Radiotherapy of high-grade gliomas: current standards and new concepts, innovations in imaging and radiotherapy, and new therapeutic approaches

Abstract

The current standards in radiotherapy of high-grade gliomas (HGG) are based on anatomic imaging techniques, usually computed tomography (CT) scanning and magnetic resonance imaging (MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma (AG) or a grade 4 glioblastoma multiforme (GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume (GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume (CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase (CTV1) including any T2 hyperintensity area (edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in < 10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators (LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose-painting concept. Advanced imaging techniques provide functional information on cellular density (diffusion MRI), angiogenesis (perfusion MRI), metabolic activity and cellular proliferation [positron emission tomography (PET) and magnetic resonance spectroscopy (MRS)]. All of these non-invasive techniques demonstrated good association between the images and histology, with up to 40% of HGGs functionally presenting a high activity within the non-contrast-enhanced areas in T1. New LINAC technologies, such as intensity-modulated and stereotactic radiotherapy, help to deliver a simultaneous integrated boost (SIB) > 60 Gy. Trials delivering a SIB into a biological GTV showed the feasibility of this treatment, but the final results, in terms of clinical benefits for HGG patients, are still pending. Many issues have been identified: the variety of MRI and PET machines (and amino-acid tracers), the heterogeneity of the protocols used for image acquisition and post-treatment, the geometric distortion and the unreliable algorithms for co-registration of brain anatomy with ...

Classification of High-Grade Glioma into Tumor and Nontumor Components Using Support Vector Machine

“…Standards of treatment-planning techniques differ geographically. 24 Accurate delineation of tumor area may either limit the size of the radiation field and decrease radiation exposure to nontumor brain tissue or define more accurately the optimal radiation field to include the entire tumor area and enable more efficient treatment.…”

A concurrent ultra‐fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma

“…5,[21][22][23] Currently, concomitant and adjuvant TMZ chemotherapy during RT is the standard of care for adult GBM patients aged up to 70 years and in good general and neurological condition; however, the OS for unresected GBM (biopsy) remains low, approximately 10 months. 5 Despite their high inherent radioresistance and survival fraction at 2 Gy, GBM tumors receive the same dose per fraction, similar total dose and equivalent overall duration of RT as others tumors considered less radiosensitive, such as breast tumors.…”

“…5 Despite their high inherent radioresistance and survival fraction at 2 Gy, GBM tumors receive the same dose per fraction, similar total dose and equivalent overall duration of RT as others tumors considered less radiosensitive, such as breast tumors. [21][22][23] In the past decade, many drugs have been developed to improve the outcome of GBM patients, but novel approaches to the RT regimen have been ignored, except for the development of the ballistic and intensity-modulation radiation therapy techniques (IMRT). [21][22][23][24] In the past, alternative regimens of radiotherapy utilizing fractionation were proposed based on the hypothesis that radiation therapy could be improved by increasing total dose or decreasing overall time of treatment.…”

“…[21][22][23] In the past decade, many drugs have been developed to improve the outcome of GBM patients, but novel approaches to the RT regimen have been ignored, except for the development of the ballistic and intensity-modulation radiation therapy techniques (IMRT). [21][22][23][24] In the past, alternative regimens of radiotherapy utilizing fractionation were proposed based on the hypothesis that radiation therapy could be improved by increasing total dose or decreasing overall time of treatment. [25][26][27][28][29][30] These regimens are called "hyperfractionation"…”

Survival of High Grade Glioma Patients Treated by Three Radiation Schedules with Chemotherapy: A Retrospective Comparative Study

“…Radiation therapy (RT) after surgical resection increases the survival rates of patients with HGG compared with patients who were not irradiated 4 . To avoid extensive neurologic toxicity, the standard safe radiation dose is considered 60 Gy with conventional fractionation schedule (1.8-2 Gy per fraction and 5 fractions per week) 5 . Because of the short survival times of patients with glioblastoma, delivering the full therapeutic radiation dose within the shortest possible overall time is important.…”