Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group

Abstract

Background

Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized.

Methods

The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively.

Results

Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment.

Conclusions

Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Craniopharyngioma is a histologically benign tumor derived from embryologic remnants of Rathke’s pouch that accounts for 4% of all central nervous system tumors.¹ Most craniopharyngiomas arise at or near the sella turcica and commonly lead to the pituitary and hypothalamic dysfunction, visual disturbance, and headache. Though survival is rarely limited by craniopharyngioma directly, secondary effects of both tumor and treatment often lead to life-long disability and, in some cases, premature death.^2–4 Notable morbidity includes hormonal and metabolic dysfunction, visual and neurocognitive deficits, and vascular injury that negatively impact the physical health and psychosocial functioning of survivors.⁴ In recent years, surgical, radiation oncology, and medical oncology communities have increasingly focused on functional preservation, particularly related to extent of tumor resection and delayed use of radiotherapy (RT), especially in young children.

Standard management includes surgical resection with or without RT. A complete resection is often favored for tumors that lack hypothalamic involvement. For tumors that involve the hypothalamus, subtotal, and hypothalamus-sparing resection followed by focal RT is often recommended. Medical management has historically been limited, though a greater understanding of craniopharyngioma biology has led to the recent introduction of potentially beneficial targeted and/or immunomodulatory agents. Intra-cystic therapy is also uniquely relevant to craniopharyngioma, particularly for the more common cystic adamantinomatous type.

Specific challenges exist for response assessment, including the distinct behavior of solid versus cystic tumor components in response to therapy. Additionally, greater acknowledgment of long-term morbidity, especially in the setting of excellent overall survival, has lent credence to integrating functional parameters for response assessment, similar to pediatric low-grade glioma (LGG).⁵ Use of Ommaya reservoirs for cyst drainage or instillation of cyst-directed therapy also imparts unique challenges for clinical trial design and response definitions.

We formed an international committee of pediatric experts in neurosurgery, radiation oncology, medical oncology, ophthalmology, endocrinology, neurology, and neuroradiology to devise the Response Assessment in Pediatric Neuro-Oncology (RAPNO) consensus recommendations for craniopharyngioma in children. The committee met multiple times to define important questions related to response assessment. Assignments were divided amongst committee members, who based on available medical literature and expert opinion, created consensus recommendations.

Specific Issues and Challenges With Response Assessment in Pediatric Craniopharyngioma

Disease Classification

Craniopharyngioma consists of 2 distinct tumor types: Papillary and adamantinomatous. Papillary craniopharyngioma is almost exclusively restricted to adulthood and characteristically harbors the BRAF^V600E driver mutation. Adamantinomatous craniopharyngioma predominates in children and adolescents and is characterized by CTNNB1 mutation in a subset of cells, which may lead to WNT-pathway activation. Overexpression of cytokines, most notably interleukin-6, have been implicated in the pathogenesis of adamantinomatous craniopharyngioma.⁶ Both papillary and adamantinomatous craniopharyngioma are classified by the World Health Organization as grade 1 tumors.⁷

Unique Patient Population

Craniopharyngioma arises in approximately 0.5–2.5 per million persons annually and exhibits a bimodal age distribution with the peak incidence in children between 5–15 years ^8-10 Craniopharyngioma often presents with headache, vision disturbance, and pituitary and hypothalamic dysfunction secondary to its characteristic suprasellar location. Given the benign histopathology, metastatic spread is rare. Genetic susceptibility to craniopharyngioma has not been identified, though rare cases have been described in association with germline APC mutation in which craniopharyngioma is often ectopically located.¹¹ Prognostic relevance of clinical factors, including age, and sex, has not been consistently demonstrated; however, incidence has been reported to be highest in African Americans with some literature supporting worse outcomes in this population.^8,12 The relative rarity of craniopharyngioma has made performance of clinical trials in homogeneous populations difficult.

