Accepted Manuscript
Planned Gamma Knife Boost After Chemoradiotherapy For Selected Sinonasal And
Nasopharyngeal Cancers
José Armando DíazMartínez Yoshua Esquenazi Magda Martir Martin J Citardi
Ron J Karni Angel I Blanco
PII S18788750(18)316619
DOI 101016jwneu201807183
Reference WNEU 8748
To appear in World Neurosurgery
Received Date 20 February 2018
Revised Date 18 July 2018
Accepted Date 20 July 2018
Please cite this article as DíazMartínez JA Esquenazi Y Martir M Citardi MJ Karni RJ Blanco AI
Planned Gamma Knife Boost After Chemoradiotherapy For Selected Sinonasal And Nasopharyngeal
Cancers World Neurosurgery (2018) doi 101016jwneu201807183
This is a PDF file of an unedited manuscript that has been accepted for publication As a service to
our customers we are providing this early version of the manuscript The manuscript will undergo
copyediting typesetting and review of the resulting proof before it is published in its final form Please
note that during the production process errors may be discovered which could affect the content and all
legal disclaimers that apply to the journal pertain
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
1
Planned Gamma Knife Boost After Chemoradiotherapy For Selected Sinonasal And
Nasopharyngeal Cancers

José Armando DíazMartínez 1 Yoshua Esquenazi 2* Magda Martir 2 Martin J
Citardi 3 Ron J Karni 3 and Angel I Blanco 2
1 Radioneurosurgery Unit National Institute of Neurology and Neurosurgery
Mexico City Mexico
2 Vivian L Smith Department of Neurosurgery McGovern Medical School The
University of Texas Health Science Center at Houston Houston TX USA
3 Department of OtorhinolaryngologyHead & Neck Surgery McGovern Medical
School The University of Texas Health Sciences Center in Houston Houston TX USA

*Corresponding Author Yoshua Esquenazi
6400 Fannin Suite 2800
Yoshuaesquenazilevy@uthtmcedu
713 7047100


MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
1
• Abstract

Objective
To determine the feasibility of a Gamma Knife boost following Intensity Modulated
Radiation Therapy in combination with multimodal therapy in patients with nasopharyngeal
carcinoma and sinonasal malignancies with skull base or cavernous sinus involvement

Methods
Nine patients were treated with Intensity Modulated Radiation Therapy followed by a
Gamma Knife boost In one case Gamma Knife was given as salvage treatment following
resection Five patients had sinonasal malignancies and four had nasopharyngeal carcinoma
The mean radiation therapy dose was 643 Gy (range 5470 Gy) at 2 Gy per fraction The
median interval from completion of radiation therapy to Gamma Knife boost was 22
months (range 14 months) The most common indication for Gamma Knife boost was
involvement of the cavernous sinus which was identified in 7 patients The median margin
Gamma Knife dose delivered was 13 Gy (range 1220 Gy) with median prescription isodose
of 50

Results
All patients tolerated the procedure well with minimal toxicity Local control rates were
achieved in all patients and no acute grade 35 toxicity was observed One patient
experienced late grade 4 toxicity which was potentially attributable to treatment Distant
failure occurred in three patients (one nasopharyngeal carcinoma patient and 2 sinonasal
malignancies patients)

Conclusions
Planned Gamma Knife boost followed Intensity Modulated Radiation Therapy is feasible
safe and provides excellent local control in patients with sinonasal malignancies and
nasopharyngeal carcinoma particularly in cases with cavernous sinus involvement Further
followup will be necessary to determine the longterm effectiveness and complication
profile

MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
2


Introduction

Sinonasal malignancies (SNM) and nasopharyngeal carcinomas (NPC) represent uncommon
neoplasms with distinctive clinical and pathological features For SNM treatment options
include resection radiation and systemic therapy with combined modality treatment
necessary in most SNM cases Both neoadjuvant and adjuvant radiochemotherapy
approaches have been utilized and treatment decisions are typically individualized in
consideration of tumor extent and histology 12 Recent trends in surgical management have
emphasized minimallyinvasive endoscopic techinques in place of traditional open
craniofacial resection 3 NPC tumors in contrast are typically managed nonsurgically given
unresectability and radiosensitivity

