Radiation-Induced Neuropathies in Head and Neck Cancer: Prevention and Treatment Modalities

Radiation-induced neuropathies in head and neck cancer: prevention and treatment modalities

Patrick Azzam1, Manal Mroueh1, Marina Francis1, Alaa Abou Daher1 and Youssef H Zeidan1,2

1Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon 2Department of Radiation Oncology, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon

Abstract

Head and neck cancer (HNC) is the sixth most common human malignancy with a global incidence of 650,000 cases per year. Radiotherapy (RT) is commonly used as an effective therapy to treat tumours as a definitive or adjuvant treatment. Despite the substantial advances in RT contouring and dosage delivery, patients suffer from various radiation- induced complications, among which are toxicities to the nervous tissues in the head and neck area. Radiation-mediated neuropathies manifest as a result of increased oxidative stress-mediated apoptosis, neuroinflammation and altered cellular function in the nervous tissues. Eventually, molecular damage results in the formation of fibrotic tissues leading to susceptible loss of function of numerous neuronal substructures. Neu- Review ropathic sequelae following irradiation in the head and neck area include sensorineural hearing loss, alterations in taste and smell functions along with brachial plexopathy, and cranial nerves palsies. Numerous management options are available to relieve radiation- associated neurotoxicities notwithstanding treatment alternatives that remain restricted with limited benefits. In the scope of this review, we discuss the use of variable management and therapeutic modalities to palliate common radiation-induced neuropathies in head and neck cancers.

Keywords: radiation, neuropathy, head and neck cancer, treatment, prevention

Correspondence to: Youssef H Zeidan Email: [email protected] ecancer 2020, 14:1133 Background https://doi.org/10.3332/ecancer.2020.1133 Published: 03/11/2020 Head and neck cancer (HNC) is the sixth most common human malignancy accounting Received: 16/05/2020 for 3% of all cancers, with 650,000 cases and 330,000 deaths per year [1, 2]. HNC is a Publication costs for this article were supported by disease involving heterogeneous regions in the head and neck area such as the pharynx, ecancer (UK Charity number 1176307). larynx, paranasal sinus, nasal cavity, oral cavity and salivary glands. There are histopath- Copyright: © the authors; licensee ological and molecular differences between these cancers, along with their treatment ecancermedicalscience. This is an Open Access modalities and outcomes. About 90% of cases occurring in these anatomically complex article distributed under the terms of the regions are squamous cell carcinomas, which are diagnosed at a late stage when clinical Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which symptoms arise. Tumorigenesis in HNC has genetic and environmental roots. Long-term permits unrestricted use, distribution, and tobacco and alcohol consumption along with high-risk types of human papillomavirus reproduction in any medium, provided the original were found to be the main oncogenic risk factors. work is properly cited.

ecancer 2020, 14:1133; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1133 1 neck cancer along with theavailable radioprotection andtreatment methods. In thisreview, wemolecular discuss radiationunderlying mechanisms mediated neuropathies, followed by pathological aspectsinheadand neuropathies emanating from HNCradiotherapy isessential for improving patients’ quality of life, dueto theirreversible nature of suchinjuries. nerves were alsoreported, along with optical neuropathies andtrouble inswallowing (dysphagia) andspeaking(dysphonia). Understanding (SNHL) andalterations intaste andsmellsensory functions(dysgeusia anddysosmia, respectively). Injuries to thebrachial plexus andcranial lasting compromise inthepatients’ well-being. Radiation-induced neuronal damage inHNCmanifests mainly assensorineural hearingloss capacity for repair andregeneration of thenervous tissues. While not ascommon asother adverse effects inHNC,neuropathies leave along- head andneckregion. Radiotherapy canhave deleterious anddetrimental damagingeffects onthenervous system becauseof thelimited Patients with HNCundergoing radiotherapy are at great riskof developing neuropathies dueto theabundance of thenervous tissuesinthe increased survival owing to novel advanced treatment protocols andresearch. ogy cancompletely protecthealthy from tissues radiation damage. patients HNC stillhave to cope treatment-relatedwith symptoms, despite impair patients’ quality of life (QoL) andeven worsen theprognosis. While RT hasgreatly evolved inthepastcouple of decades,notechnol- to neighbouringuninvolvedexhibiting normaltissues, acute (weeks to months) or late (months to years) toxicities. The latter could severely proliferationthe of tumour cells throughdifferent molecular Despite mechanisms. itseffectiveness, radiation may induce collateral damage 80% ofpatients HNC undergo RT at leastonce duringtheir course of theillnessasprimary or adjuvant treatment [3].RT isknown to inhibit The treatment approaches of involve HNC surgery, radiotherapy (RT), chemotherapy, immunotherapy or combinational modalities. Around ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 13]. Intetracyclines addition, derivates andceftriaxone relieved neurons from oxidative stress andsubsequent apoptosis [14].Irradiated administrationof free radicalsscavengers asmelatonin,and kukoamine rhubarb rescued neurons from radiation-mediated apoptosis [11– The key behind neuronal death isindeeddirector indirectradiation-induced ROS upregulation. Modulating oxidative stress levels by mechanism rather thancell death [10]. or neuronal synapses.Such low dosesresultin mitochondrial andtheexpression fusion of complexes IandIII,promoting anadaptive cellular reduce cell death inneurons [9].Interestingly, a low dose of radiation (0.2Gy) didnot affect whatsoever reactive oxygen species(ROS) levels on neurons’impact fate. For instance, fractionatingdoses tothe allow DNA repair inbetween fractions proved to beagood strategy to to astrocytes remainwhich radioresistantat 32Gy [9]. Total doseadministration anddelivery methods were found to have aninteresting apoptosis inpostmitoticcortical neurons asearly as4hours post-irradiation. Therefore, neurons were shown to beradiosensitive incontrast Manyhave studies establishedthat neuronal apoptosis isdose-dependent andoccurs shortly after RT [8]. A doseof 2Gy was ableto induce to ionising radiation, andneural substructures have large variabilities inmolecular reaction. ferences inlocalisation,oftypes cells (neurons andneuroglia) andcell–cell interaction mechanisms. Thus, there is nohomogenous response tion of radiation-induced DNAin theneuronal adducts genome leadsto apoptosis [7].Neuronal tissuesare very heterogeneous dueto dif Neurons are differentiated postmitoticcells reducedwith ability to repair radiation-mediated DNA damage. Consequently, aslow accumula- IR andneuronal apoptosis induced neuropathies inHNC. activity. Ultimately, molecular damage leadsto apoptosis, neuroinflammation andaltered neuronal function,themainhallmarksof radiation- RT targets numerous molecular entitiesas theintegritysuch of theDNA molecule,oxidative stress, inflammatory cascadesandsynaptic Similarly, peripheral nerve radiationis defined insult by altered axonal growth along formationwith perineurium [5,6].On thecellular level, thatoccur 6monthsafter radiotherapy, characterised by morphological damage asdemyelination, gliosisandabnormal vascularisation [4]. abnormalities andcognitive impairments are progressive and often permanent. Radiation-induced late brain injuries are irreversible changes and headachesare usually reversible andmay resolve spontaneously. However, long-term sideeffects asradionecrosis, such white matter Radiation-induced neuronal injury isamultifactorial pathogenesis with acute andlong-term onsets. Acute symptoms like drowsiness, nausea Molecular pathophysiology of radiation-induced neuronal injury 2 -

