Abstract: Comparisons were made by structured review with the

Abstract: Objectives: to assess patient’s loco-regional control rates, associatedtoxicity rates and related prognostic factors as a consequence of reirradiationof recurrent head and neck cancer with intensity modulated radiotherapy (IMRT)or volumetric arc therapy (VMAT).Data Sources: Medline databases (PubMed, MedScape, ScienceDirect. EMF-Portal) and all materials available in the Internet from 2007to 2017.Study Selection: The initial search presented 50 articles of which 33 met theinclusion criteria. The articles studied the relation between re-irradiation ofrecurrent head and neck cancer with IMRT or VMAT and loco-regional controlrate, associated toxicity rate and related prognostic factors that affectedoutcomes.Data Extraction: If the studies did not fulfill the inclusion criteria, they were excluded.

Study quality assessment included whether ethical approval was gained,eligibility criteria specified, appropriate controls, adequate information anddefined assessment measures.Data Synthesis: Comparisons were made by structured review with the resultstabulated.Findings: Intotal 33 potentially relevant publications were included. The studies indicated an associationbetween re-irradiation of recurrent head and neck cancer with IMRT or VMAT and goodresponse rates, whereas re-irradiation toxicity rate had controversial results,Some reported accepted low toxicity rates, while others reported high rates. Wefound that good performance status, re-irradiation dose more than 60 Gy, smalltumor volume and disease free interval more than 12 months were associated withbetter outcomes.Conclusion: We found betterloco-regional control rates with accepted associated toxicity afterreirradiation of recurrent HNC with IMRT or VMAT especially for patients withfavorable selection criteria.

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Key words: Head and neckcancer, Re-irradiation,Recurrent, toxicity. IntroductionLocal recurrence is the most common cause of death among patientswith recurrent head and neck cancer, acquiring local control may have direct effecton their survival and quality of life. 1 Management of recurrent head and neck cancer (HNC) is difficult,although surgery offers the best local control; it is only feasible in minorityof patients. Moreover, systemic chemotherapy failed to exhibit any curabilitychance with poor survival benefit. 2 Reirradiationis the alternative best option when surgery is not possible with the aim of obtaininglocal control and improving survival benefit with accepted toxicity; which is rangingfrom acute to late toxicity and cumulative radiation doses to normal nearbyorgans should respect different tissue constrains. 3 Recently, Intensity-modulated radiation therapy (IMRT) andVolumetric modulated arc therapy (VMAT) help use of higher dose to local tumorrecurrence and lower dose to nearby organ at risk which result in better local control and moresurvival benefit.

However,prospective studies about using IMRT and VMAT in re-irradiation setting ofrecurrent head and neck cancer (HNC) are rare. 4 reirradiationof recurrent HNC is challenging and finding the most optimal plan in sparingthe different normal nearby organs at risk(OAR) is difficult, Also the bestselection criteria for the patients associated with better outcomes is widely advisable.5 Fewprospective studies have been published for the role of IMRT and VMAT inrecurrent HNC, while many retrospective studies observed good tumor control andsurvival benefit with accepted toxicity rate. 6 The aim of this studywas assessing the response rate of re-irradiation with modern techniques inrecurrent HNC anddetermining associated toxicity rates and better prognostic factors.

MATERIALS AND METHODSSearch Strategy: We reviewed papers on the role of IMRT and VMAT on re-irradiationof recurrent head and neck cancer from Medline databases which are (PubMed, MedScape, Science Direct) and also materialsavailable in the Internet. We used recurrent/ head and neck/ re-irradiation andIMRT/response/ toxicity/ VMAT/survival as searching terms. In addition, weexamined references from the specialist databases EMF-Portal(http://www.

emf-portal.de), reference lists in relevant publications andpublished reports from different re-irradiation research journals. The searchwas performed in the electronic databases from 2007 to 2017. Study Selection: All the studies were individually assessed for inclusion. They wereincluded if they fulfilled the following criteria: Inclusioncriteria of the published studies: -Published in English language. -Publishedin peer-reviewed journals. -Focused on re-irradiation with IMRT or VMAT ofrecurrent HNC.

