1 Introduction

In addition to surgery and systemic therapy, radiation therapy is an integral component of the treatment of oncological diseases of the central nervous system in general. However, especially in pediatric patients or patients with a curative treatment concept and an expected favorable prognosis, the treatment is always performed in the balancing act between maximum tumor control on one hand and the avoidance of therapy-related late effects on the other. Conventional radiation therapy techniques based on high-energy X-rays have undoubtedly made progress in recent years, but they reach their limits in some clinical scenarios. There is a need for new approaches, particularly in the treatment of tumors with critical proximity or those with intrinsic high radiation resistance, to enable a more precise and effective treatment. Due to its characteristic physical and biological properties, ion beam therapy can significantly contribute to avoiding radiation-induced acute and late effects and is increasingly establishing itself as an alternative to conventional photon-based radiation therapy.

2 Protons

2.1 Pediatric patients

The preservation of the surrounding healthy normal tissue is of particular importance in the radiation therapy treatment of pediatric malignancies. Since the child’s tissue is often still in development, the goal is to minimize the risk of therapy-related side effects and significant long-term consequences. Thanks to its physical advantages, proton irradiation allows for optimal target volume coverage, even in the case of complexly configured tumors directly adjacent to sensitive organs at risk (OAR). This is achieved without exceeding the tolerance dose of the adjacent healthy tissue [1]. Ideally, not only does the probability of tumor control (TCP) increase, but there is also a reduction in the risk of radiation-induced side effects (NTCP). Especially in the treatment of brain tumors, achieving as conformal irradiation as possible is of crucial importance to decrease the likelihood of neurocognitive impairments and the rate of long-term side effects on critical neurovascular structures and eloquent areas. In recent years, proton irradiation has established itself as the preferred treatment option, particularly in the pediatric age group, for brain tumors. Despite a rapidly increasing number of new facilities internationally, a lack of availability often remains the primary cause when treatment is nonetheless carried out with photons. Thanks to numerous dosimetric comparison studies, the superior dose distribution of proton irradiation is undisputed [1,2,3,4]. The more conformal treatment and the associated lower low-dose exposure in the surrounding healthy tissue can be translated into clinically relevant advantages. This is of essential significance because, thanks to continuous improvements in diagnostics, therapy, and follow-up care, oncological diseases in over 80% of pediatric patients in Germany can be controlled long-term, allowing them to become long-term survivors [5]. Thus, the avoidance of severe therapy-related late effects is increasingly coming into focus alongside the mere control of the underlying condition.

The rationale for local irradiation of central nervous system or skull base tumors using protons is widely accepted, as clear dose-response relationships exist for many clinically relevant endpoints. For example, Vatner et al. have clearly demonstrated the increasing risk of endocrine deficiencies with an increasing dose to the hypothalamus [6]. Conversely, the benefit of the lower dose exposure to the hypothalamus or pituitary gland through the use of protons can be estimated by comparing plans with photons. Providing unequivocal evidence for improved neurocognitive outcomes after proton irradiation proves to be more challenging. Prospective, randomized evidence is elusive, but there is a growing body of literature that comparatively examines the results of neuropsychological testing for both irradiation modalities. For instance, Kahalley et al. previously found in a preliminary study that there was no deterioration in IQ after proton irradiation, while the decrease of 1.1 points per year after photon-based irradiation did not reach statistical significance [7]. Gross et al. also discovered that proton irradiation positively influences neuropsychological outcomes compared to conventional irradiation in the treatment of pediatric brain tumors [8]. Recently, Kahalley et al. were able to examine, for the first time, the effects of proton or photon-based treatment on the neurocognitive outcome of pediatric patients with medulloblastoma using comparable protocols from the same treatment period [9]. Proton irradiation resulted in a favorable outcome in most examined domains compared to photon treatment. Only processing speed was found to be impaired regardless of the type of radiation used. These results support the rationale for using protons in the treatment of brain tumors with the goal of preserving cognitive function.