Functional Deficits

Craniopharyngioma, based on its location, most frequently affects pituitary, hypothalamic, and/or visual function. Hypothalamic function, the key to appetite control and metabolic homeostasis, is often irrevocably damaged by tumor involvement and/or radical tumor resection. Similarly, pituitary insufficiency, common at diagnosis, is often made worse by surgery and/or RT. Few patients have an intact pituitary function after diagnosis and treatment and patients often present with some degree of vision disturbance. Several retrospective studies have defined long-term visual implications of this disease,^13,14 though no prospective assessment of visual endpoints has been undertaken. While no craniopharyngioma-specific vision assessment guidelines exist, measures defined by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration may be applied.^15,16 Survivors of craniopharyngioma also commonly experience psychosocial and neurocognitive consequences, including development of therapy-related vasculopathy.^17–19

Current Imaging Assessment in Clinical Trials for Pediatric Craniopharyngioma

Magnetic resonance imaging (MRI) is the modality of choice for preoperative evaluation and long-term follow-up of patients with craniopharyngioma.²⁰ If CT is performed prior to MRI, identification of calcifications within a suprasellar lesion strongly suggests the diagnosis of craniopharyngioma. If MRI is obtained initially and findings are consistent with a craniopharyngioma, performing a CT may be unnecessary. If, however, a lesion’s appearance is nonspecific, CT may narrow the differential diagnosis and can be useful to define residual tumor after resection.¹⁰

Recommendations for Imaging Assessments in Clinical Trials for Pediatric Craniopharyngioma

Baseline Imaging and Frequency of Surveillance

Whenever possible, patients with suspected craniopharyngioma should undergo presurgical whole brain MRI with a detailed evaluation of the suprasellar region. Baseline spine imaging is not routinely advised given very low incidence of tumor dissemination. Postoperative MRI, performed within 2 weeks after tumor resection, should be considered baseline imaging for response evaluation except for biopsy of a solid tumor portion (without cyst fenestration) for which preoperative imaging may be considered baseline. If cyst dynamics are likely to have changed because of surgical intervention, a new postoperative MRI should be obtained and considered the baseline. Follow-up MRIs should be performed using a similar protocol to facilitate evaluation of residual or recurrent disease.

If a patient is undergoing adjuvant therapy, treatment should ideally commence within 4–6 weeks of the baseline MRI. Longitudinal imaging after baseline studies should be performed approximately every 3 months while on therapy to assess ongoing disease response.

Magnetic Resonance Imaging Specifications for Pediatric Craniopharyngioma

Minimum recommended sequences for the baseline MRI are defined in Table 1. A comprehensive evaluation of the suprasellar region should be performed with a small field-of-view, high in-plane resolution, and multiplanar spin echo images without and with contrast.²¹ At a minimum, the protocol should include targeted sagittal/coronal T2-weighted images, sagittal/coronal T1-weighted images without contrast, and post-contrast T1-weighted images in the sagittal and coronal planes with a slice thickness of ≤3 mm and no interslice gap, if feasible. These targeted acquisitions allow for optimal tumor characterization and systematic evaluation of the involvement of adjacent structures (e.g., optic pathway, hypothalamus, and internal carotid arteries). In the experience of the RAPNO committee, required sequences for craniopharyngioma assessment do not require special approval for payment, as these are considered standard of care.

Table 1.

Recommended Imaging Sequences and Parameters for Assessment of Pediatric Craniopharyngioma

