Rapid advancements in radiotherapy and molecularly targeted therapies have resulted in the development of potential paradigm-shifting use of radiotherapy in the treatment of cancer. In this review, we will discuss some of the most promising therapeutic approaches in the field of radiation oncology. These strategies include the use of highly targeted stereotactic radiotherapy and particle therapy as well as combining radiotherapy with agents that modulate the DNA damage response, augment the immune response, or protect normal tissues.

https://clincancerres.aacrjournals.org/content/clincanres/21/15/3393.full.pdf

Emerging Treatment Paradigms in Radiation Oncology

We hypothesized that hippocampal-sparing radiotherapy via volumetric modulated arc therapy (VMAT) could preserve the neurocognitive function (NCF) of patients with primary brain tumors treated with radiotherapy. We reviewed data from patients with primary brain tumors who underwent hippocampal-sparing brain radiotherapy via VMAT between February 2014 and December 2015. The optimization criteria for the contralateral hippocampus was a maximum dose (Dmax) of less than 17 Gy. For NCF evaluations, the Seoul Verbal Learning Test for total recall, delayed recall, and recognition (SVLT-TR, DR, and Recognition) was performed at baseline and at seven months after radiotherapy. A total of 26 patients underwent NCF testing seven months after radiotherapy. Their median age was 49.5 years (range 26–77 years), and 14 (53.8%) had grade III/IV tumors. The median Dmax to the contralateral hippocampus was 16.4 Gy (range 3.5-63.4). The median mean dose to the contralateral hippocampus, expressed as equivalent to a 2-Gy dose (EQD2/2), was 7.4 Gy2 (0.7–13.1). The mean relative changes in SVLT-TR, SVLT-DR, and SVLT-Recognition at seven months compared to the baseline were − 7.7% (95% confidence interval [CI], − 19.6% to 4.2%), − 9.2% (95% CI, − 25.4% to 7.0%), and − 3.4% (− 12.7% to 5.8%), respectively. Two patients (7.7%) showed deteriorated NCF in the SVLT-TR and SVLT-DR, and three (11.5%) in the SVLT-Recognition. The mean dose of the left hippocampus and bilateral hippocampi were significantly higher in patients showing deterioration of the SVLT-TR and SVLT-Recognition than in those without deterioration. The contralateral hippocampus could be effectively spared in patients with primary brain tumor via VMAT to preserve the verbal memory function. Further investigation is needed to identify those patients who will most benefit from hippocampal-sparing radiotherapy of the primary brain tumor.

/pdf/hippocampus-sparing-radiotherapy-using-volumetric-modulated-4g4mbcyyef.pdf

Hippocampus-sparing radiotherapy using volumetric modulated arc therapy (VMAT) to the primary brain tumor: the result of dosimetric study and neurocognitive function assessment

Neurocognition is a very important aspect of a brain tumor patient’s quality of life following radiotherapy. The aim of the present study was to assess neurocognitive functions of patients diagnosed with high-grade gliomas undergoing radiotherapy by using the NeuroCogFx® test and to examine relevant dose/volume parameters as well as patient characteristics potentially influencing the neurological baseline status and subsequent outcome. The cohort consisted of 44 astrocytoma World Health Organization grade III/IV patients. The NeuroCogFx® test was carried out on patients during (N = 44) and after (N = 21) irradiation. The test examines verbal/figural/short-term/working memory, psychomotorical speed, selective attention and verbal speed. The results were compared with regular patient and treatment data with an emphasis on the dose applied to the hippocampus. Overall there were only slight changes in the median test results when comparing the baseline to the follow-up tests. In the ‘verbal memory test’ lower percentile ranks were achieved in left-sided tumors compared to right-sided tumors (p = 0.034). Dexamethasone intake during radiotherapy was significantly correlated with the difference between the two test batteries. Concerning figural memory, a correlation was detected between decreased figural recognition and the radiation dose to the left hippocampus (p = 0.045). We conclude that tumor infiltration of the hippocampus has an impact on neurocognitive function. However, treatment with radiotherapy seems to have less influence on cognitive outcome than expected.

