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Table of Contents
REVIEW
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 149-153

Particle radiation therapy in the management of adult high-grade glioma: A narrative review


Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center; Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China

Date of Submission08-Dec-2020
Date of Decision16-Dec-2020
Date of Acceptance07-Jan-2021
Date of Web Publication1-Feb-2021

Correspondence Address:
Dr. Jiade J Lu
Shanghai Proton and Heavy Ion Center, 4365 Kangxin Road, Pudong, Shanghai 201315
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_30_20

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  Abstract 


This narrative review summarizes the current status of the use of particle radiation therapy on the treatment of adult malignant gliomas. Due to the unique physical property, particle (e.g., proton or carbon-ion) beam radiation therapy can improve radiation dose distribution, thereby therapeutic radio for patients with brain malignancy. Therefore, particle beam radiation therapy is associated with low adverse events which have implications for improving quality of life for long-term survivors. In addition, there is a potential for safe dose escalation in selected patients. Malignant glioma is considered radioresistant; thus, particle beams of higher relative biological effectiveness, carbon-ion beam, for example, may further improve disease control in theory. Data on carbon-ion beam RT alone for the management of brain tumor are scarce. Most literature described proton beam alone or the use of combined proton/photon and carbon-ion beam boost for the treatment of glioma. Existing clinical evidence describes virtually no acute high-grade toxicities and limited late effects. Prospective clinical trials are needed to confirm the improved efficacy and favorable toxicity profile of particle beam radiation therapy on adult malignant glioma described in retrospective studies. Currently, multiple prospective trials are ongoing to answer such questions.

Keywords: Adult, carbon-ion beam, glioblastoma multiforme, glioma, particle therapy, proton beam, radiation therapy


How to cite this article:
Kong L, Lu JJ. Particle radiation therapy in the management of adult high-grade glioma: A narrative review. Glioma 2020;3:149-53

How to cite this URL:
Kong L, Lu JJ. Particle radiation therapy in the management of adult high-grade glioma: A narrative review. Glioma [serial online] 2020 [cited 2022 Dec 8];3:149-53. Available from: http://www.jglioma.com/text.asp?2020/3/4/149/308488




  Introduction Top


Malignant glioma is the most commonly diagnosed primary tumor of the central nervous system (CNS) and is one of the most aggressive malignancies known to humans. High-grade gliomas (HGGs), which include glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), make up approximately 80% of all brain gliomas in adults and are characterized by rapid progression and diffuse infiltration. The complete resection of HGGs is very difficult. Although the use of postoperative radiation therapy (RT) markedly improves both disease control and overall survival (OS) rates, recurrence is universal after surgery followed by RT.

The use of temozolomide has modestly improved OS rates, especially in cases with methylation of the O6-methylguanine-DNA methyltransferase promoter. Nevertheless, the median survival time (MST) remains dismal, at approximately 15 months.[1] A more recent investigation of temozolomide dose intensification failed to demonstrate any further improvements.[2] In addition, investigations into novel treatment modalities, such as vaccination, targeted biological agents, and immunotherapy agents, have failed to show substantial benefits for prolonging the MST of HGG patients.

HGGs of the CNS rarely metastasize, and the main mode of treatment failure is local recurrence in the irradiated region. Radiation dose escalation may therefore improve disease control, at least in theory. In a comparative study published in 1991, conventional RT delivered to 60 Gy in adult HGG patients significantly improved both disease control and OS compared with patients who received 45 Gy only.[3] However, further investigations of radiation dose escalation to over 60 Gy (i.e., 70–80 Gy in conventional or altered fractionation RT) or of adding a stereotactic RT boost before conventional RT have failed to improve the OS rates of HGG patients. Whether a further increase in RT dose may improve disease control (and even OS) has become a focus of debate in the field of neuroradiation oncology. Nevertheless, it is generally agreed that a substantial dose escalation –to over 80 Gy, for example – is not feasible using conventional RT technology and may induce considerable damage to organs at risk that are adjacent to the tumor (i. e., normal brain tissue, eyes, and/or cranial nerves).