Review ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 effect of radiation [38].Dendritic architecture is compromised following a 10 Gy irradiation neurons,in hippocampal marked by a decrease in neuronal tissues largewith doses.In fact,intrinsic neuronal membrane alterations were noted 3months after exposure, hinting along-term While neurons can small dosesofwithstand radiation [10],acute andlong-term morphological and electrophysiological changes occur in IR andalterations inneuronal function radiation field where nerve fibres are includedandpatients’ comorbidities [34]. todamage such a large including totaldose (>50Gy to plexus,>60 Gy to cranial nerves), alarge doseper fraction >2.5Gy, aconsiderable and demyelination, followed by a pronounced fibrotic tissuearound nerve trunks and decreased vascular supply. Many risk factors can lead Peripheral nerves display electrophysiological changes inearly phasesof RIF pathogenesis. The pathological process includesaxonal injury Managing chronic neuroinflammation could alleviate asubstantial partof theneuropathies observed following RT. CCL2-CCR2 chemoattraction cytosis of bothdamaged andhealthy neurons. Thisis accompanied phenomenon by therecruitment of peripheral macrophages through inflammatory process by secreting(HighHMGB1 mobility groupbox 1) This process acts through the NF-κb pathway coupled with the upregulation of microglial MHC and CD68. Injured neurons contribute to the A similaris initiated mechanism central inthe nervoussystem where along with lymphocytes recruitment, there isanactivation of microglia. tissue atrophy [36] inhibition of extracellular matrix-degrading enzymes. Thus, fibrotic areas are generated, leadingto susceptible lossof or function even fibroblasts are differentiated into myofibroblasts that produce a surplusof extracellular matrix components suchascollagen, along with beta) (TransformingfactorTGF-βThrough growth cells. mesenchymal circulating offerentiation PDGF (Platelet-derived growth factor) immunoreactivity along with theinvasion of lymphocytes into thespinalparenchyma [35]. Afterwards, monocytes are transformed into sion molecule-1) stances, neutrophils are engaged via increased ICAM-1(Intercellular Adhesion Molecule 1)andPECAM-1 (Platelet endothelial cell adhe- activate nonspecificinflammatory cascadesandpromote neutrophils andmonocytes recruitment to thesite of injury. In suchcircum- sis, tissues secrete chemoattractants known as proinflammatory cytokines, such as TNFα, IL-1ß, COX2 and AP-1 radiation injury. RIF occurs between 4and 12 months after therapy, anditspathogenesis is well established.Following injury andapopto- The mainhallmarkfor neuroinflammation istheoccurrence of radiation-induced fibrosis (RIF) which isalate, unavoidable complication of IR andneuroinflammation inhibition halted excitotoxicity induced apoptosis after radiation exposure neurons inhippocampal [32]. inhibitors suppressed p53accumulation andhalted radiation-mediated cell death HT-22 inhippocampal cells [31].Furthermore, NFAT3/c4 bypromotingautophagyapoptosis neuronal inhibited to targetingAMPKα1 its via Targeting apoptosis-related pathways could beatherapeuticmodality inrescuing neurons from RT-induced death. For instance, minocycline in radiation-induced apoptosis of different neuronal substructures [28,29]. neurons by abrogating p53-dependent apoptosis remainsto beelucidated. On another note, suggest multiplestudies theimplication of c-Jun ions Calcium were alsoshown to modulate RT-induced cell death inimmature dorsal ganglionroot [26,27]. Whether ionsrescue calcium p53 pathway didnotinduce apoptosismediated but neuronal entry into theG0-G1transition phaseby increasing p21andcyclin-D [25]. remainsunclear [19–23].Similarly, cell deathin glialstructures was found to bep53-dependent [24].In sensory ganglionratcells, the ATM/ Radiation-induced apoptosis was foundto Bax- bep53-, and ATM-dependentneuronal inmost structures, while therole of caspase-3 nism [18]. Thus, promoting free radical scavenging rescued neurons from cell death post-irradiation. [15–17]. Furthermore, metallothioneinprotected neurons andastrocytes from ionisingradiation potentially through anantioxidantmecha- cell-conditionedculture medium promoted oxidative stress andcell death, which were alleviated if neurons were co-cultured with glialcells expression onendothelial cells [4,34].In fact, nerve injury to lumbar the root inrats increases ICAM-1andPECAM-1 . [4]. Eventually, persistent microglial activation will lead to neuronal amplified damage inthelongterm [8,37]. secreting M2-macrophages, promoting therecruitment of stromal fibroblasts along thedif with and calreticulin which are ligandsto microglia, thuspromoting phago- [14, 30]. Similarly, administration of and GSK3ß MDM2 secreted by M2-macrophages, stromal . These molecules [8, 33].These 3 -