2.2 Glioma CNS WHO grade 2 and3

Patients undergoing radiation therapy for low-grade gliomas typically have a favorable prognosis. The overall survival rate from the randomized RTOG 9802 study for low-grade gliomas, as reported by Shaw et al., was 85% after 2 years and 72% after 5 years [10]. The reported overall survival rates from the randomized EORTC studies 22,844 and 22,845 were similar, with 85% at 2 years and 59% and 67% at 5 years [11, 12]. Regarding proton radiation therapy both prospective studies [13, 14] and retrospective studies [15,16,17] have investigated its use in patients with grade 2 and 3 gliomas. While older studies had relatively small sample sizes, more recent publications present results for over 100 patients [15, 18, 19]. The majority of treatments involved a median dose of 54 Gy relative biological effectiveness (RBE), with WHO 3 gliomas receiving a higher median dose of 60 GyRBE. The reported 5-year overall survival (OS) for grade 2 and 3 gliomas ranged from 23 to 87%, and recent publications indicate a more favorable 5-year OS, approximately 85% for grade 2 tumors and 67% for grade 3 tumors. The comparative examination of current data on photons and protons appears somewhat insufficient due to the substantial heterogeneity in applied treatment regimens and included molecular tumor subtypes. Therefore, the asserted increased efficacy of proton radiation therapy (pRT) still requires validation. Ongoing controlled trials, such as the German GlioProPh trial (NCT05190172) and the US trial comparing intensity-modulated proton therapy (IMPT) versus intensity-modulated radiation therapy (IMRT) (NCT03180502), are anticipated to provide a comprehensive comparison and answer the question regarding the superiority of proton versus photon treatment in lower-grade gliomas.

Regarding toxicity, proton treatment exhibits potential in reducing the dose to surrounding tissues. Severe toxicity equal to or greater than grade 3, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), is rare. Across multiple studies involving several hundred patients with grade 2 or 3 gliomas who underwent pRT, the reported acute toxicity was less than 1% [13, 14, 17, 19].

An intriguing aspect related to late radiation induced effects is the phenomenon of radiation-induced contrast enhancement (RICE) on MRI, observed in 17–29% of patients following pRT. The observed lesions are in most cases clinically silent and do not cause severe symptoms [18,19,20]. It is important to note that the detection of RICE symptoms requires standardized interdisciplinary follow-up and comprehensive knowledge of the treatment plan. RICE typically begin to develop around 6 months after the start of treatment, and their frequency is strongly dependent on the administered radiation dose. They can resolve over time, but distinguishing between RICE and tumor progression is an extremely challenging task that often cannot be conclusively resolved. This exacerbates the impact of RICE occurrence: patients may potentially be treated incorrectly, either leaving tumor progression untreated or exposing the patient, and particularly the existing lesion, unnecessarily to radiation or chemotherapy, further complicating the situation [21]. It is known that these radiation-induced contrast enhancement lesions do not occur randomly but are highly concentrated in regions where parts of the beam with increased (assumed) biological effectiveness coincide with the periphery around the brain ventricles. The increased incidence of asymptomatic radiation-induced brain injuries with an elevated average linear energy transfer dose (LET) provides strong clinical evidence supporting the hypothesis that the relative biological effectiveness of protons is variable and different from the currently globally used fixed factor of 1.1, emphasizing the need for biologically optimized treatment planning. Based on these observations, predictive voxel-based models for the probability of complications in healthy tissue (NTCPvoxel) were successfully developed, calculating the risk and predicting the potential location of the occurrence of RICE [22, 23]. The results of previous experiments have also shown that reducing the risk of RICE occurrence cannot be achieved through conventional treatment planning strategies, such as the use of multiple radiation fields [24]. A prospective clinical study is currently underway to provide evidence for a variable relative biological effectiveness (RBE) of proton radiation, along with a quantitative estimation of the RBE. Additionally, it is testing the hypothesis of an increased radiation sensitivity in the ventricular periphery, which potentially should be considered as a new organ at risk for radiation therapy in the future (NCT05964569).