        -Discussed therelation between re-irradiation, response rates and toxicity. -If a study hadseveral publications on certain aspects we used the latest publication givingthe most relevant data. Data Extraction: If the studies did not fulfill the abovecriteria, they were excluded such as, Studies on re-irradiation withconventional techniques, report without peer-review, not within nationalresearch programmes, letters/comments/editorials/news and studies not focusedon re-irradiation with IMRT or VMAT.  Theanalyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification ofthe U.S.

Preventive Services Task Force & UK National Health Serviceprotocol for EBM in addition to the Evidence Pyramid (Fig 1).U.S.

Preventive ServicesTask Force: Level I: Evidence reported from atleast one efficiently designed randomized controlled trial. Level II-1: Evidence obtained from properly designed controlledtrials with no randomization. LevelII-2: Evidence obtained from properly designed cohort or case-controlanalytic studies, better from more than one center or research group. LevelII-3: Evidence achieved from multiple time series with or without the intervention.

Unexpected results in uncontrolled trials might also be regarded as this typeof evidence. Level III: considerations of respected authorities, based onclinical experience, descriptive trials, or reports of expert committees. QualityAssessment: The quality of all the studies was evaluated. Considerablefactors included, study design, fulfillment of ethical approval, evidence of apower calculation, defining eligibility criteria, appropriate controls, sufficientinformation and specified assessment tools. Confounding factors were reportedand controlled, suitable data analyses were verified in addition to anexplanation of missing data. Data Synthesis: A structured systematicreview was performed with the results tabulated. Study selection and characteristics: In total 50 potentially relevant publications were identified, 17 articleswere excluded as they did not meet our inclusion criteria. A total of 33studies were included and the majority of the studies examined the role ofre-irradiation with IMRT or VMAT on recurrent head and neck cancer patients andthe risk of toxicity.

The studies were analyzed with respect to the studydesign using the classification of the U.S. Preventive Services Task Force& UK National Health Service protocol for EBM.RESULTSRegarding loco-regional control rate, Re-irradiation of recurrent headand neck cancer with IMRT or VMAT was investigated in 20 studies. There weredifferent results with 14 studies reported better locoregional responserate more than 40% and 2 year survival benefit rate more than 40%. However, sixstudies reported that there was mild response rates as regard loco-regionalcontrol and minimal or no survival benefit.Regarding re-irradiation dose, it was investigated in 20 studies. Most ofthem were retrospective studies, 12 studies reported that better response rateswere correlated with higher doses more than 60 Gy, 6 studies reported thatdoses more than 50 Gy was associated with survival benefit while only twostudies showed that doses with a mean of 45Gy had a good results with acceptedtoxicity.

As regard toxicity, weidentified 10 studies that published the associated toxicity outcome after re-irradiationwith IMRT or VMAT of recurrent HNC and we found that 6 studies reported toxicityrate of 20% to 30% However, two studies represented high rates of toxicity morethan 30%. Also two studies reported lower toxicity rates of less than 20% (Tab1). Selection criteria correlated with better response outcome wereinvestigated in 7 studies. There were 5 studies that reported multiple factorslike advanced techniques, free disease interval, low tumor volume, reirradiationdose more than 60, early nodal recurrence and post operative re-irradiation wereassociated with better outcome. While 2 studies reported that time intervalbetween primary and re-irradiation was the only factor associated with betteroutcome and survival benefit.DISCUSSIONResearch into the re-irradiation of recurrent HNC is an area inwhich there are a limited number of scientific studies with no randomizedprospective studies and majority of retrospective nature.

These studies coverthe role of advanced radiotherapy techniques in reirradiation era as regardingresponse and toxicity rates. Both IMRT and VMAT had been conducted in recent investigations,and include studies measuring the loco-regional control and toxicity. Most ofthe studies reported better loco-regional control and survival benefit overconventional reirradiation. However, because of the nature of retrospective andrare prospective studies, it can be some difficult to provide the exact role ofIMRT or VMAT in re-irradiation of recurrent HNC as regard not only therapyresponse but also therapy related toxicity. This can result in themisinterpretation of results or false impression about scientific findings.