Review stages for patients to have better survival chances. From apoptosis to radiation-induced fibrosis, andimpaired neuronal function,thispathological cascadeneedsto behalted initsearliest Overall, unattended imbalance inROSlevels dueto radiation exposure may bebehindtheobserved ‘domino effect’ intheseneuropathies. nism manifested inanupregulation of antioxidant enzymesandanti-inflammatory cytokines [44]. reduced mitochondrial function Intriguingly, low dosesof radiation(0.1–0.5 Gy) increased synaptic excitability along with dendriticspinesandneural outgrowth coupled to a [41]. Conversely,mentioned some studies adramaticincrease insynaptic activity after irradiation leadingto neuronal excitotoxicity [32]. (LTP) acid) GABA(γ-aminobutyricinhibitory of increase concurrent a with tors synapticefficacy. Furthermore, radiation exposure resulted inanacute declineinexcitatory NMDAR (N-methyl-D-aspartate receptor) recep- recorded intheCA1region ofafter thehippocampus radiation, characterised by thedownregulation of spike generation, excitability and branching, length and density of dendritic spines,along with changes in synaptic protein levels ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 tea extractcomponent, abrogated apoptosis andpreserved mitochondrial membrane potential after radiation exposure and inHEI-OC1 Other agentshave beeninvestigated for radioprotectionin theauditory system theoxidative outside stress context. Epicatechin, agreen tected organ of Corti rat explants from irradiation asitreduced thelevels of oxidative stress andapoptosis inadose-dependent manner [ consequently promoted better ABR responses incomparison with thecontrol group [51].Similarly, thesynthetic steroid dexamethasone pro- apoptosis 72hours after irradiation [50].In addition,aminothiol prc-210 alleviated inflammation andspinalganglioninjury inguineapigsand the auditory milieu.For instance, L-N-Acetylcysteine was shown to protect OC-k38 auditory hair cell lineby promoting survival andinhibiting However, pharmacological agents have rarely beentested inclinicaltrials.ROS scavenging agents were found to have aradioprotective role in Many experimental studieshave beenconducted invitro andinvivo, to develop pharmacological drugsagainstradiation-induced ototoxicity. the auditory apparatus regardless of thetreatment technique received by patients. patients who withdrew fromthe study leadingto areductionin itsstatistical power [49]. Another suggestion could betheradiosensitivity of balance assessment, ototoxicity, QoL andprogressive hearingimpairment. These results could beexplained by theconsiderable number of therebyfrom sparingnormal tissues radiation [48].Both groupshad hearinglosssuperior to 10db, while nodiscrepancies were found in and intensity-modulated radiotherapy (IMRT).IMRT isanadvanced technology that conforms radiation doseto theshapeof thetumour, randomisedprospective 110 patientsincluding trial, noted nosignificant differences incochlear sparingbetween conventional radiotherapy kHz) was lessdamaged. Incidence of SHNL increased progressively with timeand was A found to bedose-dependent andpermanent [46]. High-frequency hearing(above 4kHz) was mainly affectedpatients inHNC receiving radiotherapy, whereas speechfrequency (below 4 mal auditory brainstem responses (ABR) mediatedcochlearin the oedema nerve [47].Para-cochlear structures asthespiral ganglionneurons may alsobeinjured, resulting inabnor radiation-induced auditorymanifests insult ashearingloss/decline, potential ossification of theinner ear fluidspace andeven inflammation- chronic injury to theauditory pathway manifested inp53-dependent apoptosis of theouter andinner auditory hair cells [46].Therefore, inflammatory cells isensured by thestria vascularis,triggeringthus inflammation andROS imbalance intheauditory milieu. This promotes affected by radiation injury are thestria vascularis and organ of Corti of the cochlea. Following irradiation, recruitment of macrophages and developing SNHL isnoted when theinner cochlea is the radiationwithin fieldof primary tumour sites [45]. Auditory organs that are most Sensorineural hearing lossisacommonneurological complication that emerges following radiotherapypatients. inHNC A higher riskof Sensorineural hearingloss to address theseissuesinpreclinical experiments inorder to thepathological tackle mechanismsanddevelop curative strategies. taste and smell alterations, along with different neuropathies involving the brachial plexus and cranial nerves. Thus, it is of importance utmost Head andneckcancer radiation-induced neuropathies canaffectfundamental sensory functions. This canmanifest ashearingloss/decline, Sensory dysfunctions and radioprotection [40]. In addition,radiation suppressed theexpression of Arc, anessential protein insustainingLTP andspatial memory consolidation [42, 43]. There isalsogrowing evidence that low radiation doseconfers to neurons aradioadaptive mecha - [46]. receptors corresponding with suppressed long-term potentiation [39]. Changes in synaptic transmission were 52]. 4 -