Over the past 2 decades highly conformal radiation treatment modalities including Intensity
Modulated Radiation Therapy (IMRT) and proton beam therapy have become standard for
skull base tumors given obvious dosimetric superiority in target coverage and sparing of
surrounding critical structures 4 Nevertheless delivery of tumoricidal doses for SNM and a
subset of nasopharyngeal tumors is problematic for even such technologies given the dose
volume constraints of the optic apparatus temporal lobes brainstem and normal brain 5

A Stereotactic Radiosurgery (SRS) boost represents one potential solution to address the
aforementioned dosimetric shortcomings and improve the therapeutic ratio for selected skull
base tumors SRS can accurately deliver high radiation doses to small treatment volumes To
date however literature documenting the safety and efficacy of SRS boost for these tumors
is scarce In particular to the best of our knowledge there are no published reports
employing the Leksell Gamma Knife (GK) as an SRS boost technique 6–9 for either SNM or
NPC Given its known dosimetric precision and steep dose falloff the GK platform
potentially represents an excellent option for treatment of difficult cases and in particular
those with cavernous sinus anterior cranial fossa andor clival involvement Because of
high historic local failure rates and substantial treatment morbidity for such highrisk cases
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
3
despite trimodality therapeutic approaches we have selectively incorporated a GK boost
since 2014 in what we consider a fourth therapeutic modality for challenging SNM and
nasopharyngeal cases in an effort to improve Local Control (LC) and ultimately survival In
the current study we present our therapeutic results with this novel technique

Materials and Methods
• Patient Population
An Institutional Review Board (IRB) – approved retrospective chart review of ten patients
treated in our center from 20142017 who underwent GK boost following IMRT as initial
management was performed From all patients informed consent was obtained before IMRT
and GK boost treatment The diagnosis of SNM was confirmed by histopathology prior
adjuvant therapy and in 9 patients was combined with chemotherapy Patients with Eastern
Cooperative Oncology Group (ECOG) Performance Status of 02 were eligible for RT and
staged according to AJCC criteria 10 Based to this classification 9 patients had a stage IV
tumor and 1 patient with diagnosis of esthesioneuroblastoma had a KadishMorita C Six
patients were male and four were female Median age was 478 years (range 2063 years)
The most common histopathology was SCC (5 of them were keratinizing and 1
nonkeratinizing) In 5 patients the tumor was arising from the nasopharynx The disease
involved the cavernous sinus in eight patients Patient characteristics are summarized in
Table 1

• Simulation and Planning IMRT
Planning was performed using preoperative and postoperative imaging Computerized
Tomography (CT) and Magnetic Resonance Imaging (MRI) All patients underwent a pre
treatment contrastenhanced CT with a slice thickness of 125 mm and immobilized in dorsal
decubitus with hyperextension of the neck with a thermoplastic mask (Posicast 5point head
neck and shoulder mask Civco Medical Solutions Orange City IA USA) IMRT Planning
was performed using Eclipse radiotherapy TPS Version 110 (Varian Medical Systems Inc
Palo Alto CA USA) RapidArc was used to deliver the Volumetric Arc Therapy (VMAT)
plan CT images were fused with T1 and T2 weighted fat suppression MRI sequences and
18 FFDG PETCT scans with the Gross Tumor Volume (GTV) was contoured using
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
4
multimodality images and physical examination findings The preoperative GTV was
contoured on coregistered preoperative CT andor MRI The clinical target volume (CTV)
was delineated as a variable expansion of the GTV and preoperative GTV in consideration
of the proximity of the target volumes to critical structures The CTV was expanded by 3
mm to construct the planning target volume (PTV) IMRT treatments were performed using
a 6 MeV LINAC (Varian Trilogy Varian Medical Systems Inc Palo Alto CA USA) a
conebeam CT was acquired and pretreatment shifts were made to match the planning scan
after immobilization of the patient and isocentric setup Mean PTV dose was 643 Gy
(range 5470 Gy) at 2 Gy per fraction Sequential or simultaneous integrated boosts were
utilized per physician preference The median interval from completion of IMRT to GK
boost was 22 months (range 14 months) Our intent was to deliver GK boost at 4 weeks
following external beam RT completion One patient received her boost treatment at 4
months due to insurance delay