Sothis study tried to provide an updated analysis that describe recent studies,classify and evaluate them according to evidence-based medicine (EBM) criteria.Reviewing the recent studies about the roleof IMRT or VMAT in re-irradiation of recurrent HNC, we found majority with 14 studies 7, 10, 11, 14,17 reported better response rate more than 40% and 2 year survival benefitrate more than 40%. Confirming that advanced techniques can improve loco-regional controland survival rates, Re-irradiation with IMRT or VMAT techniques provide higherdoses to gross tumor and lower doses to nearby organs which was associated withbetter loco-regional control and progression free survival. 3 In our review,6 studies reported toxicity rate that had ranged from 20% to 30% which was lessthan that expressed by conventional re-irradiation. 7, 8, 9 However,two studies represented high rates of associated toxicity more than 30%. 10,18 Also two studies reported lower toxicity rates of less than 20%. 12,19 Some studies on re-irradiation with IMRT orVMAT had suggested a decreased risk of reirradiation toxicity, butothers had not.

The studies to date have been conflicting about toxicity rateswith IMRT or VMAT. But most ofthe studies showed well tolerability andbetter quality of life. 4 In a study by Lee et al. which was aretrospective one From July 1996 to September 2005 included 105 patients 70% ofthem received IMRT reported loco-regional control of 45% and survival benefitof 40%. On multivariate analysis, IMRT was associated with better localresponse rate and Radiation dose more than 50 Gy was associated with improvedOS. Severe toxicity was seen in 11% of patients. None had a carotid rupture.

This study showed significant improvement in survival for those patients who acquiredgood local control rate. 9 Duprez et al.which was a retrospective study between 1997 and 2008 that included 84 patientsshowed that IMRT in re irradiation of recurrent HNC was associated with localcontrol of 48% with adverse events of about 11%. Also on multivariate analysis theyfound advanced stage, short time interval between two radiations, absence ofsurgery, and hypo-pharyngeal cancer were considered bad prognostic factors. 12Popovtzer et al. which was a retrospective study on 66 patients reported 71% ofgood response rate and adverse events rate was 19%. This study informed that aprophylactic field is not needed in reirradiation era at present.

13 Reirradiation dose is individualizedaccording to age, performance status and radiotherapy equipments, duration andtiming of re-irradiation. we found 12 studies 1, 2, 5, 6 reported that betterlocoregional control was associated with higher doses more than 60 Gy, also 6studies 9, 16 reported that reirradiation doses more than 50 Gy were correlatedwith survival benefit while only two studies 8, 14 showed that doseswith a mean of 45 Gy had a good results with accepted toxicity. Maliket al. which was a trial with a retrospective nature on 79 patients from yearof 1999 to 2011 used a dose of re irradiation with a mean of 45 Gy and foundthat progression free survival benefit was 35% and adverse events was 30% and reportedthat Reirradiation of recurrent HNC with moderate radiation doses achievedacceptable progression-free survival and toxicity rates. 14 Valez etal. which was a retrospective trial between 1998 and 2015 on 80 patients.

IMRTwas used in 71 patients (93.4%) with a median dose of 60 Gy and found that localcontrol rate was 36%, overall survival 51% and associated toxicity was 32.8%denoted good response rates but related toxicity was challenging and neededmore selection criteria. 15 Karakia et al.

which was a retrospectivestudy from year of 2007 to 2012 on 31 patients. Reported locoregional controlof 40%, overall survival of 40% and toxicity rate of 28%. Also he noted someprognostic factors correlated with better outcome based on patient’sperformance status (PS) and tumor characteristics. 20 Many selection criteria that might be correlatedwith better results have been used like advanced techniques, free diseaseinterval, low tumor volume, reirradiation dose more than 60 Gy, early nodalrecurrence and post operative reirradiation. Those multiple selection criteriawere widely shown by 5 studies 20, 22, 23. While 2 studies 7, 21reported that time interval between primary and re-irradiation was the onlyfactor associated with survival benefit. On the other hand, two studies 5,24 failed to show any criteria that correlated with better results.

In study by Bots et al which was a retrospective study between yearof 1986 and 2013 on 137 patients, he found better outcome as regard loco-regionalcontrol 46% and disease free survival 30% also he showed accepted toxicity rateof 28% and noticed that higher radiation doses and postoperative re-irradiationwere  associated with better results.17 Conclusion:Re-irradiation of recurrent head and neck cancer withIMRT or VMAT is feasible and provides a chance for not only better loco-regionalcontrol and survival benefit but also curability chance with low toxicity ratewhich is of major concern as it has a direct impact on quality of life. Forbetter results it is advised to reirradiate patients with small tumor recurrence,longer disease free interval, higher reirradiation doses in respect to tissueconstrains and advanced radiotherapy techniques.