Review ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 salivary glandsusingdetailed dosimetric data [83]. in Royal Marsden Hospitalis correlating qualitative and quantitative data for taste loss with meanof radiation dosesto theoral cavity and between hyperfractionated andconventional radiotherapy [81], while IMRT was advantageous inQoL outcome [82]. An ongoing clinicaltrial through literature, but thesweet flavour was the quickest to recover 12 monthsand was dependentdose toon the oral the cavity andtongue [80].Recovery post-treatment time varied with respectto tastes ery at 6 months. Nonetheless,loss of partial taste was stillnoted at 2 years post-radiotherapy [78, was observed at adoseofGy 40-60 totongue the area [78]. Taste impairmentsat start 5 weeks post-irradiation, followed by partialrecov- whether subjective questionnaires or objective methods were usedto assess gustatory abilities affected by radiation. The observedare disparities dueto variables that differed between asradiation studiessuch dose,cancer typeand oral cavity radiotherapy [76].Nevertheless, there are many discrepancies through literature regarding which flavour sensingisthemost after irradiation [71,75], while thesweet taste was theleast endangered [74].Sour taste lossismore common inpatients undergoing direct Radiation-induced dysgeusia inHNChadapredominant incidence rate of 69%–93%[71–74].Bitter andsalty tastes were themostaffected profile andsubsequently patients’ quality of life that could generate additionalunwanted complications. ofpurposes pleasure/survival (sweet,and salty) umami anddefence (sour, bitter) [70]. Alteration intaste influences food intake, nutritional the primary gustatory cortex. There are five basictastes (sour, salty, sweet, bitter andsavoury that umami) are sensed theevolutionarywith VII nerves. Gustatory messages are then transmitted to the brain stem, specifically to the rostral solitary and nucleus, further delivered to Flavours are detected via taste buds localised in the tongue, which are neuroepithelial cells innervated by the glossopharyngeal IX and facial pathophysiological aspects. suggested toreasonmain bethe loss of behindthe gustatory abilities;however, research showed that abnormalitiesintaste have alternative tortion isusually acomplication associated xerostomiawith (dry mouth), another radiation-induced sideeffect Hyposalivation inHNC. was Similar todysgeusia SNHL, or taste alteration isacommonside effect observed inpatients undergoingwith HNC radiotherapy. Taste dis- Dysgeusia multidisciplinary approach inpatients with severe SNHL [69]. hearing sense. Whilehas beennot it effective auditory inmild impairment, HBOT mightcontribute to hearingimprovement as apartof a pathway andacousticnerves. On another note,remains it unclear if hyperbaric oxygen treatment(HBOT) couldbe effective inretrieving thatelicits someauditory nerve fibres cansurvive radiotherapy, albeittheextensive damage that radiation exerts onthecentral hearing As for non-pharmacologicalcochlear modalities, implantations were successful inrecuperating hearingpost-treatmentfinding [68].This radiation context inHNCunder clinicaltrials. or oral administration of steroids was effective inauditory recovery [67]. All of thepreviously mentioned drugsshouldbeinvestigated ina knockout mice abrogated TNF-mediated apoptosis in auditory hair cells silencing RNANOX3 and flunarizine neurotrophicfactor),(Brain-derivedBDNF trophin-3, thiosulphate,ine, sodium ebselen, diethyldithiocarbamate, D-methionine,acid, lipoic 4-methylthiobenzoic salicylate, acid,sodium neuro - 62–64]. Numerous agents have beenproven effective inalleviating cisplatin-induced ototoxicity. These includeagents asN-acetylcyste - scavenger, amifostine,results haddisputable regarding cisplatin mediated hearinglossandhadneurotoxic sideeffects onitsown [57,58, of radiationand cisplatin resulted in worse hearingthresholds compared to subjectstreated to radiationROS alone[61].A well-established be cisplatin andradiation dose-dependent and was associated with age, tobacco andalcohol consumption [59, 60].Combined treatment from chemoradiation or chemotherapy-induced ototoxicity, incontrast those with who usedionisingradiation solely. SNHL was found to cisplatin,a well-knownototoxic agent Sensorineural hearinglossisfurther exacerbated inpatientsreceiving chemoradiotherapy, specifically concomitantwith administration of analysis [56]. [55]. Alternatively, miRNA-207stood as amicroRNA out key player inradiation-induced damage cell inHEI-OC1 linefollowing microarray role of metformin was alsoinvestigated inradiation-induced hearingimpairment; however, nootoprotective role was elucidated for thedrug the degeneration of thespinalganglion,stria vascularisand outer auditory hair cell inafractionated irradiation guine [57, 58].Muchexperimental data regarding treatment-related hearingimpairment have beenobtained [79]. Furthermore, no differences in dysgeusia prevalence were noted [66]. In a sudden loss of sensorineural hearing loss, intratympanic [57, 65].Under basalconditions, Nfatc4 double [77]. A manifestationmaximum of dysgeusia 79]. Dysgeusia improved between 1and 5

Review extract Zingiber officinale that was found to reduce lipidperoxidation andincrease superoxide anionscavenging [95]. radiation was foundto alleviate taste aversion inrats Medicinalherbs were alsoconsidered for treatingtaste alterations. Prophylactic intravenous administration of mint oil,Mintspicata, pre- compared to control inonestudy [93]. yet Dow University aimsto further examine therole of zincinradiation-induced dysgeusia. However, noresults have emerged from thisstudy by anotherin trial clinical sulphatezinc which failed to preventradiation-induced dysgeusia [91]. A recent clinicaltrialcompleted in2019 [89]. Onother the hand,astudy noted nodifference inrecovery between zinctreated andplacebo groups [90]. The latter was supported A randomisedthatclaimed trial administrationthe of zincsupplements improved patients’ gustatory abilitiesone-month post-radiotherapy taste buds.It alsopromotes gustinsynthesis, aprotein essential for theregeneration and proliferation of taste buds. ies reportingcontradictory results.Zinc is anessential nutrient antioxidantswith properties andacofactor for many enzymespresent inthe Very few drugshave beendeveloped to mitigate radiation-induced taste alterations. Zinc sulphate was investigated inthisregard, with stud- suppressor protein CHK2 was found to partially abrogate p53-mediated apoptosis of taste cells [88]. ofinhibition protein deacetylaseSIRT1 in taste organoids buds promoted survival after irradiation [87].Similarly, genetic lossof thetumour showstemporary thesudden interruption of cell proliferation post-irradiation, which isresumed around one week later [86].Furthermore, arrest (1–3days), entry into SandMphases(5–6days) andareduction of differentiated taste budcells (7days). The establishedtimeline treatmentfor patients HNC thatdownregulationthe of genes the in Wnt/β-cateninpathway-repressed proliferationtastebuds after fractionated irradiation, mimicking by theinhibitionof taste budcells’ proliferation, particularlyII cells type detecting sweet flavours [84]. A pivotal molecular study established proliferationthe of tastecells. bud Irradiated mice showed anincrease insucrose threshold compared to control, which couldbe explained Experimental studies were developed to investigate behind radiation-induced themechanisms dysgeusia ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 the cessationwith of mitosis, especiallyInterestingly,basal lamina. inthe nodifferences regarding apoptosis were noted intheolfactory irradiation, completely abolishedat 24hours andrecovered 5 weeks later. Layers of theolfactory are epithelium alsoaffected by radiation, neuroepitheliumfollowing radiation mice. inadult The proliferation of theolfactory stem cells hasbeeninhibited asearly as2hours post- The aetiology of radiation-induced dysosmia hasbeenpoorly examined. One study investigated themorphological changes inolfactory ryngeal cancer [101], which was found to beassociated with theextent of thetumour andnasalirrigation [102]. radiotherapy andIMRT [100].Moreover, IMRT increasedincidence the of olfactory alterations andrhinosinusitisinpatients with nasopha- irrigationalong and obstruction with hyposmiain patients subjected to chemoradiation, no with differences reported between conventional Besides its direct effects on the olfactory epithelium, radiation also impacts the nasal cavity environment. Exposure to X-rays increased nasal [99]. Similar to dysgeusia, thepaucity of subjective andobjective assessment hinders theability to measure smellalterations [77]. tification was lessinfluenced by treatment. A study reported noeffect onolfactory identification thresholdto up 5 years post-radiotherapy Olfactorythelium. alterations were reported asfar as5 years post-radiotherapy. Although odour detection was heavily affected, smelliden- treatment. Olfactory recuperation was further prolongedto up 20months if patients received adosehigher than10Gy to theolfactory epi- were further exacerbated if patients hadconcurrent chemotherapy. Recovery of odour perception was reported asearly as6months post- A systematicreview reported thatodour detectionand identification thresholds were impaired rightafter radiotherapy completion and intake, well-being andinability to detect safety hazard situations [98]. neuroepitheliumcompared to other tissues is sparedwhich fromradiation injury patientswhen are treated for themore common regeneration (3)andthequick HNC of theolfactory occurrence of nasalcavity andparanasal tumours (3%ofmalignancies) HNC [96],(2)theupper anatomical localisation of theolfactory milieu Radiation-induced olfactory dysfunctionsin patients head andneckcancerwith remain poorly studied. This canbeattributed to (1)therare Dysosmia [92]. Amifostine fell shortinrelieving taste alterations following RT, which were surprisingly more common intheagent-treated arm [85]. FollowingRT, of achain molecular events unfolds intaste buds,starting with apoptosis (1day), cell cycle [97]. Nevertheless,dysosmia isstillasideeffectthat impactssurvivors’ day-to-day life, from food [94]. Similar results have beenuncovered with intravenous administration of aginger in vivo. Most studies focused on 6

