Patient position , immobilisation, and reproducibility of position for daily treatment are important considerations when planning external-beam radiation. For the treatment of a craniopharyngioma, patients are typically in the supine position and immobilised using a face/head mask with or without a bite plate to reduce intra- and interfraction motion (Fig. 3). Patients undergo a CT simulation scan with a slice thickness of 1–2 mm. Marks on the mask in conjunction with triangulating lasers in the room are used for the daily alignment of the patient for treatment. Daily image guidance is recommended to minimise set-up uncertainties. Cone-beam CT , when available, provides robust image guidance. For proton therapy , daily image guidance is currently performed with orthogonal kV X-rays typically aligned to bony landmarks of the skull (Fig. 4). Digital radiographic reconstructions (DRRs) generated from the CT simulation images are used to reproduce the position set during CT simulation. As bone development is incomplete in the prepubertal age group, bony landmarks may be suboptimal for daily patient alignment in this age group [30]. As a result, some institutions recommend placement of four small titanium fiducial markers prior to proton radiotherapy for these young patients to assist in optimal daily alignment. In addition, daily patient set-up can be aligned to existing surgical hardware when present.

In the delivery of proton therapy, patients undergo a CT simulation scan with a slice thickness of 1 mm. A similar set-up is used for fractionated stereotactic radiotherapy and stereotactic radiosurgery. Young children may require a general anesthetic for CT simulation as well as for each fraction of radiation treatment delivery.

Target volumes are defined on the CT simulation images. Diagnostic high resolution MR (1–1.5 mm slice thickness) T1 and T2 weighted post contrast and FLAIR sequences are used, with image fusion to the planning CT images for accurate delineation of targets and organs at risk. Calcifications seen on the CT scan also help define the gross tumour volume (GTV). The gross tumour is expanded by 5 mm to obtain the clinical target volume (CTV), which may be subsequently enlarged to encompass any surface originally in contact with the tumour, or decreased based on anatomical constraints. A further 3–5 mm institution specific margin is added to the CTV for set-up uncertainty to establish the planning target volume (PTV). A 10-mm CTV margin is known to be adequate [31]. Other data showed no difference in progression-free survival at 5 years between those treated with a >5 mm versus ≤5 mm CTV margin [32]. An ongoing phase II protocol (RT2CR) at the University of Florida in collaboration with St. Jude Children’s Research Hospital is examining the efficacy of limited surgery, proton therapy, and a limited margin (5 mm CTV) for craniopharyngioma. Cyst enlargement during radiation is well recognised and, therefore, early, regular surveillance and adaptive planning are recommended (Fig. 5) [33–35].

In addition to the treatment target volumes, normal tissues or organs at risk are contoured as avoidance targets, including the optic chiasm, optic nerves, brainstem surface, brainstem core, bilateral retinae, lens, bilateral cochlea, lacrimal glands, temporal lobes, hippocampal head and tail bilaterally, pituitary, hypothalamus , bilateral mastoid air cells, posterior nasopharynx, scalp, and supratentorial brain.

The standard dose for the treatment of craniopharyngioma with fractionated external beam radiotherapy is 54 Gy at 1.8 Gy per fraction, and a range from 50 to 60 Gy has been reported in the literature [16, 18, 24, 36].

Conventional external-beam radiotherapy , the most common type of radiation used worldwide, is delivered in the form of photon beams (X-rays) using linear accelerators. The total dose of radiation is usually delivered over a fractionated course of 1.8–2 Gy per fraction, each day, allowing for normal tissue repair between fractions. Normal tissue tolerance to radiotherapy along with the therapeutic dose required to adequately treat the tumours guide radiotherapy design. The fundamental principle of radiotherapy is to deliver a therapeutic dose to the target volume while minimising the dose to adjacent normal structures. The tolerance dose of the brainstem is 54–59.4 Gy and that of the optic nerves and chiasm is 55–60 Gy [37]. Sensitivity of the pituitary’s endocrine function varies with growth hormone demonstrating the highest sensitivity (QUANTEC) [38]. These goals are achieved by incorporating modern techniques in the radiotherapy planning process, such as the use of three-dimensional (3D) imaging including CT and MRI to assist with target volume and normal structure delineation, reproducible patient immobilisation, and enhanced precision delivery techniques like image guidance.

