Systematic Review and Meta-Analysis of Particle Beam Therapy versus Photon Radiotherapy for Skull Base Chordoma: TRP-Chordoma 2024

Simple Summary Chordoma is a rare cancer that often occurs at the base of the skull. Treating skull base chordoma is challenging because the tumor is difficult to completely remove with surgery and has low radiosensitivity. This study compared two types of radiation modality: particle beam therapy (PT) and photon radiotherapy (RT). We found that PT provides better progression-free survival compared to photon RT. However, PT also has a higher risk of causing brain necrosis. Our findings suggest that PT is more effective for controlling skull base chordoma, but careful planning is needed to minimize side effects. Abstract [Objective] The aim of this study was to compare the efficacy of particle beam therapy (PT) with photon radiotherapy (RT) for treatment of skull base chordoma. [Methods] A systematic review was conducted for skull base chordoma treated with PT or photon RT reported from 1990 to 2022. Data were extracted for overall survival (OS) and progression-free survival (PFS), late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality. Random-effects meta-regression analysis with the treatment modality as an explanatory variable was performed for each outcome to compare the modalities. [Results] A meta-analysis of 30 selected articles found 3- and 5-year OS rates for PT vs. photon RT or combined photon RT/proton beam therapy (PBT) of 90.8% (95% CI: 87.4–93.3%) vs. 89.5% (95% CI: 83.0–93.6%), p = 0.6543; 80.0% (95% CI: 75.7–83.6%) vs. 89.5% (95% CI: 83.0–93.6%), p = 0.6787. The 5-year PFS rates for PT vs. photon RT or photon RT/PBT were 67.8% (95% CI: 56.5–76.7%) vs. 40.2% (95% CI: 31.6–48.7%), p = 0.0004. A random-effects model revealed that the treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS (p = 0.42) and 5-year OS (p = 0.11), but was a significant factor for 5-year PFS (p < 0.0001). The rates of brain necrosis were 8–50% after PT and 0–4% after photon RT or photon RT/PBT. [Conclusion] This study shows that PT results in higher PFS compared to photon RT for skull base chordoma, but that there is a tendency for a higher incidence of brain necrosis with PT. Publication and analysis of further studies is needed to validate these findings.


Introduction
Chordoma is a rare disease, with an incidence of 0.18 to 0.84 per million people [1].The common sites of occurrence are the sacrum and skull base, followed by the spine [1].NCCN guidelines recommend surgical resection as standard treatment, with postoperative radiation recommended for cases in which residual disease is suspected [2].However, treatment of chordoma presents significant challenges because complete resection is difficult in common regions of the disease, such as the sacrum and skull base, and the tumor is resistant to radiotherapy (RT) and chemotherapy, which complicates the achievement of local control [3,4].The prognosis for cases with complete resection is significantly better compared to those with incomplete resection [5,6].Postoperative RT is useful for skull base chordoma, but a high dose of over 65 Gy is required for local control because of the low radiosensitivity [6].Thus, advanced irradiation techniques are needed to deliver high doses to the tumor while sparing critical organs such as the brainstem and optic nerves.
Particle beam therapy (PT) is frequently used for skull base chordoma due to its high dose concentration [7].However, while meta-analyses have shown superiority of PT over photon RT for chordomas in general, no meta-analysis has compared PT to photon RT for skull base chordoma [8].Compared to chordomas in the sacrum or spine, skull base chordomas are characterized by a younger age of onset, difficulty achieving complete resection due to surrounding anatomical structures, and a greater need for postoperative RT [9,10].Furthermore, skull base chordomas are often treated similarly to skull base chondrosarcomas.However, chondrosarcomas have higher radiosensitivity and clearly superior survival and local control rates compared to chordomas [11].While several meta-analyses have compared PT and photon RT for skull base chordomas and chondrosarcomas, it is unclear if these results can be directly extrapolated to skull base chordomas [12,13].To address these issues, we extracted literature on treatment outcomes and background factors for skull base chordomas to compare the therapeutic effects of PT and photon RT.