Review ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 months of follow-up to 60Gy [124].Moreover, only 2%of patients reported early transient radiation-induced brachial plexopathy after theseventh and eighth ing the tolerance dose of the brachial plexus. In fact, somereported no brachial plexopathies in 72% of patients receiving a dose superior ing known asparaesthesia (40%)andmotor weakness oratrophy muscle (25%)[123] . However, contradictory results were reported regard- in combination chemotherapy.with Theprevalent most symptom reported was ipsilateral pain(50%),followed by or numbness tinglingfeel- Injury ofbrachial the plexus was reportedof in22% patients had receivedwho radiotherapy foreither HNC post-operatively, definitively or severe cases.Current literature investigating plexopathies andneuropathies following irradiation comes mostly from casereports. radiation-induced brachial plexopathycould (RIBP) affect patients’ motor and sensory activities, along pain, with weakness and paralysis in the muscular, and motor-sensorycutaneous innervation of the shoulder, chest and upper extremity. Thereby, injury to this plexus known as Brachialplexus is defined as anetwork of nerves emerging fromthe upper cervical andthoracic partof thespinalcord. It isresponsible for tissues by neighbouringcells [34,122]. signalling ofamplified inflammatory cytokines. Neuroinflammation is stimulated as a consequence of lysosomal digestion of necrotic neural poorwith vascularisationand entrapment of nerve bundles. This process isorchestrated by adramatic increase inoxidative stress along with worsen over several years. Following disruptioninflammation-mediated inhomeostasis, fibrosis may develop, leadingto afibroatrophic state many variables,as radiation such dose,neuronalinvolved, tissues physiological conditions of thepatient, RIPNmay resolve spontaneously or Radiation-induced peripheral neuropathiesare (RIPN) first characterised by achange inneurons’ electrophysiological state. Depending on regions, followed by theshoulder andarmareas [121]. ropathies have beenreported by patients undergoingHNC with radiotherapy. Neuronal pain was mainly identified intheheadandoral cavity BothHNC. entities manifestas radiation toinsult neuronal closeto tissues or within theradiation field.Intermittent andcontinuous neu- Brachial plexopathies andcranial neuropathies are amongthelate neurological complications emanating from radiotherapy inpatients with Brachial plexopathies andcranial neuropathies advantage of previously establishedtreatments for smelldisorders. the patient permanentwith smellinglossor anosmia[109].Further studiesare warranted inmanagingradiation-induced dysosmia taking betweentions theolfactoryolfactory bulbandthe neuroepithelium to haltphantosmia. While thismethod treats thesymptoms, itleaves [120]. Furthermore, radicaland invasive as surgery solutions have beenadopted. Surgical treatments are effective inannihilating connec role of oral zincadministration was alsoexamined, where it was found to have regenerative properties inpost-traumatic olfactory disorders stimulation administration of corticosteroids was proposed for sinonasalsmelldisorders [110],along with acupuncture [111,112],transcranial magnetic drops have beenadvocated for anaesthetising olfactory neurons may but exhibit undesired effects [109].In addition,short-term systematic ing phantosmia. However, alltheabovementioned lacktesting in clinical trialsandmay exert severe unwanted sideeffects. Topical cocaine ception.Sedatives, anti-depressantsand anti-epileptic havedrugs beensuggested inblockingtheolfactory functioninpatients experienc saline andoxymetazoline HCldrops have beenproposed for patients experiencing dreadful smelling(phantosmia) to reduce their odour per There are limited treatments available to ameliorate smellalterations regardless of theunderlyingaetiology. Nasal occlusions, topical nasal enhanced olfactory function,especially inthosetreated with concurrent corticosteroids [106]. sense ofover smell time therapy. No results have beenreported from thisstudy to date [105].Prior studiesestablishedthat olfactory training improves patients’ study theeffectof olfactory training inimproving smellperception inpatients nasopharyngealwith andparanasal sinuscancers after radio- No radioprotective agents againstdysosmia have been adopted. However, one clinicaltrialat Stanford University was launchedin 2017 to bulb were alsonoted, with amarked decrease of GABA-ergic subtype [104]. unchangedto up 60days after irradiation. Changes inthesubtypes of theinterneurons connecting theolfactory to epithelium theolfactory days post-irradiation. This depletion was marked by adecrease inBrdU-positive cells intheglomerular andintralaminar layers, remaining betweenepithelium irradiated the andcontrol [113], caroverine [125]. In addition,thetherapeuticdose was neither ariskfactor for brachial plexopathy insequential IMRT [126].While [106–108]. For instance, exposure to 4different odours twice aday over 8months inpatients smelldisorderswith [114], pentoxyphilline [115], theophyllinevitamin A [116], [103]. A reduction inneurogenesis andsize of theolfactory bulb was revealed 15 , lipoic acid[118]and [117], minocyclinelipoic [119]. The 7 - - -