  Advantages of Particle Beam Radiation Therapy for High-Grade Glioma Top


Charged particle (e.g., proton, helium, or carbon ion) beams are characterized by a sharp lateral penumbra, minimal dose deposition at the beam path before a steep energy deposition (i.e., the Bragg peak), and a subsequent sudden and nearly complete dose fall-off. The dosimetry and clinical advantages of particle beam RT (PBRT) have been repeatedly demonstrated in neoplasms of the CNS or base of the skull such as chordoma, chondrosarcoma, and pediatric medulloblastoma.[4],[5],[6],[7] For intracranial lesions, such as primary or recurrent gliomas, results of dosimetry studies have demonstrated more superior dose distributions for PBRT compared with photon-based RT, with the potential for improved efficacy and toxicity profiles.[8],[9],[10]

In addition to the advantages of their physical characteristics, heavy ion particles, such as carbon ions, have higher linear energy transfer. Furthermore, the relative biological effectiveness (RBE) of carbon-ion beams is suggested to be 3–5. Carbon-ion beams may inflict more damage through direct DNA double-strand breaks.[11] In vitro studies in both GBM and glioma stem cell lines have demonstrated the greater cell-killing efficiency of carbon-ion beams compared with either proton or photon beams, with lower linear energy transfer.[12],[13],[14],[15] Furthermore, the cytocidal function of carbon-ion beams is considered most effective in hypoxic conditions, which is a feature of HGG, and especially of GBM.[16],[17],[18]


  Clinical Application of Particle Beam Radiation Therapy for Adult High-Grade Gliomas Top


The effectiveness of proton RT (PRT) for HGG has been investigated in a single-arm phase 2 trial at Massachusetts General Hospital.[19] Twenty-three postoperative patients with GBM were treated with photon RT, followed by PRT boosts with escalated doses of >90 GyE. The tumor volumes ranged between 0 and 42 mL. The MST of the entire group was 20 months. Recurrence developed in the dose region of 60–70 Gy, whereas no patients developed recurrence in the high-dose region (90 GyE). Interestingly, patients who experienced radiation necrosis in the treatment field had longer survival time.[19]

In a more recently published phase 1/2 trial from the University of Tsukuba, Japan, twenty patients were irradiated using a hyperfractionated concomitant boost scheme, to 50.4 Gy in 28 fractions in the morning and 46.2 GyE in 28 fractions in the afternoon (≥6 h later).[20] The MST was 21.6 months for the entire cohort. The progression-free survival (PFS) and OS rates after 1 year were 45.0% and 71.1%, and after 2 years, they were 15.5% and 45.3%, respectively. Late radiation necrosis and leukoencephalopathy were observed in one patient each. Notably, the updated results of this study revealed that radiation necrosis was observed in all six long-term survivors.[21]

Both of the aforementioned studies used PRT in the pre-temozolomide era, either alone or as a boost to photon-based radiation, to a total dose of >90 GyE. The improved MSTs, which exceeded 20 months in both trials, suggest that high-dose irradiation using proton beams might improve patients' survival while limiting RT-induced adverse effects.

The clinical use of carbon-ion RT (CIRT) in the management of HGG was pioneered by researchers at the National Institute of Radiation Science (NIRS), Japan. These researchers investigated a group of 48 HGG patients (n = 32 GBM, n = 16 AA) in a dose-escalation trial using conventional photon RT delivered to 50 Gy in 25 fractions, followed by eight-fraction CIRT (dose escalated from 16.8 to 24.8 Gy RBE, in three dose levels).[22] All patients also received nimustine chemotherapy. The authors observed no severe (i.e., Grade 3 or 4) RT-induced toxicity. The MSTs were 35 and 17 months for AA and GBM patients, respectively. Notably, the MST for patients who received the highest dose of CIRT boost was 26 months. In addition, the MST of patients who received the lowest dose of CIRT boost was significantly lower than that of patients who received intermediate and high doses of CIRT boost (combined).

