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Purpose of Review: Craniopharyngiomas represent one of the most challenging diseases to treat. Despite their benign histology, and after many decades of surgical experience and technological advancements, there is still no clear consensus regarding the most effective management for this tumor. Due to their location and aggressive local characteristics, purely surgical approaches all too often result in unacceptable morbidity., Recent Findings: Partial resection combined with radiation therapy results in similar control rates when compared to aggressive surgery, while also minimalizing the neuro-endocrinological morbidity. In this manuscript, we describe the historical progression of the shifting strategies in the management of pediatric craniopharyngioma. Time has also altered our expectations for outcomes, evolving from purely morbidity and mortality to simple Glasgow Outcomes Scales, now to formal neuro-psychometric and quality of life data., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity., Methods: In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0-21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067., Findings: Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39-13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28-8·53) for patients who did not have progression and 7·62 years (IQR 6·48-8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4-99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3-4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff., Interpretation: Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared., Funding: American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness., Competing Interests: Declaration of interests We declare no competing interests, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Pediatric patients with craniopharyngioma risk cognitive deficits when treated with radiation therapy. We investigated cognitive outcomes after conformal photon radiation therapy (CRT) and the effect of visual deficits and hormone deficiencies., Methods and Materials: One hundred one pediatric patients were enrolled on a single institutional protocol beginning in 1998 (n = 76) or followed a similar nonprotocol treatment plan (n = 25). CRT (54 Gy) was administered using a 1.0- or 0.5-cm clinical target volume margin. Median age at CRT was 9.50 years (range, 3.20-17.63 years). Patients were followed for 10 years with assessment of hearing, vision, hormone deficiencies, and cognitive performance., Results: Intellectual functioning (intelligence quotient) was significantly lower in children treated at a younger age and those who received higher doses to temporal lobes and hippocampi. Black race (-17.77 points, P = .002) and cerebrospinal fluid shunting (-11.52 points, P = .0068) were associated with lower baseline intelligence quotient. Reading scores were lower over time in models incorporating age, shunt, and dose to specific brain structures. Patients treated for growth hormone deficiency within 12 months of CRT had better intelligence and attention outcomes. Among patients with normal baseline vision, the 10-year cumulative incidence of change in visual acuity was 4.00% ± 2.82% and in visual field 10.42% ± 4.48%. Reading scores decreased after treatment (0.7873 points/y, P = .0451) in those with impaired baseline vision., Conclusions: Cognitive outcomes are selectively affected by dose to brain subvolumes, comorbidities of visual deficits, and treatment of endocrinopathy in pediatric craniopharyngioma. Improved treatment selection, normal tissue sparing methods of irradiation, and posttreatment management of endocrinopathy should be considered., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To estimate the incidence of endocrinopathy in children and adolescents with craniopharyngioma after treatment with photon-based conformal and intensity-modulated radiation therapy (CRT)., Methods: One hundred one pediatric patients were enrolled on a phase II single-institution protocol beginning in 1998 (n = 76) or followed a similar non-protocol treatment plan (n = 25). Surgery was individualized. CRT (54 Gy) was administered using a 1.0-cm or ≤0.5-cm clinical target volume margin. Patients underwent baseline and serial evaluation of the hypothalamic-pituitary axis., Results: The 10-year cumulative incidence (CI) of growth hormone deficiency (GHD) was 68.42% (±11.27) for black patients and 94.23% (±3.57) for white patients (P = .0286). The CI of thyroid-stimulating hormone deficiency (TSHD) was 70.94% (±8.44) at 10 years for non-shunted patients and 91.67% (±10.40) at 6 years for shunted patients (P = .0260). The CI of TSHD was 100% (±14.29) at 4 years for those with diabetes insipidus (DI) and 71.36% (±8.86) at 10 years for those without DI (P = .0008). The 10-year CI of adrenocortical hormone deficiency was 70.00% (±16.15) for those with DI and 48.39% (±9.19) for those without DI (P = .0080). The 10-year CI of LH/FSH deficiency was 43.33% (±9.32) age <7 years, 61.29% (±9.11) aged 7-10 years, and 78.95% (±6.38) age ≥10 years (P < .0001). BMI was significantly greater prior to CRT in white patients with DI (P = .0004) and preexisting GHD (P = .0275)., Conclusions: Hormone deficiencies are common in pediatric patients with craniopharyngioma and are associated with host, tumor, and treatment factors. Understanding the incidence and time to onset may facilitate intervention and patient selection for treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Our