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Radiation-induced neurocognitive dysfunction in head and neck cancer patients

Abstract

It might seem odd that a special issue about Gianni Bonadonna would publish a review on radiation-induced neurocognitive dysfunction. Dr. Gianni Bonadonna is considered a pioneer in medical oncology history, mainly due to new and revolutionary treatment approaches proposed in breast cancer and Hodgkin lymphoma. He had an active role in the field of medical oncology, especially through lectures and textbooks. He shared his considerable insight of understanding cancer behavior and evaluating research advances over the years to prevent tumor recurrence and preserve patients from unnecessary toxicity. From a theoretical point of view, this complex vision is valid for all malignancies and can be indirectly shifted to every primary cancer, including head and neck cancer (HNC). During the last decades, multidisciplinary treatment for HNC has improved clinical outcomes but makes acute and late toxicity challenging. This article highlights the main central nervous structures that have a major impact on the development of neurocognitive dysfunction after radiotherapy for HNC. We briefly summarize the specific structure contouring instructions and the dose-volume histogram parameters. The aim is to raise awareness in clinicians in defining normal tissues to optimize radiotherapy regimens.

Tumori 2017; 103(4): 319 - 324

Article Type: REVIEW

DOI:10.5301/tj.5000678

Authors

Francesca De Felice, Pierre Blanchard

Article History

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.

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Introduction

The incidence and mortality of head and neck cancers (HNC) in Italy are approximately 9,300 and 2,820 patients per year, placing this disease at the 11th rank in terms of incidence and 15th rank in terms of mortality (1). Due to substantial improvement in locoregional control and survival rates of HNC patients, it is essential to understand, quantify, and prevent significant long-term radiation effects (2). In particular, a significant increase in the incidence of neurocognitive dysfunction has been observed, potentially related to the dose bath delivered using modern radiotherapy techniques to nontarget area of brain (3, 4).

The central nervous system consists of various anatomic structures, including temporal lobes, basal frontal lobes, olfactory bulbs, brainstem, hippocampus, hypothalamus, pituitary, and cerebellum. The hippocampus, the temporal lobes, the olfactory bulb, and the brainstem are the main compartments related to radiation-induced cognitive impairment, due to their close vicinity to target structures (5, 6). Radiation-induced toxicities largely depend on the dose received by these normal structures. Exceeding the tolerance of these structures could lead to brainstem dysfunction or brain necrosis (7). Accurate structures delineation is necessary, with potentially the use of subregions (7). However, neurocognitive dysfunction correlates with pathologic alteration after radiation therapy (RT), notably in the inferomedial temporal lobes (8). When using altered fractionation regimens, the quantity of brain area that receives fraction size >2 Gy was related to worst neurocognitive outcomes (7). Thus the delineation of central nervous system substructures could permit the inverse planning system to reduce high dose to these “new” critical sites.

The aims of this review are (1) to establish the main structures related to cognitive function and to summarize contouring details; (2) to explore the impact on cognitive impairment following RT; and (3) to identify where further radiation constraints are required and to potentially provide them.

Literature search strategy

A comprehensive search of PubMed database was performed, using the following combinations of research criteria: “neurocognitive dysfunction,” “cognitive function,” “neurotoxicity,” “brain injury,” “memory,” “attention,” “head and neck cancer,” “radiotherapy,” “radiation,” “organ at risk,” “sparing.” Only English-literature articles were considered. Preclinical and clinical studies of contouring organs at risk (OARs) in HNC were analyzed, as well as consensus guidelines. Additional references were selected from relevant articles. An attempt was made to include all relevant studies and systematic reviews. Search strategy was performed up to June 2017.

Structures involved in cognitive function

Physiologically, temporal lobe, hippocampus, perirhinal cortex, and brainstem play a predominant role in neurocognitive function. We briefly describe their anatomical and functional characteristics in adults.

Hippocampus

Hippocampal structure sits in the medial temporal lobe and comprises the cornu ammonis and the dentate gyrus. Because of its curved shape, it has been conventionally analogized to a seahorse. In adult subjects, the volume of hippocampus is approximately 3.5 cm3 (9). It is a paired structure. Hippocampus has a crucial role in the consolidation of information from short-term to long-term memory and spatial navigation.

Perirhinal cortex

Perirhinal cortex is located between the medial temporal lobe and the ventral visual pathway. Anatomically and functionally it is associated to the hippocampus. It is involved in odor detection, discrimination, and olfactory memory, as well as associative flexibility and recall (10).