Sequence	Slice Thickness (mm)	Gap %	In-Plane Resolution (mm)	Comments	Acquisition Time:
Focused suprasellar imaging
Sagittal 2D T1 TSE/FSE	≤3	0*	0.4 × 0.4		4 min
Coronal 2D T1 TSE/FSE	≤3	0*	0.4 × 0.4		4 min
Sagittal/coronal 2D T2 TSE/FSE	≤3	0*	0.4 × 0.4		4 min
Whole-brain imaging
3DT1-weighted MPRAGE/SPGR/FFE/TFE	1-1.5	0*	1 × 1	Native acquisition can be in the sagittal, coronal, or axial plane and reformatted into the others
Axial 2D T2 TSE/FSE	≤4	0*	≤ 1 × 1		6 min
Axial 2D T2 FLAIR TSE/FSE	≤4	0*	≤ 1 × 1	At least one FLAIR acquisition is required. Individual institutions can choose to perform pre-contrast, post-contrast, or both.	2 min
Axial DWI (b = 0, 1000)	≤4	0*	2 × 2	Images should include the Trace diffusion image and the estimated ADC Axial DTI with higher number of directions	2 min
Gadolinium-based contrast agent administration
Focused suprasellar imaging
Sagittal 2D T1 TSE/FSE + C	≤3	0*	0.4 × 0.4		4 min
Coronal 2D T1 TSE/FSE + C	≤3	0*	0.4 × 0.4		4 min
Whole-brain post-contrast imaging
3DT1-weighted MPRAGE/ SPGR/ FFE/ TFE + C	1–1.5 mm	0*	1 × 1	Native acquisition can be in the sagittal, coronal, or axial plane.	6 min
Or axial 2D T1 TSE/FSE + C	≤4	0-10%	≤ 1 × 1		2 min
Optional
Axial 2D T2 FLAIR TSE/FSE + C	≤4	0*	≤ 1 × 1	Institutions may choose to acquire only pre-contrast FLAIR.	2 min
Sagittal CISS/FIESTA	≤1	0	≤ 1 × 1	Can be replaced with Sagittal SPACE/CUBE/VISTA	5 min
Axial SWI	1.25	0	≤ 1 × 1	Consider in cases without concurrent CT imaging	4 min
“Fast MRI” Sequence
Focused suprasellar imaging
Axial T2 SS-TSE/FSE	≤4	0	0.4 × 0.4		1 min
Coronal T2 SS-TSE/FSE	≤4	0	0.4 × 0.4		1 min
Sagittal T2 SS-TSE/FSE	≤4	0	0.4 × 0.4		1 min

*No gap is preferred whenever possible. The acquisition times provided represent estimates based on the protocols used at the authors’ institutions using a 3 Tesla scanner; these may vary substantially based on a choice of imaging parameters such as number of slices, slice thickness, and use of commercially available acceleration techniques (parallel imaging, simultaneous multi-slice methods, among others).

MPRAGE: magnetization prepared rapid gradient echo imaging, FLAIR: Fluid Attenuated Inversion recovery, TSE: turbo spin echo, FSE: fast spin echo, FF: fast field echo, SPACE: Sampling Perfection with Application Optimized Contrasts, SPGR: SPoiled Gradient-Recalled, TFE: turbo field echo, ASL: arterial spin labeling, ADC: apparent diffusion coefficient, DSC: dynamic susceptibility contrast, DWI: diffusion-weighted imaging, CISS: constructive interference in steady state, FIESTA: Fast Imaging Employing Steady State, VISTA: Volume Isotropic turbo spin echo acquisition, SWI: susceptibility-weighted imaging, +C: contrast-enhanced.

Whole-brain imaging using a larger field of view and more modest spatial resolution is also recommended. This can be accomplished with a 3D-magnetization prepared rapid gradient echo imaging (MPRAGE) before contrast, axial T2 and T2 fluid attenuated inversion recovery (FLAIR) sequences, axial diffusion weighted imaging, and whole-brain post-contrast images with either a 2D T1-turbo spin echo (TSE)/fast field echo or a 3D-MPRAGE. If a 2D TSE is utilized for post-contrast whole-brain imaging, the slices can be thicker than those utilized for the detailed suprasellar evaluation. If sites elect to perform a 3D T1 sequence, this should coincide with the type of sequence used for 3D pre-contrast imaging (generally a 3D-MPRAGE) rather than obtaining imaging with other sequences, such as a T1-sampling perfection with application optimized contrasts (SPACE). While T1-SPACE post-contrast offers the advantage of higher sensitivity for detecting leptomeningeal disease,²² the convenience of a direct comparison to the same pre-contrast sequence outweighs the potential benefits given the low incidence of craniopharyngioma dissemination. There is insufficient evidence to make a specific recommendation regarding performance of pre-contrast versus post-contrast T2 FLAIR. At least 1 whole-brain T2 FLAIR should be performed. There is also insufficient evidence to routinely recommend advanced imaging modalities, including perfusion MRI with arterial spin labeling, dynamic susceptibility contrast or T1 permeability, or MRI Spectroscopy.

