Given the rarity of craniopharyngiomas, there are currently no evidence-based guidelines and no clear consensus. Craniopharyngioma is most common in children and adolescents [23]. Moreover, surgery and RT are the main treatment strategies [4,5,6]. However, the balance between treatment effectiveness and long-term complications is of great concern for neurosurgeons and radiation oncologists. The hypothesis that PBT is superior to photon therapy has not been rigorously confirmed [17, 21]; however, some reduction in radiotherapy-associated toxicity has been supported by small-sample dosimetry and clinical studies [10, 24]. We analyzed studies on the efficacy and toxicity of PBT for craniopharyngioma. Our systematic review suggests that PBT for craniopharyngioma result in encouraging LC and OS rates with acceptable acute and late toxicities.

In our systematic review (Table 3), most patients with craniopharyngiomas underwent surgical resection before PBT. In addition, seven studies reported reasons for PBT, including definitive RT, postoperative RT, and salvage RT (Table 3) [15, 16, 18,19,20,21,22]. Previous studies have revealed that patients who undergo GTR and STR combined with RT may achieve survival outcomes similar to those who undergo GTR [5, 6]. Zhang reported the survival results regarding GTR, RT, and STR + RT in 1218 cases of craniopharyngioma [25]. The results suggested that there was no significant difference in the OS or cause-specific death in patients receiving GTR, RT, and STR + RT (P > 0.05) [25]. Although these data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, more data are required to validate these findings [25]. A meta-analysis of recurrence rates for craniopharyngiomas showed that although the recurrence rates favored GTR, the difference in recurrence risk between GTR and STR + RT was not significant [6]. In that study, the recurrence rates regarding GTR, STR + RT, and STR were 17%, 27%, and 45%, respectively [6]. The risk of developing recurrence was not significant for GTR vs. STR + RT (odds ratio [OR]: 0.63, 95% CI: 0.33–1.24, p = 0.18) [27]. However, the recurrence risk regarding GTR vs. STR and STR vs. STR + RT were significant, which were (OR: 0.24, 95% CI: 0.15–0.38) and (OR: 0.20, 95% CI: 0.10–0.41), respectively [6]. Based on these findings, there may be no significant difference in survival and recurrence risk between GTR and STR + RT. Therefore, neurosurgeons should seek a balance between efficacy and complications when determining surgical strategies for GTR and STR to avoid substantial treatment-associated long-term morbidity [5, 6, 25]. For patients inoperable or with a moderate or high surgical risk associated with the nerves and/or vascular structures, we recommend limited surgical removal and postoperative RT to balance the incidence associated with optimal tumor control and treatment.

In recent years, with the increasing application of PBT in children with central nervous system tumors, encouraging clinical results have been reported. Some radiation oncologists believe that PBT may become the radiotherapy strategy of choice for craniopharyngiomas in the future [26, 27]. In our systematic review, the meta-analysis revealed that the LC rates at 3 and 5 years were 99% and 93%, respectively (Fig. 2). After 3 and 5 years of PBT, the OS rates for craniopharyngiomas were 100% and 100%, respectively (Fig. 3). PBT is currently performed in only a few clinical centers, whereas XRT is conducted in many clinical institutions. However, whether PBT for craniopharyngioma can improve survival outcomes compared with conventional photon RT remains an interesting question. Merchant et al. compared the clinical outcomes of PBT and XRT for craniopharyngioma. They found that the survival associated with PBT was slightly better than that associated with XRT; however, the difference was not significant [17]. The study included 94 patients with craniopharyngiomas treated with PBT, with 3-year and 5-year progression-free survival (PFS) of 96.8% (95% CI: 90.4–99.0) and 93.6% (86.3–97.1), respectively; and 101 patients treated with XRT, with 3-year and 5-year PFS of 96.0% (95% CI: 89.7–98.5) and 90.0% (82.2–94.5), respectively [17]. Similarly, Friedrich et al. obtained similar results [21]. Ninety-nine patients with craniopharyngioma were enrolled in the study, 64 of whom received PBT and 35 received XRT. The 5-year event-free survival (EFS) rates after PBT and XRT were comparable (92% ± 4% vs. 91% ± 4%, p = 0.42) [21]. Bishop et al. compared the clinical outcomes of PBT and XRT for craniopharyngioma. They found that the survival associated with XRT was slightly better than that associated with PBT; however, the difference was not significant [15]. Fifty-two patients with craniopharyngioma were enrolled in the study, 21 of whom underwent PBT, and 31 underwent XRT. The 3-year nodular failure-free survival (NFFS) rates after PBT or XRT were comparable (91.7% vs. 96.4%, p = 0.546). Moreover, the 3-year OS rates after PBT or XRT were comparable (94.1% vs. 96.8%, p = 0.742) [15]. These results suggest that PBT does not affect survival outcomes for craniopharyngioma compared with XRT. However, the utilization of both radiation techniques differed over time, with PBT being more predominant at the end of the inclusion period. Therefore, a bias through other evolving techniques in XRT cannot be excluded [21]. In addition, this was only a 5-year follow-up study, and results of follow-ups of 10 years or more need to be determined in the future.