Selection Criteria for Meta-Analysis
The review was conducted in accordance with the principles and recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [14].The study has not been registered.PubMed was searched using the keywords "(chordoma OR chondrosarcoma) AND (radiotherapy OR proton OR carbon) AND (skull OR head)" for articles published from 1990 to 2022.Only articles written in English were included.Two reviewers independently screened all retrieved papers.The process for selecting studies for analysis was as follows: (1) Clinical studies related to chordomas or chondrosarcomas located at the skull base were identified.(2) Articles that reported overall survival (OS) or progression-free survival (PFS) were selected.
(3) Studies with ten or more cases per treatment modality were included to ensure robust sample sizes for analysis.(4) Studies in which a single treatment modality accounted for at least 80% of the cases were included.(5) For multiple publications from the same institution covering overlapping periods, only the most recent study was included.Data were extracted for the number of cases, 3-or 5-year OS, 3-or 5-year PFS, late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality (PT vs. photon RT or combined photon RT/proton beam therapy (PBT)).If the 3-or 5-year OS and PFS were not specified in the text, these rates were estimated from figures.

Statistical Analysis
Random effects meta-analyses of 3-and 5-year OS and PFS were performed for each modality, and forest plots were drawn.For studies with missing accuracy data, missing values were imputed using the number of cases, risk set size at each year, and mean dropout rate.Heterogeneity in each meta-analysis was evaluated by I-square statistics.Random-effects meta-regression with modality as an explanatory variable was performed for each outcome to compare the modalities.All analyses were performed using R version 4.3.2(R Core Team, Vienna, Austria) and its accompanying meta package [15].
The random-effects meta-regression analysis with modality as an explanatory variable was adjusted primarily for age and gender.This was due to the high rates of missing data for other potential variables, such as GTR and tumor volume, which required exclusion of these variables from the analysis.The results are shown in Table 2. Neither age nor gender were significant factors for any of the indicators.Treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS (p = 0.42) and 5-year OS (p = 0.11), but was a significant factor for 5-year PFS (p < 0.0001).The rate of brain necrosis as a late adverse event is listed in Table 1 for each article.This rate was 8-50% in PT cases, but only 0-4% after photon RT.

Statistical Analysis
Random effects meta-analyses of 3-and 5-year OS and PFS were performed for each modality, and forest plots were drawn.For studies with missing accuracy data, missing values were imputed using the number of cases, risk set size at each year, and mean dropout rate.Heterogeneity in each meta-analysis was evaluated by I-square statistics.Random-effects meta-regression with modality as an explanatory variable was performed for each outcome to compare the modalities.All analyses were performed using R version 4.3.2(R Core Team, Vienna, Austria) and its accompanying meta package [15].

Discussion
This study is the first meta-analysis comparing the efficacy of PT with photon RT for skull base chordoma.Comparisons of PT with photon RT for chordomas without specifying the site have been reported, but skull base chordoma needs to be treated independently due to the younger age of onset and low rate of complete resection [8].The biological and physical properties of PT make it useful for skull base chordoma, but the rarity of the disease has prevented randomized comparative studies of PT and photon RT.The current study shows a significant benefit of PT over photon RT for skull base chordoma for 5-year PFS, and PT resulted in 3-and 5-year OS of 90.8% and 80.0%, and 3and 5-year PFS of 71.7% and 67.8%.These findings show that the challenges posed by the rarity of the disease and the historical reliance on retrospective studies can be overcome using a meta-analysis.