Fast MRI Examinations

Abbreviated MRI examinations consisting of rapid acquisitions may be useful for craniopharyngioma follow-up evaluation. The most common pulse sequence utilized in “fast MRIs” is a single-shot fast (or turbo) spin echo T2-weighted sequence²³ that retains sufficient contrast to outline fluid-filled structures and can be used to monitor the craniopharyngioma cysts or ventricular spaces.²⁴ A “fast MRI” (Figure 1) consisting of 3 orthogonal acquisitions of a single-shot T2-weighted sequence is well tolerated, particularly by older children. Evaluation of surrounding brain parenchyma, optic pathway, pituitary gland, hypothalamus, and solid tumor components is limited with “Fast MRI” and should not replace a complete contrast-enhanced examination if required.

Figure 1.

Craniopharyngioma in a 6-year-old boy who presented with new headaches. The upper images show coronal T2-weighted sequences and the bottom row shows coronal T1 post-contrast sequences. (A) MRI at presentation shows a suprasellar mass with cystic components and T2 hypointense enhancing components; severe distortion of the optic pathway was appreciated (not shown). (B) An MRI obtained 4 weeks after the surgery shows gross total resection. Visual acuity 6 months post-resection was 20/40 on right, 20/80 on left, and 20/50 both eyes. Subtle enhancement was detected 1 year after surgery and confirmed to be recurrence on an MRI obtained 18 months after resection (C) due to the enlarging cystic components near the foramen of Monro. An MRI obtained 2 years post-resection (D) showed further growth of the cystic and enhancing components in the foramen of Monro. The patient remained asymptomatic, with stable visual deficits, and diabetes insipidus successfully managed with DDAVP. (E) An MRI obtained 3 years after the original resection in the setting of headaches showed acute hydrocephalus due to obstruction at the level of the third ventricle due to the enlarging craniopharyngioma.

Clinical, Nonimaging Recommendations for Response Assessment for Pediatric Craniopharyngioma

Visual Outcomes

Most children with craniopharyngioma present with vision loss²⁵ and more than half have long-term visual deficits.^13,14 The RAPNO committee recommends baseline and serial vision assessment using REiNS guidelines for all children with craniopharyngioma, regardless of tumor location or extent. Baseline assessment should be performed within 4 weeks of diagnosis. If visual deficits are noted, testing should be repeated 4–6 weeks after upfront surgical intervention, as some vision recovery may be observed after relief of pressure on the optic apparatus or after refractive correction. The best corrected visual acuity (VA) must be used as the baseline. Subsequent vision assessments should be performed up to every 3 months and can be aligned with imaging assessments to provide a comprehensive evaluation of treatment response. Frequency thereafter should be determined by the primary team based on patient-specific risks.

The RAPNO committee supports the integration of VA into response assessment for children with craniopharyngioma (Table 2). Specifically, new or worsening VA loss that cannot be attributed to another cause should be classified as progressive disease (PD) even in the absence of radiological progression. VA should be assessed using Teller Acuity Cards, HOTV testing, or Snellen acuity; decline is defined as ≥ 0.2 log MAR decrease from baseline. If due to age or developmental stage, cooperation is poor, testing should be repeated 1–2 weeks later to verify the best possible result. In instances where VA is decreased (≥ 0.2 log MAR loss) and imaging is stable, VA evaluation should be repeated within 4 weeks to confirm decline. If the repeat examination is stable from baseline, the patient should be classified as having a stable vision. If instead decline is confirmed, the patient should be classified has having had vision loss from the date of the baseline exam.

Table 2.

Response Assessment in Pediatric Neuro-Oncology (RAPNO) Response Criteria for Assessment of Pediatric Craniopharyngioma

	Complete Response	Partial Response	Stable Disease	Progressive Disease
Brain MRI	No evidence of disease compared to the baseline MRI maintained for ≥12 weeks	≥ 50% decrease in the product of the greatest 2 perpendicular diameters of the tumor (solid + cystic) compared to baseline MRI maintained for ≥12 weeks. Response to intra-cystic therapy will be defined by individual clinical trials.	Does not meet criteria for complete response, partial response, or progressive disease	Solid disease: • ≥25% increase in product of the greatest 2 perpendicular diameters of the solid component compared to the baseline MRI or best-recorded response for comparison • New functional impairment attributable to lesser change of the solid component Cystic disease: • New functional impairment attributable to any degree of cystic change • Any cystic change requiring surgical intervention, except within 12 months of RT completion
Neurologic exam	Stable or improving	Stable or improving	Stable or improving	Clinical deterioration not attributable to another cause
Vision exam	Stable or improving	Stable or improving	Stable or improving	Visual acuity decrease of ≥0.2 log MAR from baseline sustained for 4 weeks
Pituitary evaluation	Stable or improving	Stable or improving	Stable or improving	New neuro-endocrine deficit requiring medical intervention