The results of a collaborative, retrospective study from the Heidelberg Ion-Beam Therapy Center (HIT) and NIRS revealed that the addition of a CIRT boost to photon-based conventional RT might improve outcomes compared with photon RT alone.[9] In this study, 96 HGG patients who received photon RT to the standard dose scheme (i.e., 60 Gy in 30 fractions), with or without temozolomide (n = 32 GBM and n = 16 AA patients in each group), were randomly selected from the HIT database and compared with the patients from the aforementioned NIRS dose-escalation trial for PFS and OS. The MSTs were 9, 14, and 18 months for GBM patients who received photon RT alone, photon RT + temozolomide, and photon RT + CIRT boost, respectively. The MSTs for the AA patients were 13, 39, and 35 months, respectively. Thus, the addition of chemotherapy or a CIRT boost significantly improved MST in both GBM and AA patients compared with those who received photon RT alone. Furthermore, the addition of a CIRT boost significantly improved the median PFS for both GBM and AA patients compared with patients who did not receive a CIRT boost.

The initial results of patients treated at the Shanghai Proton and Heavy Ion Center (SPHIC) are also encouraging. Data from the first fifty consecutive HGG patients (n = 16 AA, n = 34 GBM) treated at SPHIC have been analyzed and published.[23] Patients who had complete resection were treated with PRT only, while those who had residual gross tumor or who only underwent a biopsy received PRT with CIRT boost. No patients received CIRT only. With a median follow-up of 14.3 months, the 18-month PFS and OS rates were 60% and 74%, respectively. Of the 34 patients with GBM, the 18-month PFS and OS rates were 42.7% and 61.0%, respectively.[23] The updated data from 58 GBM patients revealed similar outcomes. The 18-month PFS and OS rates in this larger group were 40.0% and 57.6%, respectively (unpublished data). In this study, temozolomide was also routinely used for patients with methylation of O6-methylguanine-DNA methyltransferase or for patients under the age of 65.


  Salvage Re-irradiation using Particle Beam Radiation Therapy for Recurrent High-Grade Gliomas Top


Because of its precise dose distribution and relatively high biological effectiveness, PBRT is particularly attractive for use in HGG patients who have failed previous RT treatments. Unfortunately, data on the use of PBRT for re-irradiation in patients with recurrent HGG are scant, and there are currently no data on the use of CIRT for salvage treatment. In a retrospective study of 26 diverse cerebral cases, eight patients (including five GBM patients and one anaplastic glioma patient) who had failed previous high-dose RT (median dose = 55 Gy) received salvage PRT. The median interval between the two courses of RT was 16 months. For these eight patients, the MST was 19.4 months, and no patients experienced PRT-induced toxicity of Grade 2 or above, although two patients developed radiation necrosis without overt clinical consequences. However, it must be emphasized that the dose used for salvage PRT was just 33 GyE.[24] Thus, considering the small sample size and the palliative dose that was used in this study, these seemingly encouraging results should be interpreted with caution.


  Ongoing Clinical Trials and Future Directions Top


The clinical advantages of PRT versus photon-based RT have not yet been investigated in a prospective randomized trial. This will in part be addressed by the NRG-BN-001 trial (“Randomized Phase 2 trial of hypofractionated dose-escalated photon IMRT or PRT versus conventional photon irradiation with concomitant and adjuvant temozolomide in patients with newly diagnosed GBM”).[25] At this stage, investigators have completed the analysis of dose-escalated photon intensity-modulated radiotherapy (IMRT) versus conventional photon RT, and no differences in OS were observed. Any differences in outcomes between PRT versus photon-based RT are currently under investigation.