aim was to estimate long-term disease control and complications after conformal radiation therapy (CRT) in children and adolescents with craniopharyngioma., Materials and Methods: Pediatric patients with craniopharyngioma (n = 101) were enrolled on or treated according to a phase II single institutional protocol from 1998. Surgery was individualized, and CRT (54Gy) was administered using a 1.0 cm or 0.5 cm clinical target volume margin. Patients were followed for 10 years by serial MR imaging and MR angiography and a battery of tests to measure the effects of treatment., Results: Twenty patients had tumor progression. Twelve patients who had tumor progression died due to tumor (n = 6) or complications related to tumor or treatment (n = 6). With a median follow-up of 14.94 years for survivors, the 10 year estimates (±SE) of progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) were 78.84% ± 4.10%, 77.12% ± 4.19%, and 96.02% ± 1.95%, respectively. OS, EFS, and PFS were significantly associated with race, shunt status, and tumor volume. The 10 year cumulative incidence (±SE) of the secondary tumor (1.99% ± 1.40%), secondary malignant tumor (1.0% ± 1.0%), necrosis (1.98% ± 1.39%), vasculopathy (8.47% ± 2.90%), and permanent neurologic deficits (8.28% ± 3.37%) were estimated by competing risk analysis. Three patients required revascularization surgery. Salvage therapy was successful in 13 patients using surgery and radiosurgery., Conclusions: Limited surgery and CRT using photons results in excellent tumor control. Tumor control and the incidence and severity of complications are associated with host, tumor, and treatment factors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Radiotherapy alone, without tumor-directed surgery, may be appropriate for selected patients with craniopharyngioma reducing the risks associated with neurosurgery. Understanding outcomes for patients with craniopharyngioma treated with radiotherapy alone will further refine patient selection and treatment options., Methods: Since 2002, 13 children, adolescents and young adults, with craniopharyngioma were treated with radiotherapy alone and followed for disease control and functional outcomes at a single institution. The median age at treatment was 13 years (range, 3-21 years). All patients received 54 Gy/54 Gy(RBE) in 30 fractions. Five patients were treated with intensity-modulated photon therapy, four with passively scattered proton therapy, and four with intensity-modulated proton therapy., Results: With a median follow-up of 5 years (range 3 months-14 years), all patients were alive. One experienced tumor progression 8.5 years after treatment. No significant changes in vision, hearing or neurologic function attributed to radiotherapy. Hormone deficiencies and body mass index were within the expected range at baseline and 5 years after treatment. There was no evidence of cognitive decline based on assessment of IQ, memory and attention. Unexpected complications included single cases of out-of-field malignancy, white matter changes, large vessel narrowing, and pontine capillary telangiectasia. Six patients had sphenoid bone abnormalities on follow-up imaging attributed to radiotherapy., Conclusion: Radiotherapy alone is an important treatment option to consider when radical resection is contraindicated, or surgical intervention is not required to alleviate symptoms. Disease control and functional outcomes are excellent after radiation therapy alone in appropriately selected patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Craniopharyngioma survivors experience cognitive deficits that negatively impact quality of life. Aerobic fitness is associated with cognitive benefits in typically developing children and physical exercise promotes recovery following brain injury. Accordingly, we investigated cognitive and neural correlates of aerobic fitness in a sample of craniopharyngioma patients., Methods: Patients treated for craniopharyngioma [N=104, 10.0±4.6 years, 48% male] participated in fitness, cognitive and fMRI (n=51) assessments following surgery but before proton radiation therapy., Results: Patients demonstrated impaired aerobic fitness [peak oxygen uptake (PKVO2)=23.9±7.1, 41% impaired (i.e., 1.5 SD&lt;normative mean)], motor proficiency [Bruininks-Oseretsky (BOT2)=38.6±9.0, 28% impaired], and executive functions (e.g., WISC-IV Working Memory Index (WMI)=96.0±15.3, 11% impaired). PKVO2 correlated with better executive functions (e.g., WISC-IV WMI r=.27, p=.02) and academic performance (WJ-III Calculation r=.24, p=.04). BOT2 correlated with better attention (e.g., CPT-II omissions r=.26, p=.04) and executive functions (e.g., WISC-IV WMI r=.32, p=.01). Areas of robust neural activation during an n-back task included superior parietal lobule, dorsolateral prefrontal cortex, and middle and superior frontal gyri (p&lt;.05, corrected). Higher network activation was associated with better working memory task performance and better BOT2 (p&lt;.001)., Conclusions: Before adjuvant therapy, children with craniopharyngioma demonstrate significantly reduced aerobic fitness, motor proficiency, and working memory. Better aerobic fitness and motor proficiency are associated with better attention and executive functions, as well as greater activation of a well-established working memory network. These findings may help explain differential risk/resiliency with respect to acute cognitive changes that may portend cognitive late effects. (JINS, 2019, 25, 413-425).