Visual field (VF) testing and optical coherence tomography (OCT) are important tools for vision assessment. VF testing (Humphrey or Goldman method) is validated in children aged≥ 8 years but may be attempted in those as young as age 5 years. Ideally, 2 VF assessments should be undertaken 4–6 weeks apart to validate findings on the initial examination. Reliability depends on indices related to fixation loss, with < 20% being defined as reliable. OCT, a sensitive imaging technique for quantification of retinal nerve fiber thickness, is similarly reliable in most children aged≥8 years and can be assessed in younger children under sedation using a hand-held device. Image signal strength is an objective measure of reliability, with >5 on a scale of 1–10 being considered reliable. OCT has been increasingly utilized in children with sellar/optic pathway tumors,^26,27 and there is increasing evidence that nerve fiber thickness is associated with functional outcomes in children with craniopharyngioma.^27–29 Though patient age and level of cooperation will influence the feasibility of VF testing and OCT, the RAPNO committee strongly recommends the integration of both modalities into visual assessment of children with craniopharyngioma whenever feasible. Additionally, both should be included (with age-appropriate cutoffs and as available at the institutional level) in all prospective clinical trials for pediatric craniopharyngioma.

Pituitary, Hypothalamic, and Metabolic Outcomes

Pituitary and hypothalamic function heavily impact health- and quality of life (QoL)-related outcomes in patients with craniopharyngioma. Hypothalamic function is best evaluated by trending anthropometric measures (height, weight, and body mass index), vital signs, sleep patterns, and behavior. Most rapid weight gain occurs in the first 6–12 months after neurosurgical treatment; this represents a pivotal time for patient and family counseling and possible medical intervention^30–32 to mitigate later metabolic consequences.³³ The RAPNO committee recommends assessment of hypothalamic function at baseline (including height, growth velocity, and symptom history preceding diagnosis) and every 3 months for the first 2 years. The RAPNO committee does not support the integration of hypothalamic function into response assessment since dysfunction is more often caused by tumor and/or initial surgery rather than later therapy, and functional measures are often subjective and may be influenced by other factors. However, hypothalamic function (including long-term outcome measures, if possible) is important to study as a secondary research-focused objective in patients enrolled in prospective trials.

Pituitary dysfunction is very common in children with craniopharyngioma, though a subset maintains at least partial function long-term. The RAPNO committee recommends defining new loss of pituitary function that requires hormone replacement (diabetes insipidus [DI]; or thyroid, growth hormone, or adrenal insufficiency; or hypogonadism) as a marker of PD in select patients (Table 2). Because of variability in upper and lower limits of normal, gradation of the severity of hormone deficiency is not possible; thus, binary “normal/abnormal” designation based on institutional parameters (or specific clinical trial metrics) should be followed. The pituitary function should be assessed pre- and post-operatively and then at a frequency of every 3–6 months. Given the high likelihood of transient peri-operative DI,³⁴ either laboratory values to confirm a diagnosis of DI or continued requirement of desmopressin therapy should be assessed 4–6 weeks after surgery. Recommended laboratory tests for pituitary function include the following: TSH, T4, ACTH, 8AM cortisol, IGF1, IGFBP3, sodium level, and if pubertal age, also DHEAS, LH, FSH, estrogen, or testosterone. “Baseline” pituitary function should be defined based on laboratory values prior to study enrollment or those drawn 4–6 weeks after surgical intervention. Endocrinopathies due to RT effect on the hypothalamus and pituitary is often diagnosed within 2 years from RT, with the majority occurring before 6 years after treatment.³⁵ Given longer evolution of hormone deficiencies following RT, pituitary function should not be considered in response assessment for patients who have undergone RT unless clinical trials evaluating very long-term outcomes are considered.

