volume included an anatomically defined margin of 0.5 cm surrounding the gross tumor volume, which was defined as the postoperative tumor bed and residual tumor. These patients received a total dose of 54 Gy (relative biological effect [RBE]) using conventional fractionation of 1.8 Gy (RBE) per day.

Clinical target volume margins in the photon therapy cohort were 1.0 cm among the first 25 patients and a reduced margin of 0.5 cm or less among the remaining patients in the cohort as conformal methods improved.

Median follow-up was 7.62 years (IQR, 6.48-8.54) in the full proton therapy cohort; median follow-up was 7.52 years (IQR, 6.28-8.53) among those without progression. The corresponding figure was 13.25 years (IQR, 9.43-16.65) in the photon therapy cohort.

Necrosis of the central nervous system (CNS) occurred in 2% of those in the proton therapy cohort and 2% in the photon cohort. Severe vasculopathy occurred in 4% and 7% of patients, respectively; permanent neurological conditions occurred in 3% and 7%, respectively.

The most frequent grade 3/4 adverse effects (AEs) in the proton therapy cohort were headaches (6%), seizures (5%), and vascular disorders (6%).

“Our study has several limitations. The use of a historic [photon therapy] cohort is susceptible to the inherent differences encountered when performing and interpreting assessments, and external factors beyond the health-care environment, such as socioeconomic status…. Craniopharyngioma is a rare disease, and a randomized study would not be feasible,” the investigators concluded. “Further improvements [in treatment] will require careful study, assessment of relevant domains, and long-term follow-up.”


Merchant TE, Hoehn ME, Khan RB, et al. Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study. Lancet Oncol. 2023;24(5):P523-534. doi:10.1016/S1470-2045(23)00146-8

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