Review satisfactory results Nevertheless, large arestudies clinical neededto determine theeffectiveness of invasive such treatments, asto date, they donot deliver over, thephysical release of entrapped nerve bundlesfrom excessive fibrotic tissuesmay improve symptoms inlate stages of nerve fibrosis. procedures used to treatinjuries clean-cut with a proximal available stump for grafting, usually done inbrachial plexopathies [146]. More- conductionby degeneratingtargeted specific groupsof neurons responsible for thepainmanifestation. Nerve graftand neurotisation are More severe cases may require surgical interventions as neurolysis, nerve grafting or removal of fibrotic tissue. Neurolysis may improve nerve in other radiation-induced sideeffects inHNCdemonstrated by thesamegroup istrationof pentoxyphilline-tocopherol-clodronate didnotelucidate any beneficial effect inRIBP,the promising albeit effects of thesedrugs brain injury [142].Contrastingly, nosufficient evidencethe useof supports HBOT ineasingRIBP [148].On that note, acombinational admin- Apatinib,a selective tyrosine kinaseinhibitor for VEGF-2,is another agent under clinicalstudy inChinapatients with radiation-induced administration of theanti-epileptic drugshowed improvement inQoL of patients despite themanifestation of someadverse effects [147]. cal trialshowed theeffectiveness of another anti-convulsant, pregabalin, intreating radiation-induced neuropathic patients. paininHNC The ther theuseof gabapentin asanalternative to opioidsfor neuropathic painafter radiotherapy [144].Furthermore, inHNC arandomised clini- (gabapentin)drugs andtricyclicanti-depressants (amitryptiline) hasbeensuggested [34,146]. A clinicaltrialinBelgium will investigate fur in MD trial Anderson Cancer Center [143].Neuropathicis usuallypain symptomatically treated by opioids;however, theuseof anti-epileptic effects alleviate neuroinflammation,NSAIDs areas first-line used treatment, followed by thetemporary useof corticosteroids dueto potential side a curative strategy has yet to beestablished.Incidentally, numerous ongoing clinicaltrialsare focusing [142–144].To onmanagingRIPN While management of RIBP andRICP mainly focuseson treating thesymptoms asneuropathic such pain,motor andsensory weakness, tion or fieldsize to limitneuropathic collateral damage. vulnerable to radiationinjury [140,141]. Althoughcontouring nerves isessential, somecasesrequire reducing thetotal dose, dose per frac most the are those as nerves XII through IX and Vthe forespecially nerves, cranial forvariousdeveloped been also have Manyguidelines Radiation oncologists usuallythe brachial outline plexus asorgan-at-risk (OAR) following consensus guidelinesandcontouring atlases [137]. resonance imagingandCT techniquesleads to better contouring, assuggested for thebrachial plexus [138]andthecranial nerves [139]. computed-tomography (CT) helpsinlocalisingneuraland subsequent tissues sparingfrom radiation [137]. A combination of both magnetic Contouring both thebrachial andcranial nerve bundlesisusedasafirst-line intheprevention of both RIBP andRICN.Delineation using V, abducens VI andfacial VII nerves [128,134,136]. patients displayed asymmetry of facial sensitivity, facial weakness, abnormalitiesineye movement or vision dueto palsiesinthetrigeminal nia), swallowing (dysphagia) andchewing (discussedfurther below). Upper cranial nerves are affected to alesser extent. As aconsequence, hypoglossalXII the IX, and glossopharyngeal X vagusthe chemotherapy, upperfibrosis neck andlonger durationof therapy [135,136].Lower cranial nerves thatare most vulnerable to treatment are at 20 years post-radiotherapy (44.5%).Overall, radiation-induced cranial nerve palsy correlated with atotal doseof radiation along with quently inlower nervescompared (25.5%) toupper the ones(13.9%). The cumulative incidence of cranial nerve insultreached itshighest longer followIn up. across-sectionalstudy involving 317nasopharyngeal cancer patients, 30.9%developed cranial nerve injury, more fre- frequent one[132–134]. The inconsistencies could beexplained by differences infollow-upperiods ahigherwith incidence reported with regardingancies incidence the rate ofinjury, this definingsome with as arare it outcome [128–131], while others itasamore supporting Radiation-induced cranial neuropathyhas beeninvestigated (RICN) asacomplication following treatment in HNC. There are many discrep- ing doseandtheoccurrence of theinjury [127]. Therefore, theradiation doseandmodeof delivery may beimplicated inRIBP. a systemic meta-analysis reported alow percentage ofincidence RIPB inmostcohort studies,itsupported theassociation between increas- ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 ranges from 10to 58months post-RT [153,154].Usually painless,RIONisanuncommon sideeffect with anearly incidence of 9%–11% progressive-to-abruptipsilateral or bilateral loss, monthsvisual to years following irradiation. Onset culminates at 1–2.5 years [151,152]and Opticneuropathies are potential neurologic sequelaeof RT Radiation-induced inHNC. optic neuropathy (RION)isdefined asanirreversible, Optic neuropathies [145]. The useof prednisone andmethylprednisone for radiation-induced neuropathic isthesubjectof paininHNC acurrent clinical [150]. [128, 133, 135]. Clinically, injuries such manifest in speech(dysphoin difficulties - [149]. 8 - -