Defining Radiographic Response for Pediatric Craniopharyngioma

Several characteristics of craniopharyngioma infer unique considerations for response assessment. Craniopharyngioma arises in a single central nervous system location, is nearly always unifocal, and frequently presents with both solid and cystic tumor components. Few prospective trials have been performed for pediatric craniopharyngioma^21,36–38 offering limited precedent on which to base RAPNO response guidelines; thus, most recommendations presented here are derived from expert opinion.

Measurable Disease

The primary sellar/suprasellar tumor is, in most cases, the target lesion. Measurable disease is defined as a lesion ≥10 mm in diameter, or at least 2 times the MRI slice thickness, that is visible in 2 planes. Solid and cystic components of craniopharyngioma are both considered measurable and should be considered jointly regardless of “intrinsic” or “extrinsic” cyst location relative to solid disease; however, response assessment of solid versus cystic tumor may, in certain contexts, be considered separately (Table 2). In published prospective pediatric craniopharyngioma trials, the response has commonly been defined based on linear 2-dimensional measurements; 3D approximations as volumetric estimates have also been incorporated into some trials.^21,36–38 The RAPNO committee supports the continued use of 2-dimensional measurements for response assessment but also strongly recommends obtaining 3-dimensional measurements concurrently in prospective trials to enable future evaluation of the utility of 3D assessment as a surrogate for tumor volume. Automated volumetric assessments, which more accurately capture overall tumor size, have been increasingly employed in clinical practice.^39–42 Given the resource-intensive nature of this task, limited availability of imaging software required for segmentation at some centers, and inadequate literature relating volumetric changes to patient outcome, the RAPNO committee does not recommend routine automated volumetric response assessment for craniopharyngioma. However, prospective collection of volumetric data as a secondary aim is strongly encouraged, particularly for those with endpoints pertaining to cystic change secondary to RT or intra-cystic therapy.^42,43

Solid Versus Cystic Disease

Solid and cystic craniopharyngioma components exhibit distinct natural history and response to therapy, attributable to unique biological factors that drive and maintain these discrete components.^6,44 Solid disease often demonstrates an indolent growth trajectory, while tumor cysts that house a complex inflammatory milieu, may exhibit more precipitous growth and commonly lead to functional impairment. RAPNO guidelines for LGG, high-grade glioma, and diffuse intrinsic pontine glioma define cystic disease as nonmeasurable unless the cyst is nonseparable from the solid tumor component.^6,45,46 Tumor cysts are present in most adamantinomatous craniopharyngiomas. The RAPNO committee recommends that cystic disease be considered in craniopharyngioma tumor measurements regardless of cyst location relative to solid disease; however, cystic changes should only be defined as PD if attributable to a new functional deficit or if it requires therapeutic/surgical intervention, except within 12 months of RT completion (Figure 2 and Table 2). Cystic changes are common in craniopharyngioma without accompanying solid tumor growth. Future individual prospective clinical trials may recommend interventions (observation only in some patients) for isolated cyst enlargements without a new functional deficit as part of regular tumor management and not designate the growth as PD. Cystic disease should, when possible, be reported separately from solid disease in the radiology report, offering measurements of the entire tumor and cysts that can be clearly distinguished. In the case of numerous tumor cysts, the committee recommends bi- and tri-dimensional measurement and reporting of up to 4 of the largest cysts. Factors, such as the influence of RT, are considered separately in response assessment, as described below.

Figure 2.

Multiplanar single-shot T2-weighted sequences in an 11-year-old with recurrent craniopharyngioma who presented to the emergency room with headaches. (A) Axial, (B) Sagittal, and (C) Coronal images allowed for diagnosis of interval enlargement of the known residual cystic components. The acquisition of the three planes was less than 3 minutes.

Cyst Change During and After Radiotherapy

RT often correlates with craniopharyngioma cyst growth. Though potentially transient, a significant number of patients require acute surgical intervention and/or adaptive RT planning to avoid underdosing target structures.^36,47–50 The time following RT completion during which cyst growth may occur despite effective radiation is variable in the medical literature, though the highest incidence is between 3 and 12 months.^49–51 Published trials for pediatric craniopharyngioma have provided leeway for cyst growth during and after RT, even allowing cyst aspiration(s) for functional impairment in some cases.²¹

Practically, “fast MRI” is more cost-effective than a complete MRI and typically does not require sedation. The RAPNO committee recommends weekly “fast MRI” during RT, if feasible, to evaluate cyst dynamics and to determine the need for changes in RT mapping. If logistically challenging (including an inability to obtain payor approval) and/or if sedation is required, MRI assessments during weeks 2 and 4 of RT are recommended. If “fast MRI” is not available or if payor approval cannot be obtained, the committee does not recommend routine CT scans during RT to avoid excess radiation exposure.