3 Carbon ions

Until end of 2022, more than 300,000 patients worldwide were treated with protons, and around 50,000 patients were irradiated with carbon ions [25]. The distinctive feature beside physical advantages is the increased relative biological effectiveness (RBE) of ion beams other than protons. The RBE is a measure of how much more effective ion beams are in inducing biological cell damage compared to X-rays. The significantly higher biological effectiveness is primarily attributed to the property of ion beams to cause considerably more ionization events per unit distance, quantifiable as linear energy transfer (LET). While X-rays (and typically protons) are considered loosely ionizing types of radiation, the ionization density of carbon ions, for example, is an order of magnitude higher. This spatially focused energy deposition leads to a substantial increase in more severe direct radiation damage, such as the increased induction of DNA double-strand breaks, rather than merely causing single-strand breaks.

However, RBE is by no means a constant; instead, it is influenced by numerous factors such as tumor tissue, ion type, energy, observed endpoint, or cell cycle phase, among others. Therefore, the precise determination of RBE is crucial for the successful application of ion beams in the treatment of oncological diseases. The following points are of particular relevance for the use of ion beams in oncology:

  • Improved tumor ablation: Heavy ions, due to their high mass and charge, have a higher linear energy transfer (LET) in tissue compared to photon radiation. This results in a stronger ionization of atoms and molecules in the target tissue, leading to an increased induction of DNA double-strand breaks in tumor cells. The high LET of heavy ions allows for improved tumor ablation and a higher likelihood that the tumor cells are no longer capable of proliferation.

  • Overcoming radiation resistance: In some cases, tumor cells develop resistance to conventional radiotherapies, compromising the effectiveness of the treatment. Heavy ions have the ability to overcome typical radiation resistance mechanisms, such as cell cycle dependence, and more effectively damage resistant tumor cells.

  • Damage to hypoxic tumor tissue: Hypoxic cells, which exhibit reduced oxygen levels, are less sensitive to conventional radiation. However, heavy ions have more effective radiation biology and can efficiently damage hypoxic cells as well.

3.1 Meningeoma

Meningiomas constitute the most prevalent type of primary brain tumor, accounting for approximately 15–26% of all intracranial neoplasms [26]. While 80% of meningiomas exhibit a benign clinical course and can typically be effectively treated through resection alone, about 20% of these tumors experience recurrence following surgery. For this more aggressive subset, additional interventions are frequently recommended, including further surgical procedures, radiotherapy, and/or chemotherapy. The current WHO classification of CNS tumors recognizes three grades in meningiomas, generally reflecting the degree of malignant behavior, ranging from WHO grades 1 to 3. Radiation therapy plays a crucial role in the treatment of patients with meningiomas, particularly those not safely eligible for surgery or following incomplete surgical resection. The existing guidelines from EANO (European Association of Neuro-Oncology) present Class 3 evidence supporting the utilization of fractionated radiotherapy, especially in the postoperative setting for atypical meningiomas [27]. Patients having undergone nonradical resection show significantly worse outcomes relative to patients who underwent radical neurosurgical resection emphasizing the need for improving postoperative treatment strategies. Novel radiation modalities such as ion beam therapy offer a promising alternative. A phase I/II trial performed at GSI Helmholtz Centre for Heavy Ion Research investigated the efficacy and safety of a carbon ion boost of 18 Gy RBE to macroscopic residual disease followed by photon-based irradiation with a total dose of 50.4 Gy. With an 86% progression-free survival rate over a 5-year period, the study demonstrated a positive clinical outcome, especially considering the existence of a macroscopic residual tumor during the course of radiotherapy [28]. In the follow-up trial Deng et al. concluded that escalating the dose through a bimodal radiotherapy approach, employing 50 Gy of photons and an 18 Gy RBE carbon ion boost, potentially enhances local progression-free survival in patients diagnosed with WHO grade 2 meningiomas, particularly those with Simpson grades 4 and 5. The study indicates a favorable 3-year local PFS rate of 86.7%, in contrast to the 72.7% reported in the RTOG 0539 trial for subtotally resected WHO grade 2 meningiomas. Therefore, for well-selected patients with molecularly confirmed intermediate- and high-risk meningiomas, situated at a sufficient distance (> 5 mm) from the cerebral ventricles, considering bimodal therapy may offer improved control over local tumor progression [29].