The goal of this study was to investigate the impact of patient-, disease-, and treatment-related variables upon neurocognitive outcomes in pediatric patients with craniopharyngioma prior to treatment with proton therapy or observation after radical resection. For all participants (N = 104), relevant clinical and demographic variables were attained and neurocognitive evaluations completed prior to irradiation or planned observation. One-sample t-tests were conducted to compare performance to published normative data. Linear models were used to investigate predictors of performance on measures where performance was below normative expectations. Participants showed poorer performance in comparison to the normative group across neurocognitive domains including executive functions (e.g., working memory; Wechsler Digit Span Backward p = 0.03), learning and memory (e.g., California Verbal Learning Test [CVLT] Total T p = 0.00), and fine-motor coordination (e.g., Grooved Pegboard Dominant Hand p = 0.00). Poor performance across areas was predicted by presurgical hypothalamic involvement (e.g., Behavior Rating Inventory of Executive Function Working Memory Index Grade 2 β = -7.68, p = 0.03; CVLT Total T Grade 2 β = 7.94, p = 0.04; Grade 3 β = -9.80, p = 0.00), extent of surgery (e.g., CVLT Total T Resection β = -7.77, p = 0.04; Grooved Pegboard Dominant Hand β = -1.58, p = 0.04), and vision status (e.g., CVLT Total T Reduced vision without impairment β = -10.01, p = 0.02; Grooved Pegboard Dominant Hand Bilateral field defect β = -1.45, p = 0.01; Reduced vision without impairment β = -2.30, p = 0.00). This study demonstrated that patients with craniopharyngioma show weaker neurocognitive performance in comparison to the normative population resulting from tumor, events leading to diagnosis, and early surgical intervention. Systematic investigation of neurocognitive performance before treatment with radiation therapy is essential to evaluating the potential risks and benefits of newer methods of radiation therapy including proton therapy.

Purpose: The purpose of this study was to determine radiation dose effect on the structural integrity of cerebral white matter in craniopharyngioma patients receiving surgery and proton therapy., Methods and Materials: Fifty-one patients (2.1-19.3 years of age) with craniopharyngioma underwent surgery and proton therapy in a prospective therapeutic trial. Anatomical magnetic resonance images acquired after surgery but before proton therapy were inspected to identify white matter structures intersected by surgical corridors and catheter tracks. Longitudinal diffusion tensor imaging (DTI) was performed to measure microstructural integrity changes in cerebral white matter. Fractional anisotropy (FA) derived from DTI was statistically analyzed for 51 atlas-based white matter structures of the brain to determine radiation dose effect. FA in surgery-affected regions in the corpus callosum was compared to that in its intact counterpart to determine whether surgical defects affect radiation dose effect., Results: Surgical defects were seen most frequently in the corpus callosum because of transcallosal resection of tumors and insertion of ventricular or cyst catheters. Longitudinal DTI data indicated reductions in FA 3 months after therapy, which was followed by a recovery in most white matter structures. A greater FA reduction was correlated with a higher radiation dose in 20 white matter structures, indicating a radiation dose effect. The average FA in the surgery-affected regions before proton therapy was smaller (P=.0001) than that in their non-surgery-affected counterparts with more intensified subsequent reduction of FA (P=.0083) after therapy, suggesting that surgery accentuated the radiation dose effect., Conclusions: DTI data suggest that mild radiation dose effects occur in patients with craniopharyngioma receiving surgery and proton therapy. Surgical defects present at the time of proton therapy appear to accentuate the radiation dose effect longitudinally. This study supports consideration of pre-existing surgical defects and their locations in proton therapy planning and studies of treatment effect., Competing Interests: Notification: No actual or potential conflicts of interest exist., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Object: In this paper the authors present their experience treating children with recurrent craniopharyngioma who were initially managed with surgery followed by conformal radiation therapy (CRT)., Methods: A departmental oncology information system was queried to identify all children (< 18 years old) who received CRT for a craniopharyngioma between 1998 and 2010 (inclusive) and specifically those who experienced tumor progression. For each patient, the authors recorded the type of recurrence (solid, cystic, or both), the time interval to first progression and each subsequent progression, the associated treatment complications, and disease status at last follow-up evaluation., Results: Among the 97 patients that met criteria for entry into this study, 18 (18.6%) experienced tumor progression (9 cystic, 3 solid, 6 cystic and solid). The median time to first recurrence was 4.62 years (range 1.81-9.11 years). The subgroup included 6 female and 12 male patients with a median age of 7.54 years (range 3.61-13.83 years). Ten patients experienced first progression within 5 years of CRT. The 5- and 10-year treatment-free survival rates for the entire cohort were 89.0% (95% confidence interval [CI] 80.5%-93.9%) and 76.2% (95% CI 64%-85%), respectively. Seven patients had a single episode of progression and 11 had more than 1. The time interval between each subsequent progression was progressively shorter. The 18 patients underwent 38 procedures. The median follow-up duration for this group was 9.32 years (range 4.04-19.0 years). Three patients died, including 1 from perioperative complications., Conclusions: Craniopharyngioma progression after prior irradiation is exceedingly difficult to treat and local control is challenging despite repeated surgical procedures. Given our results, gross-total resection may need to be the surgical goal at the time of first recurrence, if possible. Decompressing new cyst formation alone has a low rate of long-term success.