• GK Radiosurgery Boost
Typically patients selected for SRS boost had intracranial extension Given that full dose
IMRT would have exceeded tolerance doses of the optic pathways we typically delivered
5460 to the cavernous sinus and subsequently boosted with the GK (Figure 1) as an organ
preserving strategy In one case (patient 3) GK was given as a single treatment following
resection In all other cases the dosimetric plan from the prior IMRT treatment was merged
and the SRS boost was delivered using the GK Perfexion platform Treatment plan was
generated with Leksell Gamma Plan version 1021 (Elekta Instrument AB Stockholm
Sweden) planning system All individual plans were evaluated and approved by the
neurosurgeon physicist and radiation oncologist The median margin GK dose delivered
was 13 Gy (range 1220 Gy) with median prescription isodose of 50 The median number
of isocenters was 778 (range 34205) The median treatment volume was 45 cm3 (range
117–822 cm3)

• Clinical Assessment and FollowUp
Followup typically began in the outpatient clinic one week after the GK boost The patients
were subsequently evaluated at intervals of 3 to 6 months During each followup visit a
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
5
physical examination and clinical review were performed MRI was performed to assess LC
and to identify changes in tumor size or development of new lesions The duration of the
followup was calculated from the GK boost delivery until its most recent followup The
median followup interval from the time of GK treatment was 133 months

• Data Analysis and Definitions
All statistical analysis was performed with IBM SPSS Statistics Version 22 Descriptive
analysis and crude rates were reported For the purposes of this study we defined local
failure as tumor recurrence within the PTV field of the SRS regional failure was defined as
any progression of the tumor in regional lymph nodes that were not included in the PTV
Distant failure was defined as the appearance of disease outside the PTV without any
regional failure DiseaseFree Survival (DFS) was defined as any failure from the date of
SRS Overall Survival (OS) defined as the time from the date of SRS to the date of death

Treatmentrelated side effects were characterized using the RTOGEORTC Acute (<90
days) and Late (>90 days) Radiation Morbidity Scoring Schema 11 It was difficult to
establish any toxicity as directly attributable to GK boost as most of the patients underwent
trimodality management Table 1 summarized the highest degree of toxicity associated to the GK boost Overall
in our study treatment was w elltolerated and no acute G35 toxicity was observed Grade one
toxicities in this cohort included fatigue (n5) followed by dermatitis (n4) odynophagia
(n4) and xerostomia (n4) erythema (n1) hyperpigmentation (n1) and mucositis
(n1) Grade two toxicity included dermatitis (n2) fatigue (n1) mucositis (n1)
epistaxis (n1) rhinorrhea (n1) numbness (n1) facial pain (n1) and trismus (n1) One
patient experienced late G4 toxicity which was potentially attributable to treatment He
presented with acute epistaxis 15 months following SRS He was initially packed and
hemodynamically stabilized Subsequent digital substraction angiography revealed a
cavernous carotid pseudoaneurysm in the left internal carotid artery which was successfully
embolized using coils The etiology of this event is likely multifactorial and potentially
related to a combination of tumor invasion of the skull base effects of radical surgery andor
the cumulative radiation dose 1213 Importantly and especially given the high total doses and
in view of the cumulative number of patients receiving a boost to the cavernous sinus none
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
6
of the patients developed radiationinduced optic neuropathy myelitis brainstem injury
temporal or frontal lobe radionecrosis or another cranial neuropathy

Results
LC was achieved in all patients (median followup 133 months) Distant failure occurred in
three patients (one NPC patient and two SNM patients) Systemic therapy was used to treat
distant metastases and included cytotoxic chemotherapy for the NPC and immunotherapy
for the SNM patients respectively One patient (case No 8) died of the disease months after
the GK boost Overall throughout the course of followup no local recurrences were
observed