3.2 Re-irradiation

Glioblastoma, graded as WHO grade IV, is the most prevalent and aggressive brain tumor in adults. Following the initial standard-of-care surgery and/or chemoradiotherapy recurrence frequently ensues, carrying an unfavorable prognosis. The response to treatment is diverse and survival outcomes rely on factors such as tumor volume, age, performance status, feasibility of resection, and the time lapse between primary diagnosis and initial treatment. The prognosis, however, remains poor. For small volume re-irradiation, carbon ions can be applied safely and effectively, for instance, with 45 Gy (RBE) administered in 15 fractions. Efficacy of re-irradiation with carbon ions in patients with recurrent high-grade glioma was compared to a large multicenter cohort of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Median overall survival was 10.5 months in the carbon group (n = 197) compared to 7.9 months in the control cohort treated with photons (n = 565). Patients treated for recurrent high grade glioma CNS WHO grade III seemed to benefit most (overall survival for carbon ions 28.2 months vs. 10.9 months) [30].

4 Helium ions

Between 1957 and 1992, helium ions were utilized in the treatment of over 2054 patients. From 1975 onward, multiple phase I/II trials were initiated to assess the potential application of various heavy charged particles, including helium, carbon, neon, argon, and silicon ions [31,32,33].

At Lawrence Berkeley Laboratories, more than 810 patients underwent radiosurgery for pituitary gland treatment using high-energy plateau helium ions. Levy et al. conducted an 18-year follow-up on this cohort, documenting both the efficacy and tolerability of the treatment. The impressive evidence lies in the low complication rate, with only 1% of the cohort experiencing focal temporal lobe necrosis or cranial nerve injury. The achieved tumor control and successful reduction of growth hormone secretion further highlight the potential of helium ions [34].

Saunders and Castro successfully implemented high-dose helium ion irradiation for uveal melanoma, resulting in 97% tumor control [32, 35]. This success paved the way for the first randomized phase III trial in charged particle radiotherapy, investigating the outcomes of helium ion radiotherapy for uveal melanoma compared to 125-Iodine plaques in 184 patients. The long-term analysis confirmed excellent results, demonstrating significantly improved local control and eye preservation with helium irradiation [36, 37].

These remarkable findings provide a solid foundation, justifying further clinical evaluation of helium ions in radiotherapy. The detailed characterization of helium’s physical properties reveals its potential advantages. Particularly at greater depths, the proton penumbra tends to be considerably large due to lateral scattering, sometimes even surpassing that of high-energy photons. A helium beam offers a substantial reduction in lateral penumbra, which can have clinical significance [38]. Helium ion radiotherapy emerges as a promising treatment option, not only owing to its superior physical properties but also due to its radiobiological behavior, which remains similar to that of protons. Although helium exhibits only a slight increase in Linear Energy Transfer (LET), still within the range of protons, it provides an elevated Relative Biological Effectiveness (RBE) and oxygen enhancement ratio [39, 40]. Recent in-silico studies underscore the potential of the steeper lateral dose gradient for improved sparing of organs at risk [39, 41, 42].

In summary, helium radiotherapy holds the potential to amalgamate the favorable characteristics of both protons and carbon ions, enabling high-precision dose deposition and optimized sparing of normal tissue. This makes it a highly suitable candidate for reintroduction into clinical routines. Recently, the Heidelberg Ion-Beam Therapy Center (HIT) successfully treated the first patient globally with an active scanned helium beam as part of a compassionate use program and is about to start its first clinical trial with helium ions.