Regarding the median total dose of PBT for craniopharyngioma, the initial results were relatively conservative at 50.4 Gy (RBE) (Table 4) [15]. In recent years, as reported by several research centers, the median total dose was mostly 54 Gy (RBE), and the most common fraction dose was 1.8 Gy (RBE) (Table 4) [17,18,19,20,21,22]. To our knowledge, there are two different clinicopathological variations of craniopharyngiomas: classic adamantinomatous and papillary subtypes [28]. The papillary subtype occurs predominantly in adult patients, accounting for about 14–50% of tumors in this age group [6, 28]. Calcification is rare in this histopathological type, and tumor boundaries are usually marked, with less peripherally invasive growth than in the adamantinomatous type [29]. Based on the differences in the clinical treatment and clinical outcomes of craniopharyngiomas in children and adults [29], the dose pattern of PBT should be further explored in future studies. Individualized PBT for craniopharyngiomas is a problem worth discussing further.

In our systematic review, acute and late toxicities after PBT for craniopharyngiomas were mainly grades 1 and 2, respectively (Table 4) [15,16,17,18,19,20,21,22]. Acute toxicity grade 3 (including blood and lymphatic system disorders) was observed in two studiesy, and the incidence rate was 1–4% [17, 19]. Late toxicity grade 3 (fatigue, headaches, vision disorders, weight gain, vascular disorders, endocrine disorders, nervous system disorders, psychiatric disorders, and others) was observed in two articles, with an incidence of 6–6.3% [17, 22]. Moreover, grade 4 late toxicity (hypernatremia, eye disorders, sepsis, and hyponatremia) was observed in one study, with an incidence of 2% [17].

Compared to conventional XRT, PBT has superior radiophysical properties [9,10,11]. It can deposit the majority of the dose in the “Bragg peak” region, providing a more favorable dose distribution than photons [9,10,11]. The expected benefit of PBT in patients with craniopharyngioma may be attributed primarily to the reduction in the integral dose around the normal brain tissue, which is specific to PBT. A dosimetric comparison between PBT and XRT treatment regimens in children with craniopharyngioma showed that PBT was administered at lower doses to important structures, such as the hippocampus, subventricular area, and vascular system [10]. In addition, Merchant et al. (2008) revealed that PBT may help lower the irradiation dose to the temporal lobe and cochlea, reducing the risk of cognitive ability and hearing loss [30]. However, another dosimetric comparison of the treatment plans demonstrated no relevant differences in radiation doses to the hypothalamus or pituitary gland between PBT and XRT [21].