A 3D conformal plan to treat craniopharyngioma is typically delivered using non-coplanar beams shaped by a multileaf collimator. A common beam arrangement consists of a superior oblique beam arrangement and opposing lateral or posterior oblique beams (Fig. 6).

Rajan et al. reported one of the largest and earliest series of patients treated with limited surgery and external-beam radiotherapy for craniopharyngioma [16]. Of the 173 patients, 22 received radiotherapy alone. At a median follow-up of 12 years, the 10- and 20-year PFS rates were 83% and 79%. The 10- and 20-year overall survival rates were 77% and 66%. Age (<40 years old) and use of modern techniques were found to be significant independent positive prognostic factors for survival. Other prognostic factors that influenced outcome was extent of surgery, radiation dose of <55 Gy, and treatment prior to the routine use of diagnostic CT scans (between 1961 and 1974) [19].

A smaller series from Philadelphia [39] with 19 paediatric patients showed a higher 20-year survival rate for those treated for primary disease (78% versus 25%) compared to those treated for a recurrence [24]. Overall, the 20-year survival rate was 62%. In addition, surgical extent, radiation dose (≤54 Gy vs ≥54 Gy with a recurrence rate of 50% in those receiving <54 Gy and 15% in those receiving >54 Gy), and treatment prior to the routine use of CT scans (between 1961 and 1974) appeared to have a major influence on patient outcomes.

Another large retrospective analysis included 61 children treated between 1979 and 1990 [18]. Among them, nine children were treated with radiotherapy alone, 15 with surgery alone, and 37 with both surgery and radiotherapy to a median dose of 5464 cGy. At a median follow-up of 10 years (range, 2–20.5 years), the 10-year actuarial overall survival rate was 91% for all patients. The 10-year actuarial freedom from progression rate for the surgery group was 31% compared with 100% for the radiation-alone group and 86% for the patients treated with surgery and radiotherapy at diagnosis. This study established tumour size greater than 5 cm to be an important predictor of local recurrence.

IMRT uses multiple small beamlets of different intensities to treat the target volume by precisely sculpting the high-dose volume around complex target shapes, thereby significantly reducing the dose to adjacent organs at risk. IMRT is delivered using either a dynamic or static multileaf collimator or by a multileaf intensity-modulating collimator using rotational arc therapy (such as RapidArc or volumetric arc therapy). IMRT can significantly reduce the dose to adjacent organs at risk due to its ability to conform the high dose to complex shapes. However, the cost of the conformal high dose is an increased low dose exposure of surrounding normal tissue due to the multiple beams or arcs used to achieve the conformal high target dose (Fig. 7).

In a retrospective review of 24 children treated with IMRT, the 5- and 10-year PFS rates were 65.8% and 60.7% [40]. The 5- and 10-year cystic PFS rates were 70.2% and 65.2%, respectively. The solid PFS rates were no different at 90.7%. Half of these patients had received radiotherapy as salvage therapy for disease progression on imaging following initial surgical treatment. Dynamic cyst changes, both expansion and reduction (range, −20.7% to 82%), can occur during radiotherapy [33] and warrant adaptive planning based on surveillance weekly MRI. Adaptive targeting allows for both target volume coverage and the limiting of dose to adjacent critical structures such as the optic chiasm, which is particularly relevant when a smaller CTV is used with modern techniques. Compared to traditional conformal RT (CRT) using a 5-mm CTV margin and 3-mm PTV margin, IMRT with similar margins reduced the mean dose to the cochlea from 18.2 to13.3 Gy (p < 0.001), temporal lobes from 14.3 to 7.9 Gy (p < 0.001), and hippocampus from 26.8 to17.6 Gy (p < 0.001). Although IMRT plans are more susceptible to the effects of dynamic cyst changes compared to 3D–conformal plans, IMRT is favoured to reduce the dose to critical structures when weekly surveillance imaging is available [33].