Discussion
The World Health Organization (WHO) classifies head and neck tumors in groups and
subgroups based in the anatomical site of origin and the histological grade of malignancy 14
According to the classification SNM and NPC are infrequent diseases with a similar
incidence less than <1 cases per 100000 per year 15 with higher rates for NPC among
Asians especially the southern Chinese 16 They are more frequent in males and are typically
diagnosed during the 5 th decade although they can present at any age In early stages both
entities SNM and NPC presents with nonspecific clinical symptoms mimicking an
inflammatory process Unfortunately given the insidious presentation most patients are
typically diagnosed at advanced stages In certain cases particularly for keratinizing
squamous histologies the anatomical origin is usually not identified as tumors may extend
to multiple subsites of the nasal cavity paranasal sinuses and nasopharynx
Regardless of primary site management of advanced cases is complex and associated with
high rates of local failure despite multimodality therapy as these tumors typically juxtapose
critical structures in the skull such as temporal lobes brainstem cranial nerves optic
pathways and cavernous sinus decreasing the possibility of marginnegative resection
andor definitive RT In the current study we report a novel adjuvant treatment approach
incorporating an SRS boost for selected advanced cases In our experience this strategy is
well tolerated and allowed us to maximize the tumor dose while limiting the exposure of
organs at risk (Figure 2) with the ultimate goal of improving LC and survival
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
7
Surgical resection represents a cornerstone in the management of SNM and may precede or
follow adjuvant therapies depending on disease extent histology and institutional
preference 17 The goal of surgery is to achieve the highest maximal safe resection obtaining
free oncological margins Until recently craniofacial resections and other open approaches
were predominantly used 18 Recent advances in intraoperative navigation and endoscopic
techniques have established endoscopic resection as a less morbid alternative to traditional
craniofacial approaches without compromise of oncologic results 1819 In fact these
endoscopic techniques may even be applied as an initial palliative measure and owing to the
low morbidity set the stage for the radiation therapy strategy summarized in this report