Review ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 ing activity. A doseof >41Gy with >24% volume of theirradiated larynx was associated with anincreased riskof aspiration andpercutaneous improve at 6–12months after thetreatment [173,179].Chronic dysphagia could occur 1-year post-RT if there isnoimprovement inswallow- tors for late dysphagia [173,175]. According to ameta-analysis, swallowing problems peakat 0–3months after RT (acute dysphagia) andusually the incidence range [171,175].Moreover, increased age, smoking,prophylactic feeding tubes andsurgical interventions make excellent predic total dose,dose per fraction andinterfraction interval, andtheproximity of treated fieldsto thepharyngolaryngeal area, contribute inextending objective assessment methods. Dysphagia isfrequently underreported by either patients or physicians [175,178].Furthermore, thescarcity of The incidence of dysphagia varies from 15%to 55%[171, age andcould trigger theneurogenic root of dysphagia. motility [171,174–176]. Alternatively, peripheral andcranial nerves that innervate theswallowing musculature are at riskof radiation dam- cades, TGFß’s activation leadsto theincreasedof deposition collagen compromising pharyngolaryngeal structures andreducing muscular Thefibroticbehind the mainculprit ofaspect dysphagia is TGFß. Through a well-orchestrated repertoire of inflammatory cell signallingcas- Inynx andpharynx. fact,silent aspiration isfrequent inirradiated HNCpatients due to anineffective or even absent cough reflex [173,174]. nisms behindtheseimpairments are mostly dueto radiation-mediated fibrosis andoedemathat compromise themuscular activity of thelar hereafteroesophagus [172].Disordered swallowing leadsto aspiration andinsevere cases to [173]. Pathophysiological pneumonia - mecha the into and nerves) cranial Xth and IXth the through(involuntary, larynx the shielding while nerves) cranial XIIth and VIIth(Vth, pharynx nerves inadditionto acentral pattern generator located Deglutitionmedulla. inthe allows thefood bolusto passfrom theoral cavity to the persist, leadingto chronic dysphagia anddysphonia thatpatients’ impact QoL [171].Normal swallowing isorchestrated by multiplecranial Swallowing and speechimpairments are common duringRT for HNC patients. While complications such are usually transient, they can Dysphagia anddysphonia injuries related to radiation, anti-coagulants failed inameliorating RION[170]. anti-coagulantsand as heparin such warfarin have beensuggested to treat RION. While theseagents were potent intreating other neuronal and leukocytes. Largerarestudies clinical warranted to solidify thepotential therapeutic effect of these combinational treatments. Similarly, another case report [169]. This improvement might bedueto theability of pentoxifylline to increase bloodflow andflexibility of erythrocytes improvement inapatient’s vision treated pentoxifylline,with vitamin Eanddexamethasone [168]. Pentoxifylline alone enhanced RIR in A combinationof bevacizumab,pentoxifylline and dexamethasone was efficacious inacasereport [167].Others describedadramatic use of HBOT intreating RION. HBOT, itsinitiation after RT andtheseverity of acuityvisual could explain theinconsistency of theresults. Overall, very shy data the support cessfulin ameliorating impaired vision [156,164,165]incontrast to onecasereport [166].Discrepancies inoverall treatment time with proved to beeffective intreating opticneuropathies RTthe outside context [163].Conversely, HBOT andoral corticosteroids were unsuc improved resolutionof opticand disk oedema vision, reducingpapillary haemorrhages in64%ofpatients RION [161,162].Bevacizumab few therapeutichavemodalities beeninvestigatedreportcase outside studies.Bevacizumab, ananti-vascular endothelial growth factor, To date, notreatment isavailable to alleviate or restore oncevisual function visual impairment hasbegun.Given therarity of RIONandRIR, rats following adoseof 20Gy, while nodifferences were found inα-tubulin, andSMI31levels β-tubulin [160]. evoked potential p53-dependentin rats regionalcause alterations inretinal oxygen delivery and/or metabolism [157].Molecularly, retinal apoptosis was found to be ATM and vasculopathy induced retinopathyis postulated (RIR) toby becaused injury to the vascular endothelial cells of theretina leadingto occlusive retino- is damage to thecapillary endothelium,leading to demyelination ischemic andreactive astrocytosis [156] . In asimilar fashion, radiation- Pathophysiologicalunderlying optic mechanisms neuropathies are not clear. Limited evidence suggests that the main aetiology behind RION tumours place theanterior visual pathways, optic nerves andchiasmat riskof injury dueto their proximity to treated fields. maywhich to riseup 20%at5–10 years followingtreatment [153–155].Skull-b [151]. In addition,directneuronal injury toretina the andoptic nerves hasalsobeenproposed. Moreover, radiation may in vivo [158]. Treatment ramipril,with an ACE agonist, 2 weeks post-radiation mitigated RIONby restoring normal visual [159]. Insufficientlevels of axonal transportmotor proteins asdynein-1,kinesin-1andkinesin-2 were reported in 172, 175,177]. This broad range could beexplained by thedifferent subjective and 9 - - -