One decade ago, investigators from HIT in Germany initiated the prospective CLEOPATRA trial. After receiving photon-based RT of 50.0 Gy in 25 fractions, patients with GBM were randomized to either a proton boost (up to 10.0 Gy [RBE] in five fractions) or a CIRT boost (escalating doses up to 18.0 Gy [RBE] in 6 fractions).[26] The aim of this trial was to investigate whether a radiation beam of higher RBE can improve disease control and patients' survival compared with more conventional RT using lower linear energy transfer beams such as photon and proton beams. The use of proton as a boost after conventional RT may improve patients' quality of life because of the reduced dose coverage to the normal organs at risk (e.g., normal brain tissue). However, there have been no active updates from this trial in the past several years.

Despite its improved efficacy in the management of HGG, it is unlikely that further dose escalation of PBRT per se can completely prevent local recurrences, even in high-dose regions. Any efforts would be futile unless tumor targeting is improved; more accurate identification of regions of subclinical disease that harbor both a high tumor burden and more radioresistance, followed by irradiation with more effective doses, may delay recurrence, thereby improving OS. The results of several investigations have demonstrated that l-[methyl-11C] methionine (MET)/18F-fluoroethyl-tyrosine (FET) positron emission tomography (PET) uptake is associated with a higher probability of treatment failure after concurrent temozolomide and RT for GBM[27],[28] and might assist in the delineation of gross tumor volume (GTV) in GBM with a suspected nonenhancing component.[29],[30] The results of numerous studies have indicated that the use of MET-PET/magnetic resonance spectroscopy (MRS) in combination with magnetic resonance imaging (MRI) is superior for defining the extent of the disease compared with MRI alone.[28],[31],[32],[33] Therefore, positive areas on MET-PET/MRS may also be used to determine the GTV to improve disease control, in addition to the use of traditional contrast enhancement and fluid-attenuated inversion recovery (FLAIR) abnormalities indicative of residual nonenhancing tumor (edematous FLAIR signal that does not resolve after surgical decompression). However, it has not yet been addressed whether functional imaging-guided PBRT might facilitate the delineation of GTV, thus allowing for the delivery of precise radiation beams such as proton or carbon-ion beams and improving the clinical outcome. At SPHIC, a randomized trial has been initiated in GBM patients with gross residual disease after surgery, to compare between PRT using the standard dose regimen (60 GyE in 30 fractions) and the same PRT preceded by a CIRT boost to 15 Gy RBE in three fractions [Figure 1].[34] The maximal tolerated dose, of 15 Gy RBE delivered in three equal fractions, was determined by a recently completed phase 1 trial. The delineation of the GTV and clinical target volume in this randomized trial was based on both enhanced MRI and 18F-FET uptake in PET/computed tomography studies.
Figure 1: Schema of the randomized clinical trial to investigate the effectiveness of a CIRT boost before standard-dose PRT in patients with primary GBM. CIRT: Carbon-ion radiation therapy, GBM: Glioblastoma multiforme, PRT: Proton radiation therapy, RT: Radiation therapy, Rx: Treatment

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In addition to the more effective target delineation for PBRT, the combined used of PBRT with newly developed and established standard treatment modalities, such as tumor treatment field and chemotherapy, has not yet been investigated. As such, a single-arm, prospective phase 2 trial has been designed at SPHIC to investigate the efficacy of concurrent PBRT, temozolomide, and tumor treatment field in the management of GBM.

The use of PBRT for recurrent HGGs that have a failed previous course(s) of RT should be investigated based on both the physical and biological properties of proton and carbon-ion beams. However, no such study has yet been initiated. A prospective phase 2 trial, aimed at investigating the efficacy and safety of salvage CIRT, has been initiated at SPHIC for recurrent GBM patients who received a definitive dose of photon RT. This trial is expected to be completed in 2023 because patient accrual has been slow.


  Conclusion Top


Results from a small number of single-arm phase 2 and retrospective studies have indicated that PBRT, either used alone or as a boost to photon RT, might improve disease control and OS for adult patients with HGG. Higher-level clinical evidence to confirm the theoretical advantage of PRT and CIRT in the treatment of adult HGG remains lacking. Further investigations – preferably as prospective randomized trials – of PBRT in the management of both primary and recurrent HGG are needed, to investigate its efficacy, safety, and effectiveness in improving patients' quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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