Fractionated stereotactic radiotherapy combines the precise dose delivery of stereotactic radiosurgery through noninvasive immobilisation with the radiobiological advantage of fractionation, enabling the treatment of tumours that may be too large for stereotactic radiosurgery [41]. A study on stereotactic fractionated radiotherapy included 39 patients with a median age of 18 years (range, 3–68 years) treated with stereotactically guided conformal radiotherapy of 30–33 daily fractions over 6 to 6.5 weeks to a total dose of 50 Gy using 6-MV photons. All patients had previously undergone one or more surgical procedures. The 3- and 5-year PFS rates were 97% and 92%. The 3- and 5-year overall survival rates were 100%. Two patients required debulking surgery for progressive disease at 8 and 41 months. Twelve patients (30%) experienced acute clinical deterioration secondary to cyst enlargement and required cyst aspiration. Seven patients with normal pituitary function prior to radiotherapy had no deficits following radiotherapy at a median follow-up of 40 months. One patient with severe visual impairment before radiotherapy deteriorated and lost vision after radiotherapy.

Long-term outcomes from another study report local control rates of 95.3%, 92.1%, and 88.1% at 5, 10, and 20 years, respectively, with a median follow-up time of 128 months (range, 2–276 months) after stereotactic fractionated radiotherapy to a dose of 52.2 Gy (range, 50–57.6 Gy) at 1.8 Gy per fraction [42]. The overall survival rate at 10 and 20 years was 83.3% and 67.8%, respectively. This study included 55 patients with a median age of 37 years (range, 6–70 years) treated between 1989 and 2012, 8 of whom were younger than 18 years old. Toxicities reported included 1 patient with complete anosmia and 1 patient with further deterioration in vision. Of note, neuropsychological testing was not performed.

Protons are positively charged particles with a unique property of depositing their maximum energy in tissue shortly before they come to rest [43]. Therapeutic proton beams are generated from a cyclotron, a type of particle accelerator, to attain the desired energy and thus the desired depth of penetration. As protons enter and travel through tissue, they deposit little dose until their maximum depth is reached, at which point they deposit dose in a characteristic sharp, narrow distribution called the Bragg peak. As protons come to rest abruptly after the Bragg peak, the “exit dose,” or dose distal to the target, is eliminated. This lack of dose deposition beyond the target lies in contrast to photons, where additional dose is deposited beyond the target as the beam exits the body beyond the distal aspect of the target. A range of energies is used to create a spread-out Bragg peak (SOBP) . The SOBP allows dose deposition over a greater length of tissue, resulting in high dose to the entirety of the target volume. This unique property of protons results in the primary clinical advantage of decreased normal tissue exposure and thereby reduced toxicity (Fig. 8).

Protons, like photons, are an ionising radiation with a low linear energy transfer. The relative biologic effectiveness (RBE) of protons is approximately 1.1; therefore, unlike heavy ion therapy, which also eliminates the exit dose but carries a high linear energy transfer, protons and photons have a similar and more predictable impact on normal tissue.

The primary benefit of proton therapy in the treatment of craniopharyngioma is a decrease in the undesired dose to adjacent critical structures and lower integral dose while maintaining adequate dose to the tumour. This decreased dose to surrounding critical structures is expected to translate into fewer acute and late toxicities from radiotherapy . The reduction in late toxicity is particularly relevant in this predominantly childhood tumour where durable local control is achievable (Fig. 9).

This advantage of proton therapy possible through exploiting the Bragg peak has been evaluated in multiple dosimetric studies. A study of ten paediatric craniopharyngioma patients compared three-dimensional conformal proton therapy, IMRT, and intensity-modulated proton therapy (IMPT) [44]. Coverage of the PTV was adequate for all modalities. The IMRT and IMPT plans were the most conformal, but offered a less homogenous dose distribution. 3D conformal proton and IMPT plans allowed a relative reduction in the integral dose to the hippocampus, dentate gyrus, subventricular zone, vasculature, infratentorial and supratentorial brain, brainstem, and whole brain. Another study on 14 patients with craniopharyngioma compared double-scatter proton therapy, IMPT, and IMRT [45]. Conformality index was higher with IMPT and IMRT. Heterogeneity and the dose to organs at risk, such as the cochlea, optic chiasm, and brain, was lower with double-scatter proton therapy.