Review radiation-induced dysphonia with pulsedye laser of hasbeenthesubject aclinicaltrialintheUnited States [205]. methodsmultiple of surgical voice rehabilitation have beenreported to ameliorate dysphonia in case reports tion. Nonetheless, mixed dataregarding hasbeenpublished itseffectiveness intreating speechimpairments [195,200–202].In addition, treatmenttherapy.as speech modalitiessuch The latter aimsto improve theflexibility of thelarynxandto maximisephonation andarticula- glands, suggestingneurogenica possible root for voice impairment [198,199].Management of dysphonia includesnon-pharmacological mucosa leadingto vocal folds dryness[195,197].In fact,Substance P, bombesinandenkephalin are upregulated intheinnervation of these Adequate hydrationof has alsobeenproposed,larynx the considering thedamagingeffect of radiation onlaryngeal salivary glandsand induced dysphonia context. inflammation andfibrosis inlarynxes of rabbits ofuse steroids, proton and inhibitors pump TNF-αhave advocatedbeen Pharmacological treatments aiming to abrogate inflammation andfibrosis of thelarynxare usedasfirst-line intreatment of dysphonia. The ated dysphonia compared to conventional treatments [192,194]. [179, 192,194]. A doseto>49.4 Gylarynx the increases dysphonia patients riskinHNC [192].Similar to previous neuropathies, IMRT allevi- levels. The reported incidence of dysphonia varies between 10.5%and64%depending ontheassessment method andfollow-up periods [193]. Acute dysphoniaculminates at10 weeks post-RT followed by asubsequent downregulation that doesnot reach previous normal of patients’ voices. The effectpeaks at 10 weeks post-treatment, followed by gradual improvements thatnever reach pre-treatment levels Some indicateddeterioration speech after therapy deposits inthelaminapropria [190,191]. of radiation-induced fibrosis andoedemaof laryngeal structures and vocal folds. This isattributed to anincrease incollagen andfibronectin improvement be anactual in voice/speechtodue shrinkage oftumour the if treatment iseffective. Nevertheless, dysphonia canbetheresult disturb voice quality, while laryngeal tumours bothwill impede voice andspeechoutcomes [189]. The expected short-term outcome could In contrastto dysphagia,limitedaddress studies radiation-induced dysphonia. Non-laryngeal malignanciesdependingontheir location can Toronto will assesstheeffectiveness of prophylactic swallowing exercises versus intervention exercises after theoccurrence of dysphagia [ In fact, aclinicaltrialinvestigating therole of acupuncture inradiation-mediated dysphagia is in progress in China [187]. An additionalonein gia andimproving QoL. Nevertheless, noneof thepreviously mentioned were tested inlarge clinicaltrials,andtheir efficacity isquestionable. manoeuvres risk. These includeneuromuscular electricalstimulation andballoondilatation [183],tongue, pharynxandlarynxexercises [184], swallowing Treatment of radiation-induced dysphagia involves various typesof rehabilitation to improve theflow of thebolusandreduce aspiration 181, 182] might have arole inacute dysphagia [180].Late dysphagia was associated with theglottic, supraglottic larynxandpharyngeal constrictors [178, endoscopic gastrostomy dependency [179].Radiation to criticalkey structures suchasthecricopharyngeal muscleandcervical oesophagus ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 of radiationneuropathies. For instance, abetter knowledge of apoptotic andneuroinflammation pathways could shedlight onencouraging engers shouldbe investigated asfirst-lineradioprotective drugs.Several promising molecular venues canbefurther studiedfor mitigation followinginjuries radiotherapy In inHNC. fact,current ongoing clinicaltrialstacklingthissubjectare shy innumbers ( while sparingtumoursFurther inHNC. research isurgently neededto mitigate andunderstand thedifferent mechanismsunderlying neural The potency andefficiency ofbe interpretedshould findings drug-based intheir ability to selectively radioprotect normalneuronal tissues conditions. Currently availableoptions medical arein easingsideeffects, modest andpreventive measures are successfulto acertain extent. factorial pathological process that takes many shapesdependingonthetreatment modality, anatomical location andpatients’ physiological damageniques, to neighbouringhealthyis inevitable. tissues In thisregard, radiation-induced neuropathy showed inHNC to beamulti- Radiotherapy isundoubtedly oneof themajor contributors to Nevertheless, managingHNC. even advancedwith themost radiation tech- Conclusion . IMRT succeeded inlimitingradiated volumes to theseareas andtherefore reduced aspiration risks[181,182]. [175] acupuncture [185],postural techniques [186]anddiet changes [173]. All were deemedto beeffective inreducing dyspha- [196]. Thereafter, allof theabovementioned treatmentsbe investigated should inradiation- [179, 192, 193]. Radiation impacted thestrain, nasality, roughness and pitch aspects [195]. Moreover, cryotherapy promoted regeneration and reduced [203, 204]. Recently, treating table 1).ROS scav- 188]. 10

Review ecancer 2020, 14:1133; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1133 The current work hasnofundingsupport. Funding The authors declare noconflict of interest. Conflicts of interest neuropathies associated with RT inHNCunder clinicaltrials. lished treatments for nerve injuryunrelated models to radiation. The efficacity of theseinterventions ought to beinvestigated inmanaging it mighthelp inimproving neuroregeneration inradiation-induced neuropathies. Future research shouldalsobenefitfrom previously estab- in haltingneuronaloutlooks damage. Althoughnot in thisreview, discussed preclinical studiescould focus onapprehending neurogenesis, as Table 1.Listof recent clinicaltrialsinvolved ininvestigating approaches inmanagingradiation-induced neuropathies. With Post Radiation Dysphonia [205] Pulsed Dye Laser in Treating Patients Cancer [188] ing Radiotherapy Intervention for Patients Receiv- PRO-ACTIVE: Prophylactic Swallow With Head andNeck Cancer [187] apy-induced Dysphagia inPatients Efficacy of Acupuncture inRadiother Cancer Patients. (stREnGTH) Strong Opioid Use inHead and Neck Gabapentin to Reduce theNeed for Study of Efficacy andSafety of Lower Cranial Neuropathy [5] py for Late Radiation-Associated StopLCNP: High Dose Steroid Thera- Radiation-Induced Brain Injury [4] Effect andSafety of Apatinib on Nasopharyngeal Cancer [3] Patients With Paranasal Sinus or of Smell After Radiation Therapy in Olfactory Training inImproving Sense Alterations [2] Chemo-radiotherapyInduced Taste Efficacy of Zinc onConcurrent therapy inHead andNeck Cancer [1] Gustatory Function Following Radio- Trial title for Head andNeck [6] - NCT02198131 NCT03455608 NCT03336775 NCT04151082 NCT04152681 NCT03049358 NCT03824925 NCT03738657 NCT03747562 Identifier Health Sciences Wake Forest University Network, Toronto University Health Universit Hospitalof Sun Yat-Sen Sun Yat-SenMemorial Center CancerM.D. Anderson University Hospitalof Sun Yat-Sen Sun Yat-SenMemorial Stanford University Health Sciences Dow University of Foundation Trust Royal Marsden NHS Ghent University Hospital, Sponsor Single group assessment Randomized trial Single blindedrandomized Phase I/II Single group assessment – Phase II Single group assessment – trial –Phase I Single blindedrandomised controlled trial–Phase III Double-blind randomised Cross-sectional Phase III controlled trial– blinded randomised Multi-center double- Type of study

Surgery *Pulse Dye Laser *Swallowing Training 80 mg *Methylprednisolone *Acupuncture *Prednisone *Methylprednisolone *Apatinib 250mg *Olfactory training *Zinc sulfate 220mg *Placebo N/A *Gabapentin 100mg *Placebo Primary treatment Completed Recruiting Recruiting Recruiting Recruiting Terminated Completed Recruiting Notrecruiting yet Endpoint status 11

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