Temporal lobe

The temporal lobe fills the middle cranial fossa. The cortex of the temporal lobe is delineated by several major sulci and gyri (11). The superior, the middle, and the inferior temporal gyri form the lateral surface of the lobe, whereas the lateral occipitotemporal gyrus, the fusiform gyrus, and the parahippocampal gyrus constitute the inferior surface. The lateral surface is indented by the superior and the inferior temporal sulci; the inferior surface by the occipitotemporal sulcus and the rhinal sulcus. The superior border of the temporal lobe is defined by the sylvian fissure, which separates the temporal lobe from the frontal lobe and the parietal lobe above. The posterior part of the temporal lobe merges with the parietal lobe and the occipital lobe, without definite cortical landmarks. Temporal cortex is responsible for auditory, olfactory, vestibular, and visual senses, perception of spoken and written language, long-term memory, and affective behavior.

Brainstem

The brainstem is mostly located in the posterior cranial fossa and structurally continues with the cerebrum, superiorly, and the spinal cord, inferiorly. The brainstem comprises the midbrain, pons, and medulla oblongata. It mainly consists of nuclei and fibers descending from cerebral cortex and regulates vital cardiac and respiratory functions.

Contouring guidelines

Accurate delineation of brain anatomic area is an extremely delicate operation and it is essential in order to maximize therapeutic ratio and reduce risk of neurocognitive dysfunction. Contouring details are shown in Table I. Generally, the optimal way to contour more reflective volumes is a computed tomography planning scan with contrast supplemented with fused diagnostic magnetic resonance imaging (MRI) (12). Recently, a panel of European, North American, Asian, and Australian radiation oncologists have defined the consensus guidelines for delineating organs at risk in HNC patients (13). They recommended contouring the brain as a unique structure, including brain vessels and excluding the brainstem. In case of primary tumors closeness to brain, including nasopharyngeal cancer, they recommended to subdivide brain into hippocampus and temporal lobe. Substantially, the hippocampus encompasses the gray matter located medially to the lateral ventricle, whereas the temporal lobe comprises the brain tissue including the parahippocampal gyrus, excluding insula and basal ganglia, which are located anteriorly and superiorly to the hippocampus (14, 15). The brainstem is defined best on MRI (16). Generally, it is contoured as a single structure and not as 3 separate substructures. The cranial border is defined as the bottom section of the lateral ventricles and the caudal border as the cranial border of the spinal cord (the tip of the dens of C2) (13). There are no appropriate delineation guidelines available in the literature of the olfactory bulb for HNC; consequently, it makes the contouring of perirhinal structure difficult.

Contouring delineation of the main central nervous system structures (anatomical landmarks)

Organ at risk Boundaries
Cranial Caudal Anterior Posterior Lateral Medial
Temporal lobe Cranial edge of the sylvian fissure Base of middle cranial fossa Temporal bone, sylvian fissure, greater wing of sphenoid Temporal lobe, tentorium of cerebellum Temporal bone Cavernous sinus, sphenoid sinus, sella turcica, and sylvian fissure
Brainstem Third ventricle Inferior limit of the foramen magnum Mammillary bodies, prepontine and premedullary cisterns Quadrigeminal plate, cerebellum, cisterna magna
Hippocampus Anterior edge of the temporal horn Atrium of lateral ventricle Lateral ventricle Uncus, medial edge of the uncal recess, quadrigeminal cistern
Olfactory bulbs Orbitofrontal cortex Cribriform plate

The olfactory bulb appears as an oval-shaped structure and lies on the inferior side of the brain immediately above the cribriform plate of the ethmoid bone (17).