Craniopharyngioma frequently involves intracranial pain-sensitive structures. We retrospectively studied prevalence, associated risk factors, and outcome of headaches in children with craniopharyngioma. Fisher exact test and multivariate analysis were used to study association of study variables. Of the 51 craniopharyngioma patients treated at our institution from January 1994 to December 2005, 40 (78%) reported headaches (35 [68%] before tumor diagnosis). Migraine headaches were diagnosed in 32 (63%) and tension-type headaches in 11 patients (22%). The median follow-up period was 2.7 years. At the last follow-up, 38 (75%) were headache free. Presence of hydrocephalus, distortion of circle of Willis, and large tumor volume were associated with headache, and the last 2 variables were also associated with more severe and frequent headaches. Radiation treatment and insertion of Ommaya reservoir were associated with reduced headache frequency. In conclusion, headaches are common in patients with craniopharyngioma and are likely related to tumor size and volume. In most patients, headaches improve with successful tumor treatment.

Purpose: To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and to determine factors that predict for tumor progression., Methods and Materials: Eighty-eight children (median age, 8.5 years; range, 3.2-17.6 years) received conformal or intensity modulated radiation therapy between 1998 and 2009. The study group included those prospectively treated from 1998 to 2003, using a 10-mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003, yielding 2 groups of patients: those treated with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and frequency of weekly surveillance magnetic resonance (MR) imaging during radiation therapy. Median follow-up was 5 years., Results: There was no difference between progression-free survival rates based on CTV margins (>5 mm vs ≤5 mm) at 5 years (88.1% ± 6.3% vs 96.2% ± 4.4% [P=.6386]). There were no differences based on planning target volume (PTV) margins (or combined CTV plus PTV margins). The PTV was systematically reduced from 5 to 3 mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race (P=.0175), no requirement for cerebrospinal fluid shunting (P=.0066), and number of surveillance imaging studies during treatment (P=.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression., Conclusions: These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating the differences in outcome based on host factors to explain the results., (Copyright © 2013. Published by Elsevier Inc.)

Malignant transformation of craniopharyngioma is a rare event; only 3 cases have been reported in children, all in the Japanese literature. The authors describe 2 additional pediatric cases. Treatment in both of these cases consisted of multiple resections and external beam radiation therapy (EBRT). Malignant transformation occurred 7 and 8 years after EBRT. The authors also review another 6 cases in adults. A possible causative association with radiation therapy is discussed. As radiation is currently an important option in the management of craniopharyngiomas, this association requires further study.

Object: A Phase II trial of conformal radiation therapy (CRT) for craniopharyngioma was conducted to determine whether the irradiated volume could be safely reduced to decrease effects on cognitive function., Methods: Between July 1997 and January 2003, 28 pediatric patients (median age 7.3 +/- 4.12 years) received CRT in whom doses (54-55.8 Gy) were administered to the gross tumor volume (solid and cystic components) surrounded by a 1-cm clinical target volume margin. Patients were evaluated serially with neuropsychometric testing. Statistical analyses were performed to determine the effect of clinical factors and radiation dosimetry on intelligence quotient (IQ). The median follow-up period was 36.6 months (range 24.4-80 months). The estimated 3-year progression-free survival rate was 90.3 +/- 7.3%. Three patients experienced local disease progression. Cognitive outcome for patients was adversely affected by the following factors: age younger than 7.4 years (p = 0.001), an interval between symptoms and diagnosis of more than 73 days (p = 0.06), more extensive surgery (p = 0.014), multiple surgical procedures (p = 0.002), diabetes insipidus (p = 0.02), hydrocephalus at diagnosis (p = 0.009), a cerebrospinal fluid shunt (p = 0.005), shunt revisions (p = 0.01), Ommaya reservoir laterality (p = 0.005), and cyst aspirations (p = 0.02). The percentage of total brain, supratentorial brain, or left temporal lobe volumes receiving a dose in excess of 45 Gy had a significant impact on longitudinal IQ., Conclusions: The use of CRT with a 1-cm margin for clinical target volume results in tumor control equivalent to that achieved using conventionally planned radiation therapy. Surgical morbidity and a volume-receiving dose more than 45 Gy are factors affecting longitudinal IQ after CRT in patients treated for craniopharyngioma.