Regarding cyst growth following RT, the RAPNO committee recommends that within 12 months of RT completion, cyst growth with or without functional deficits (in the absence of progressive solid disease) will not constitute PD, and cyst intervention (fenestration, craniotomy for resection, or Ommaya catheter placement) is allowed, regardless of the number of interventions required. After 12 months from RT completion, any cyst growth leading to a new functional deficit or that requires surgical intervention would constitute PD. A new MRI obtained at least 12 months from RT completion should be considered the new “baseline” by which to judge cystic PD following RT. Subsequent prospective clinical trials for craniopharyngioma may shed more light on the duration of the impact of RT on cyst evolution.

Assessment of Response After Intra-Cystic Therapy

Cyst-directed therapies, including isotopes,⁵² bleomycin,⁵³ and interferon-alpha⁵⁴ have been investigated in pediatric craniopharyngioma. Challenges for response assessment include (1) changes in cyst size/morphology from cyst fluid aspiration and agent instillation, (2) altered radiographic characteristics of cyst wall and/or fluid from cyst-directed therapy, and (3) defining appropriate timing of response assessment after cyst therapy. In young children or those with predominantly cystic craniopharyngioma, cyst-directed therapy may be used as a means of delaying RT. As such, cyst stability may be considered a positive outcome (versus radiographic response). Since the cystic disease is a frequent culprit of vision loss or neurologic worsening secondary to increased pressure, functional outcome parameters should also be considered.

The RAPNO committee recommends response definitions outlined in Table 2 for patients receiving intra-cystic therapy. Specifically, ≥25% growth of the product of bi-dimensional measurements of solid disease or functional impairment with lesser change to the solid tumor component or attributable to any degree of cyst change would be considered PD. It is challenging to make uniform recommendations about the response of the cyst undergoing directed treatment based on bi-dimensional measurements since published studies have used variable response parameters and the natural evolution of cyst response may be dependent upon the agent instilled. As such, other than the parameters for PD defined above, the RAPNO committee defers the definition of cyst response to the treating physician or study principal investigator (if involving a clinical trial). Strong consideration should be given to classifying cyst stability (or ability to delay RT) as a positive patient/trial outcome measure.

Conclusions

Pediatric craniopharyngioma is a benign tumor for which long-term consequences of disease and treatment are disproportionately severe. Since few children die as a direct result of craniopharyngioma, greater emphasis has been placed on preserving functional outcomes and QoL. Integration of functional outcomes into response assessment is challenging due to a lack of validated tools and late endpoints required for assessments like hypothalamic function that are not practical to integrate into a therapeutic trial. The RAPNO committee for pediatric craniopharyngioma defined specific radiographic and select functional response assessment measures. These guidelines should be validated in future prospective trials and refined as more published literature is compiled. Future aims also include serial monitoring of relevant biomarkers, such as interleukin-6, in serum and cyst fluid, as these may represent important determinants of response.

Funding

None.

Conflict of Interest:

Nothing to declare: V.H., S.K, T.C.H, D.J.D., D.G., B.T., C.J., T.Y.P., A.R., R.M., M.C., F.M., U.B., D.M., H.L.M, S.C., K.E.W., and H.L. Advisory Board: R.P. (AstraZeneca, Novartis, and YM Pharma), L.M.H. (AstraZeneca), Speaker Honorarium: K.M. (Guerbet), Paid Lecture: B.B. (Bayerishe Rontgengesellschaft), Royalties or Licenses: C.L.T. (UpToDate), Grants or Contracts: C.L.T. (Kazia Therapeutics Ltd), C.K. (DAY101, Bristol Meyer Squibb).

Authorship Statement:

Study concept and design: L.M.H., M.C., K.W., C.J. Investigation: all authors. Writing the manuscript: L.M.H., M.C., K.W., C.J.