Decreasing the integral dose with proton therapy should decrease the incidence of radiation-induced tumours. According to the Childhood Cancer Survivor Study assessing all types of tumours, the cumulative incidence of a second malignancy at 30 years after diagnosis was 7.9% [46]. The relative risk of a second malignancy in patients treated with radiotherapy was 2.7. A 2- to 15-fold decrease in the rate of second malignancies with proton therapy compared to photon radiotherapy was demonstrated [47].

Another potential means to reducing the integral dose with the use of proton therapy is through the development of cognitive dose models to allow predictive comparison of outcomes. Based on one such longitudinal model in patients with craniopharyngioma, a diminution in intelligence quotient (IQ) was noted in younger patients (5 years vs 9 years) and with the use of photons compared to double-scatter proton therapy [48]. A large prospective study of 70 craniopharyngioma patients who underwent cognitive testing at baseline, 6 months, after radiotherapy, and then annually for 10 years demonstrated an association of longitudinal IQ with mean whole-brain radiation dose and time with a loss of 0.0027 points/cGy/year [32]. Table 1 summarises current evidence of outcomes from proton therapy for patients with craniopharyngioma.

Early reports on the use of proton therapy in craniopharyngioma primarily include patients treated with a combined proton-photon technique. In one analysis of 15 patients treated between 1981–1988, one-third of the cohort was treated with proton therapy alone and two-thirds with a combined technique [49]. The analysis included five children and ten adults. Due to a change in the calibration for proton dosimetry in 1997, the dose delivered was recalculated and found to be 6.5% greater than the prescribed dose. The median delivered dose was 55.6 Gy (RBE) for the paediatric patients and 62.7 Gy (RBE) for the adult patients. Proton dose contribution to the total dose in those who underwent a combined treatment was 47% (median dose, 26.9 Gy [RBE]). All treatments were delivered using the same non-coplanar three-field technique with two lateral beams and one superior oblique field. The actuarial 5- and 10-year survival rates observed were 93% and 72%, respectively. The 5- and 10-year local control rates were 93% and 85%, respectively. No paediatric patients experienced tumour progression. These findings were further substantiated by data from the same institution in a report of 24 children who underwent proton therapy for biopsy-proven craniopharyngioma to a median dose of 52.2 Gy (RBE) (range, 52.2–54 Gy [RBE]) between 2001 and 2007 [50]. The local control, PFS, and overall survival rates were 100%, 100%, and 94%, respectively, at a median follow-up of 45 months (range, 3–95 months).

In a study by Luu et al., proton therapy was utilised as salvage therapy in 16 patients who had undergone primary radical resection [51]. Of these, seven patients underwent more than one surgical resection. Nine others underwent one resection. Four of these received adjuvant proton therapy, five were treated with proton therapy at recurrence. One patient was lost to follow-up. At a mean follow-up of 60.2 months (range, 12–121 months), local control was achieved in 14 patients and only one patient had a relapse at 80 months.

Alapetite et al. reported on 49 patients with craniopharyngioma, 39 of whom were treated with protons alone and ten with a combination of protons and photons between 1994 and 2009. At a median follow-up of 53 months (range, 24–156 months), five patients experienced disease relapse, one of which occurred along the surgical access route after 56 months; the other four were cystic relapses at a median time of 43 months (range, 3–68 months) [52].

Indelicato et al. from the University of Florida reported early clinical outcomes in a retrospective analysis of 40 children with a median age of 7.8 years (range, 1.5–19.3 years) treated with double-scatter proton therapy from 2008 to 2012. Of these children, 35 received 54 Gy (RBE) (range, 50.4–54 Gy [RBE]). At a median follow-up of 0.7 years (range, 0.1–3.7 years), the solid tumour control and survival rates were 100% [53].