Evidence showing a dose-toxicity relationship

Increasing evidence has shown that RT for HNC is variably related with neurocognitive impairment. The main manifestations of neurologic deficits are decline in memory, attention, manual dexterity, and visual and verbal recall. However,a clear dose-toxicity relationship is poorly documented. Dosimetry to normal brain tissues has been determined in several series (18, 19). Details are listed in Table II. Generally, a correlation between radiation dose to central nervous system structures, especially to temporal lobes, and impaired cognitive function has been reported. The vast majority of data come from nasopharyngeal and paranasal sinus series, due to the target volume close proximity to brain structures, primarily including temporal lobes. Most of these studies have evaluated late neurocognitive profile and memory functions after definitive RT (20-21-22-23-24). Globally, results were unanimous to show a variety of cognitive dysfunction after HNC RT. Moreover, it has been well-documented that the volume of temporal lobe radionecrosis, one of the major neurologic complications after HNC RT, is associated with the level of cognitive impairment severity, especially on memory, language, and learning profiles (22, 23). However, literature evidence concerning a lower dose to no diseased brain tissue is not well-recognized and has received growing attention in the last years. One prospective study has explored this issue (18). Hsiao et al (18) analyzed the dose-volume data for the temporal lobes in 30 patients with newly diagnosed nasopharyngeal cancer. The authors defined the mean dose to the temporal lobes of 36 Gy and the 10% of the temporal lobe volume that had received 60 Gy (V60 = 10%) as cutoff points: patients with mean dose greater than 36 Gy and those with V60 >10% had a significantly major reduction in cognitive function. Generalization of the results from this study is mainly limited by its small sample size. However, a dose-effect relationship in determining cognitive deterioration has been demonstrated and should be considered in future HNC trials. Other studies have reported some correlation between tolerance doses and development of cognitive impairment. Data on the dose-volume measures related to toxicity of such patients were not investigated. Gan et al (25) indicated that the severity of memory injury was significantly associated with radiation dose to the temporal lobes. In Meyers et al (19), a retrospective paranasal sinus cancer analysis, higher risk for neurocognitive symptoms was significantly related to RT total dose ≥60 Gy, but not to the volume of brain irradiated. The trend that an appropriate set of dose-volume constraints in brain structures should be more helpful than maximum and/or mean dose has been also observed in an analysis from the PARSPORT phase III trial (26). In order to explain the different incidences of acute fatigue in oropharynx and hypopharynx cancer patients randomized between conventional RT and intensity-modulated RT (IMRT) arms, the authors retrospectively delineated central nervous system structures and evaluated their dose distributions. The structures investigated were the posterior fossa, brainstem, cerebellum, pituitary, pineal gland, hypothalamus, combined left and right hippocampus, and combined left and right basal ganglia. A dose-effect relationship was suggested for posterior fossa, brainstem, and cerebellum.

Major studies reporting dose-toxicity relationship in head and neck cancer patients

Author Study type Patients (n) RT technique (n) Dose-volume data Dose-effect relationship
C = chemotherapy; D = dose; HNC = head and neck cancer; IMRT = intensity-modulated radiotherapy; NA = not applicable; NPC = nasopharyngeal carcinoma; RT = radiation therapy; PNSC = paranasal sinus carcinoma.
Hsiao et al (18) Prospective NPC (30) IMRT (30) Temporal lobes: Dmean 34.4 Gy; V60 9% Decrease in cognitive function p = 0.017 p = 0.039
Gan et al (25) Retrospective HNC (10) IMRT alone (5), with C (5) Temporal lobe: NA Memory impairment
Meyers et al (19) Retrospective PNSC (19) 3D RT (19) Brain tissue: Dmax >60 Gy Memory recall impairment p<0.03
Lee et al (20) Retrospective NPC (16) 3D RT (16) Brain tissue: NA Cognitive and intellectual deficits
Lam et al (21) Retrospective NPC (60) 3D RT (60) Temporal lobe: NA Visual memory deterioration
Cheung et al (22) Retrospective NPC (50) 3D RT (50) Temporal lobe: NA Lesion volume correlates with severity of general cognitive impairment
Cheung et al (23) Retrospective NPC (53) 3D RT (53) Temporal lobe: NA Learning and memory impairment
Hua et al (24) Retrospective NPC (27) 3D RT (27) Brain tissue: NA Deficits in auditory attention/concentration, immediate and delayed verbal recall, immediate visual recall, recent memory, higher-order visuospatial abilities, bimanual dexterity

Proposed dose constraints

Safe brain RT constraints are still not precisely known. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) report for the brain included RT-induced neurocognitive injury as an endpoint (27). The evidence of cognitive deterioration in radiation fields used to treat HNC is weak, as well as the evidence that brain total dose of 72 Gy in 2 Gy fractions is linked to irreversible neurocognitive dysfunction in adults is minimal (<5%). The influence of confounding variables should be considered. For instance, the large fraction size and the volume of brain irradiated, as well as the concomitant chemotherapy delivery, should represent the main variables that could influence the neurocognitive decline in HNC patients. It was estimated that large single dose per fraction (4.2 Gy/fraction versus 2.5 Gy/fraction) is associated with a significantly higher risk of temporal lobe necrosis (19% versus 5%) in 10-year nasopharyngeal cancer survivors (28). McDonald et al (29) reported a 3-year estimated 12.4% risk of temporal lobe radionecrosis (5.7% symptomatic) from a cohort of 66 patients receiving a median radiation dose of 75.6 Gy for skull base chordoma, chondrosarcoma, adenoid cystic carcinoma, or sinonasal malignancies. Temporal lobe maximum dose and V dose levels, including V40 >16.5 cm3, V50 >9.6 cm3, V60 > 5.5 cm3, and V70 >1.7 cm3, were significantly associated with the development of radiation necrosis. Moreover, it could be important to determine if RT-related cognitive impairment observed in patients is greater than age-related cognitive decline. The QUANTEC brainstem report proposed constraints for the brainstem (30). In total, 4 studies (2 of which included HNC patients) were selected to extract brainstem tolerance data to limit neurologic toxicity. Maximum brainstem dose of 50-54 Gy, V65 <3 mL, and V60 <5 mL were associated with low risk of neurologic deficit (31, 32).