Historical results with treatment of SNM were highly suboptimal prior to the advent of
highly conformal radiation techniques hinting at a potential doseresponse for dose
escalation In a series using predominantly conventional (ie 2D) radiation Blanco et al
reported 106 patients with carcinoma of paranasal sinus treated with primary or adjuvant RT
20 LC at 5 years was achieved in 58 with DFS of 33 and OS of 27 Patients
undergoing surgery had better outcomes however locoregional tumor progression and
recurrence was the predominant failure pattern despite bimodality therapy Other historical
papers similarly reported LC rates ranging from 50 to 70 in stage IIIIV SNM 21 More
recently significant therapeutic benefit both in terms of improved local control and reduced
late toxicity has been observed using IMRT In 2012 Duprez et al reported updated results
for sinonasal IMRT at a median followup was 52 months Using a median dose of 70 Gy in
35 fractions 5y LC DFS and OS rates were 59 32 and 52 respectively 22
In contrast and owing to typically unresectable approaches and radiosenstivity NPC is
typically managed with radiationbased protocols incorporating chemotherapy for advanced
stages or in cases with involved cervical nodes 23 Historical series consistently demonstrated
10year survival rates of 30 to 40 depending on the clinical stage and WHO histology
2425 Concomitant chemotherapy has demonstrated the improvement of LC DFS and OS 26
however local recurrence rates with this therapeutic addition remained around 1015 2728
Despite aggressive therapy most patients with recurrent NPC have poor LC requiring
retreatment Reirradiation carries a high risk of injury to adjacent neurovascular structures
with a high rate of toxicity making an upfront rather than salvage GK boost a potential
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
8
solution to maximize dosage to the tumor while protecting organs at risk (Figure 2BC)
The timing and dosevolume selection for our patients deserves further comment We
acknowledge that advanced techniques for conventional fractionation (including VMAT and
proton therapy) likely suffice in many patients without orbital or intracranial extension or
cavernous sinus involvement We have simply been unable to deliver curative doses (ie 70
Gy) in those cases without exceeding the published dosevolume constraints of the temporal
lobes optic andor auditory pathways and brainstem in such cases additionally published
longterm local control using IMRT from highly experienced centers in patients with
cribriform plate extension or T4b disease are approximately 50 and provide evidence of
need for further dose escalation in such cases 22
Reports describing the benefits of SRS in the treatment of SNM and NPC with skull base
invasion have been published but there is no consensus on the optimal dose and
fractionation for SRS in the management of these malignancies Using a LINACbased
platform Cmelak et al reported their data on 47 patients with 59 skull base malignancies
in this study eleven patients were treated with SRS as a boost (median dose 12 Gy range 7
16 Gy) to the nasopharynx after a course of fractionated RT (64870 Gy) without
chemotherapy In this group LC was achieved in all patients without complications with a
median followup of 18 months (range 234 months) 8 Stereotactic andor brachytherapy
boosts have also been incorporated in the upfront treatment of advanced NPC 28–31 For
example intracavitary boost was selectively utilized in the UCSF IMRT experience and
may have contributed to excellent LC in that series (boosts were subsequently not employed
in the RTOG nasopharynx protocols) Similarly Chang et al reported their experience on 23
patients with nasopharyngeal carcinoma treated with SRS Boost (median dose 12 Gy)
following fractionated RT (median dose 66 Gy) SRS boost was delivered utilizing a
framebased LINAC platform LC was achieved in all patients with no complications at a
mean followup of 21 months However 8 patients (35) developed regional or distant
metastases 6 All of these studies demonstrate that SRS is a feasible and safe treatment
option to prevent local recurrence by maximizing the dosage to the tumor particularly those
located in or around the skull base GK provides an opportunity to deliver ablative doses to
the tumor with minimum doses to normal structures compared to other techniques In our
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
9
series we prescribed a median margin dose of 13 Gy which seems to be effective to achieve
high rates of LC (100) with minimal morbidity while protecting organs at risk (Table 1)
Our SRS dose selection also deserves comment as it reflects a compromise between
maximal achievable tumoricidal doses and our interpretation of clinically acceptable normal
tissue constraints for such advanced cases We attempted to deliver a minimum dose of 60
Gy to gross intracranial disease typically using a sequential IMRT approach (30 fractions of
2 Gy) except in cases of intraorbital extension where dose to the homeolateral optic nerve
and chiasm were limited to approximately 50 Gy in 30 fractions and 5 Gy point maximum
from SRS Using an αβ ratio of 16 for optic neuropathy 32 our target Biologically Effective
Dose (BED)16 was calculated as 123 Gy which is more conservative than the dosevolume
constraints of V 60 < 5 from Duprez et al 22 but permitting effective dose escalation to the
boost target volume to 92 Gy 10 compared to 84 Gy 10 using IMRT to 70 Gy in 35 fractions
(ignoring accelerated repopulation see Table 2) Given that IMRT and GK boost planning
was performed using 2 different platforms (Eclipse and Leksell Gamma Plan respectively)
we routinely perform preplanning for the GK boost several days prior to frame placement
and create a composite plan sum in the Eclipse workstation Target coverage and doses to
critical structures are verified prior to delivery As shown in the Figure 3
As our SRS boost approach lacks Level I supportive evidence boost timing and dose
selection were purposely kept conservative and was modeled after the preliminary Stanford
experience for NPC 6 In that study the intent was to deliver the SRS boost within 4 weeks
of RT completion It was our intent to reproduce this interval which we approached in all
but 1 patient (who had an extraordinary delay of 4 months given initial insurance denial
with subsequent approval due to persistent radiographic evidence of an enhancing nodule)
Similarly for cases of advanced NPC the standard of care for initiation of adjuvant
chemotherapy is 4 weeks following completion of RT or the last dose of cisplatin 27 While
the use of adjuvant chemotherapy is controversial recent metaanalysis continues to
demonstrate an overall survival benefit compared to RT alone and induction CT approaches
33 While in theory the 4week delay between completion of RT and SRS boost poses a risk
for tumor repopulation we believe that this is counterbalanced by cytoreduction of residual
enhancing tumor (allowing for reduced boost volume) as well as recovery from treatment
related acute toxicities and potential repair of sublethal damage in neurologic tissues
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
10
Although further prospective investigation is warranted to ascertain optimal boost timing in
this disease emerging prospective trials incorporating External Beam Radiotherapy (EBRT)
and stereotactic or brachytherapy boosts for highrisk prostate 34 and advanced stage III lung
cancer 35 respectively utilized intervals of 23 and approximately 1 month following
completion of EBRT before boost implant and planning respectively therefore our 4week
target appears reasonable in consideration of modern combinedmodality oncologic therapy
The results in our study also demonstrated excellent control of the tumor despite cavernous
sinus invasion which was present in 79 patients (78) with no evidence of cranial
neuropathy in any of the cases Despite the absence of temporal lobe necrosis in the current
series it is important to be aware of this potential complications which may not be well
reflected in our series considereing the limited followup SRS series managing both SNM
and NPC are limited To the best of our knowledge this is the first series of patients
undergoing a planned GK boost for these malignancies in addition to the current established
trimodal treatment The major limitation of the current study is the retrospective nature of
our cohort as well as the limited number of patients Additionally our study includes a
heterogeneous group of patients and the follow up period is limited Nevertheless our
findings demonstrate that a GK boost is feasible well tolerated and might potentially
improve LC and survival in patients with SNM and NPC particularly in cases with
cavernous sinus involvement and as part of an individualized visionsparing multimodality
treatment strategy
• Conclusion
In the context of current SNM and NPC management our preliminary results indicate that
GK boost seems to be an effective treatment modality for SNMNPC with prior IMRT
treatment In our series albeit with the caveat of early followup LC was achieved in all
patients and treatment toxicities were minimal Due to the rarity of these tumors and the
clinical presentation in advanced stages a cooperative or multicentric study is needed There
is a possibility that for selected cases a fourth therapeutic modality could have an impact on
the OS and DFS Additional clinical experience and longer followup are needed to validate
our results and establish the selective use of GK boost in the management of advanced
SNM
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
11