A prospective study on neurocognitive effects after primary radiotherapy in high-grade glioma patients.

Background Children with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated. Methods We delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively. Results Both whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex. Conclusions Our results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects.

/pdf/altered-brain-morphology-after-focal-radiation-reveals-3jdk51g4r4.pdf

Altered brain morphology after focal radiation reveals impact of off-target effects: implications for white matter development and neurogenesis.

Patients treated with whole-brain irradiation often develop cognitive deficits that are presumed to result from normal tissue injury. Age is a risk factor for these side effects. We compared the cognitive effects of fractionated whole-brain irradiation (300 kV X rays) in rats irradiated either as young adults or in middle age. A deficit in object memory was apparent at 3 months in rats irradiated as young adults, however, no comparable deficit was apparent in rats irradiated in middle age. In addition, the deficit in object memory in young adults was no longer apparent at 6 and 12 months after fractionated whole-brain irradiation and no radiation-induced deficit was detectable in a spatial memory task at any time, regardless of age at time of irradiation. Thus, clinically relevant fractionated whole-brain irradiation in adult rats resulted in early-delayed cognitive changes that were heterogeneous, transient and age-dependent. The results of the current and previous studies of radiation-induced cognitive changes support the continued investigation and validation of rodent models of radiation-induced brain injury, which are critical for developing and testing new therapies for treatment-induced cognitive dysfunction in cancer survivors.

/pdf/early-delayed-radiation-induced-cognitive-deficits-in-adult-7hoj3fznzu.pdf

Early-Delayed, Radiation-Induced Cognitive Deficits in Adult Rats are Heterogeneous and Age-Dependent

Neurocognitive decline observed after radiotherapy (RT) for brain tumors in long time survivors is attributed to radiation exposure of the hippocampus and the subventricular zone (SVZ). The potential of sparing capabilities for both structures by optimized intensity modulated stereotactic radiotherapy (IMSRT) is investigated. Brain tumors were irradiated by stereotactic 3D conformal RT or IMSRT using m3 collimator optimized for PTV and for sparing of the conventional OARs (lens, retina, optic nerve, chiasm, cochlea, brain stem and the medulla oblongata). Retrospectively both hippocampi and SVZ were added to the list of OAR and their dose volume histograms were compared to those from two newly generated IMSRT plans using 7 or 14 beamlets (IMSRT-7, IMSRT-14) dedicated for optimized additional sparing of these structures. Conventional OAR constraints were kept constant. Impact of plan complexity and planning target volume (PTV) topography on sparing of both hippocampi and SVZ, conformity index (CI), the homogeneity index (HI) and quality of coverage (QoC) were analyzed. Limits of agreement were used to compare sparing of stem cell niches with either IMSRT-7 or IMSRT-14. The influence of treatment technique related to the topography ratio between PTV and OARs, realized in group A-D, was assessed by a mixed model. In 47 patients CI (p ≤ 0.003) and HI (p < 0.001) improved by IMSRT-7, IMSRT-14, QoC remained stable (p ≥ 0.50) indicating no compromise in radiotherapy. 90% of normal brain was exposed to a significantly higher dose using IMSRT. IMSRT-7 plans resulted in significantly lower biologically effective doses at all four neural stem cell structures, while contralateral neural stem cells are better spared compared to ipsilateral. A further increase of the number of beamlets (IMSRT-14) did not improve sparing significantly, so IMSRT-7 and IMSRT-14 can be used interchangeable. Patients with tumors contacting neither the subventricular zone nor the cortex benefit most from IMSRT (p < 0.001). The feasibility of neural stem cell niches sparing with sophisticated linac based inverse IMSRT with 7 beamlets in an unselected cohort of intracranial tumors in relation to topographic situation has been demonstrated. Clinical relevance testing neurotoxicity remains to be demonstrated.

/pdf/neural-stem-cell-sparing-by-linac-based-intensity-modulated-3pg92kbe2y.pdf

Neural stem cell sparing by linac based intensity modulated stereotactic radiotherapy in intracranial tumors

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Neural stem cell sparing by linac based intensity modulated stereotactic radiotherapy in intracranial tumors