Robust evidence for hippocampus and olfactory bulbs dose constraints is still lacking. The constraints proposed are based on single institute experience. Hippocampus maximum dose should be less than 10 Gy, and it is suggested to maintain V7.3 <40% of bilateral hippocampi volume to reduce radiation-induced cognitive impairment (15, 33).The maximum dose tolerable for the olfactory bulbs is 40 Gy (5).

Ideally, central nervous system structures should receive a dose exposure as low as possible without compromising target volume coverage. In order to reduce dose to nontarget brain tissue, new radiation technique approaches have been proposed. Due to its physical properties, proton therapy creates highly brain-sparing treatment plans. The potential benefits of intensity-modulated proton beam therapy in HNC are currently being investigated and high-level evidence is lacking. However, a recent dosimetric study has demonstrated a consistent lower mean dose to the central nervous system structures compared with IMRT treatment plan (34).

Describing dose-volume constraints could represent a key point in order to achieve a plan optimization, without compromising target coverage. Table III summarizes dose-volume constraints of the main central nervous system structures, based upon the published literature discussed above. It is a suggestion to minimize neurocognitive dysfunction risk in HNC treatment. Top priority should be given to maximum doses, followed by dose-volume parameters. Doses to critical neurologic structures should be reduced as much as possible, but without sacrificing coverage of target volumes, especially in nasopharyngeal carcinoma, as the adequate coverage of the gross tumor volume is a major factor for local control (35). Further prospective studies incorporating central nervous system structures dose-volume histogram analysis should be undertaken to clarify the influence of low doses on the incidence and severity of neurocognitive dysfunction in HNC patients.

Dose constraints of the main central nervous system structures

Organ at risk Dose constraint
Top priority Second priority
Dmax = maximum dose; Vx %: percentage of volume receiving x Gy.
Temporal lobe Dmax 72 Gy V70 <1.7 mL
V60 <5.5 mL
V50 <9.6 mL
V40 <16.5 mL
Brainstem Dmax ≤54 Gy V65 <3 mL
V60 <5 mL
Hippocampus Dmax <10 Gy V7.3 <40%
Olfactory bulbs Dmax = 40 Gy

Discussion

The majority of available data on radiation-induced neurocognitive dysfunction is based on retrospective series and therefore definitive conclusions cannot be drawn, due to confounding clinical factors and different analysis endpoints (3, 8, 18, 36). For instance, it remains difficult to discriminate whether the neurocognitive dysfunction is associated with high radiation dose to temporal lobe or hippocampus or both of them or to other structures. Recently, Ma et al (37) recognized late delayed injury in patients with nasopharyngeal carcinoma treated with IMRT. They analyzed functional connectivity alterations using functional MRI. They proposed that functional connectivity alterations between the cerebellum and cingulo-opercular network may be involved in the cognitive functional abnormalities. This indicates that radiation-induced neurocognitive dysfunction is not restricted to the previous mentioned area, but another encephalic region, such as cerebellum and cingulo-opercular areas, should be considered in OARs delineation, as implicated in RT-related fatigue (38). However, at present, for the sake of clarity, temporal lobe and hippocampus should be considered, and thus contoured as independent structures. Further clinical trials of central nervous system structures spared during HNC treatment are needed, in order to provide the real clinical benefit of their accurate delineation and to develop and verify the consistent value of dose-volume data. In HNC patients, to prevent neurocognitive dysfunction, the whole brain should be considered a heterogeneous structure for dose-volume calculations. The addition of brain substructures and thus of specific subregion dose constrains should become routine clinical practice, especially in nasopharynx and sinuses cancer, due to their anatomic relationship with central nervous system structures. This review highlights a major unanswered question about the dose constraints definition: the absence of dose constraint to substructures. Resolution of this issue should be important to better assess morbidity associated with HNC treatment. Cognitive decline can be exacerbated by comorbidities such as alcohol consumption, vitamin deficiencies, as well as age, chemotherapy regimen, and RT schemes, suggesting that these deficits might be treatment-related but could also be related to other patient-related factors (37). Publication of detailed brain structure dose-volume parameters, as well as clinical toxicity data, should be encouraged, in order to make data pooling possible. Primary HNC sites, as well as the heterogeneity of therapies employed, results in potential clinical bias. Investigators should collect more detailed neurocognitive evaluations in follow-up programs. New RT technique and new parameters for patient quality of life should be paramount in the treatment plan evaluation to reduce and prevent neurocognitive dysfunction.

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.
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Authors

Affiliations

  •  Department of Radiotherapy, Policlinico Umberto I “Sapienza” University of Rome, Rome - Italy
  •  Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif - France
  •  Université Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre - France

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