Discussion
This study is the first meta-analysis comparing the efficacy of PT with photon RT for skull base chordoma.Comparisons of PT with photon RT for chordomas without specifying the site have been reported, but skull base chordoma needs to be treated independently due to the younger age of onset and low rate of complete resection [8].The biological and physical properties of PT make it useful for skull base chordoma, but the rarity of the disease has prevented randomized comparative studies of PT and photon RT.The current study shows a significant benefit of PT over photon RT for skull base chordoma for 5-year PFS, and PT resulted in 3-and 5-year OS of 90.8% and 80.0%, and 3-and 5-year PFS of 71.7% and 67.8%.These findings show that the challenges posed by the rarity of the disease and the historical reliance on retrospective studies can be overcome using a meta-analysis.
The better PFS after PT compared to photon RT is thought to be due to the total dose and irradiation field.The median total doses in the analysis were 65-78.4Gy relative biological effectiveness (RBE) for PT, and 14.8-81 Gy (RBE) for photon RT or photon RT/PBT .Although there were differences in the dose per fraction, the total dose tended to be higher for PT.Additionally, there were differences in the field settings depending on the treatment modality.With Gamma Knife or linear accelerator-based stereotactic radiosurgery and stereotactic radiotherapy (SRS/SRT), the tumor margins are used to define the dose, with a higher dose delivered to the tumor center [35,36].In contrast, PT planning frequently uses the pre-surgical extent of the tumor and setting of the clinical target volume (CTV) with a 5-10 mm margin to the gross tumor volume (GTV) [17,19,21].Therefore, the better 5-year PFS with PT may be attributable to the higher total irradiation dose and broader field settings.It was also reported that the high PFS achieved by PT for chordomas is superior in terms of cost-effectiveness [46,47].Generally, the cost of PT is higher than that of photon RT, but it implies the suppression of costs for reoperations and other procedures.While some reports indicate that PT may not offer significant costeffectiveness for head and neck cancer due to similar treatment outcomes [48,49], it is considered cost-effective for treating skull base chordomas.
The efficacy of PT may be somewhat offset by the higher rate of brain necrosis after PT.Theoretically, the Bragg peak in PT allows for dose concentration, enabling high-dose delivery to the tumor while minimizing the dose to surrounding normal tissues, as required for skull base chordoma [50].However, our latest retrospective analysis also identified a 13% occurrence of brain necrosis, with a high total dose found to be a risk factor for brain necrosis [51].The volume of normal brain exposed to a high dose (over 60 Gy) is known to be a risk factor for brain necrosis, and setting a wider CTV for PT compared to photon RT may also contribute to the occurrence of brain necrosis [52].In situations where the CTV is curved or U-shaped, intensity-modulated radiation therapy (IMRT) may be effective, and combined photon RT and PBT may also be useful [53].Particularly for a U-shaped target area, using only passive PT might result in insufficient dose areas to spare the brain, raising concerns about reduced local efficacy [45].However, this limitation can be overcome with the spot scanning method using intensity-modulated particle beam therapy (IMPT).Indeed, favorable treatment plans using IMPT for skull base chordoma can be created without compromising the dose to the tumor [27,54].Evidence for use of IMPT is still not widely available, but this method does create superior dose distributions for many organs, not just skull base tumors, compared to IMRT or passive PT [55].Therefore, as IMPT becomes more accessible, it is likely to facilitate further dose increases, leading to improved treatment outcomes.
The limitations of this study include the rarity of skull base chordoma and the small number of cases treated with photon RT.Due to this rarity, prospective studies are challenging to conduct, and almost all the papers used in this analysis were retrospective studies, which limits the quality of the analysis.In addition, information on dose fractionation, CTV settings, and GTR rates was missing in many papers, which made a thorough analysis difficult.Details of surgical treatment, which play a crucial role in the integrated treatment strategy for chordomas, significantly impact treatment outcomes.Future analyses, including the quality of surgery such as resection rates, are anticipated as results have improved with increased rates of complete resection in our past reports [26,31].Additionally, performing a subgroup analysis by particle type to examine the differences in biological effects between proton and carbon ion therapy would be of great interest, but due to the lack of studies on carbon ion therapy, this analysis could not be conducted at this time.More detailed analyses will be possible as more treatment outcomes are published.

Conclusions
This study shows that particle beam therapy gives higher PFS compared to photon RT for skull base chordoma.However, there is also a tendency for a higher incidence of brain necrosis with particle beam therapy.Further studies are needed to validate these findings.

Figure 1 .
Figure 1.Flow diagram of study selection for systematic review and meta-analysis.Figure 1. Flow diagram of study selection for systematic review and meta-analysis.

Figure 1 .
Figure 1.Flow diagram of study selection for systematic review and meta-analysis.Figure 1. Flow diagram of study selection for systematic review and meta-analysis.

Table 1 .
List of selected manuscripts.

Table 2 .
Meta-regression analysis of predictive factors for overall survival and progression-free survival.