Merchant et al. analyzed the toxicities associated with PBT and XRT in craniopharyngiomas. PBT did not show significant improvement in hypothalamic- or pituitary-related toxicity compared to XRT. However, improvements in cognitive function in children may be one of its advantages [17]. Studies have shown that the main benefit of PBT for craniopharyngioma is improved neurocognitive function [31]. Toussaint et al. compared the cognitive test results from two prospective trials in 2017, including PBT (NCT01419067) and XRT (NCT00187226), for craniopharyngiomas in children [32]. When the normal brain radiation dose distribution was analyzed, the academic achievement scores (reading and math) for craniopharyngioma did not change significantly after PBT, whereas patients treated with XRT showed a significant decline [32]. It is worth noting that the relationship between dose restriction in the temporal lobe and hippocampus and memory decline is still debated [33,34,35]. Based on Gondi et al.’s study, hippocampal dose restriction (D40% < 7.3 Gy) may be associated with the preservation of memory and quality of life [35, 40].

In our systematic review, five studies reported the cystic dynamics of craniopharyngiomas (Table 4) [15, 17,18,19,20], which may be related to treatment replanning, toxicity, and prognosis. Studies have shown that after XRT for craniopharyngioma in children, the cyst/tumor expansion rate is approximately 11–64% [9, 37]. In Winkfield’s study involving 17 children with craniopharyngiomas, six (35%) developed significant cystic changes during PBT, including one patient who required a modified treatment plan [38]. Merchant et al. reported 14 cases of children with craniopharyngiomas who developed cyst growth during PBT treatment. Eight patients required replanning, four required cyst drainage, and two required replanning and drainage [17]. Ajithkumar et al. reported five cyst growths during PBT treatment, in which two patients required replanning and cyst drainage [20]. In addition, studies by Bishop and Rutenberg et al. reported cyst growth during PBT, with some patients requiring replanning [15, 18]. Notably, cyst shrinkage occurs during RT, and revision of the RT plan may be necessary [15]. Evidence suggests that cyst enlargement may occur after RT. Early cyst expansion rates have been reported to be 40–60% within 6 months of RT completion [15, 37, 39, 40]. Fortunately, craniopharyngioma cyst growth after RT is usually transient, and if the patient remains asymptomatic, most cases require only close clinical and radiographic follow-up without surgical intervention [37, 39, 40]. One study revealed a lower rate of cyst change during and after PBT compared to photons [15]. However, it is unclear whether there is a difference in cyst dynamics during or after RT (protons or photons) for craniopharyngiomas of different ages (adult or pediatric) or histologic subtypes (adamantinomatous or papillary).

As an advantageous RT technique, PBT has shown promising efficacy and acceptable toxicity in the treatment of craniopharyngioma. However, some aspects of this systematic review and meta-analysis remain insufficient. First, gray literature was not included, and the results may have led to publication bias. Second, the eightstudies originated from three countries (62.5% from the USA, 25% from the UK, and 12.5% from France); therefore, our results may have been biased. Third, craniopharyngioma is a rare disease with histological types, including the classic adamantinomatous and papillary subtypes, and randomized studies are difficult to perform. Based on the differences in clinical treatment and clinical outcomes regarding craniopharyngiomas between children and adults, different types of craniopharyngiomas may have inconsistent optimal dose patterns, and individualized PBT requires further investigation. Fourth, the relative additional costs of PBT compared to photon RT, including healthcare environment, socioeconomic status [41], and access to technology, are substantial and influence the generalizability of some of the findings. Fifth, the included articles were retrospective studies with small sample sizes; in particular, some of the toxicity results may have been speculative. Craniopharyngiomas are classified as WHO grade I neoplasms, and long-term survival can be achieved regardless of surgery or combined RT. In our systematic review, the follow-up period of the included studies was relatively short, limiting the reliability of the long-term survival and toxicity assessments regarding PBT for craniopharyngiomas. Notably, in children and adolescents with craniopharyngiomas, tumor recurrence, cyst dynamics, quality of life (QoL), cognitive ability, frontal lobe encephalomalacia, hypothalamic and pituitary dysfunction, optic neuropathy, growth and development, and secondary cancer should be assessed/monitored throughout the growth and development cycles. Increasing the number of patients and extending follow-up to assess long-term outcomes are the goals of future studies on craniopharyngioma survivors. Finally, whether PBT is superior to other RT technologies must be determined through high-quality prospective randomized controlled clinical trials in patients with craniopharyngiomas.