• References

1 Bentz BG Bilsky MH Shah JP Kraus D Anterior skull base surgery for malignant
tumors A multivariate analysis of 27 years of experience Head Neck
200325(7)515520 doi101002hed10250
2 Jackson IT Bailey MH Marsh WR Juhasz P Results and prognosis following
surgery for malignant tumors of the skull base Head Neck 199113(2)8996
3 Luong A Citardi MJ Batra PS Management of sinonasal malignant neoplasms
Defining the role of endoscopy Am J Rhinol Allergy 201024(2)150155
doi102500ajra2010243451
4 Wang K Zanation AM Chera BS The Role of Radiation Therapy in the
Management of Sinonasal and Ventral Skull Base Malignancies Otolaryngol Clin
North Am 201750(2)419432 doi101016jotc201612014
5 Marks LB Yorke ED Jackson A et al Use of Normal Tissue Complication
Probability Models in the Clinic Int J Radiat Oncol Biol Phys 201076(3 SUPPL)
doi101016jijrobp2009071754
6 Chang SD Tate DJ Goffinet DR Martin DP Adler JR Treatment of
nasopharyngeal carcinoma Stereotactic radiosurgical boost following fractionated
radiotherapy Stereotact Funct Neurosurg 199973(14)6467
doi101159000029753
7 Coppa ND Raper DMS Zhang Y et al Treatment of Malignant tumors of the skull
base with multisession radiosurgery J Hematol Oncol 20092111
doi10118617568722216
8 Cmelak AJ Cox RS Adler JR Fee WE Goffinet DR Radiosurgery for skull base
malignancies and nasopharyngeal carcinoma Int J Radiat Oncol Biol Phys
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
12
199737(5)9971003 doi101016S03603016(97)001119
9 Chua DTT Sham JST Kwong PWK Hung KN Leung LHT Linear accelerator
based stereotactic radiosurgery for limited locally persistent and recurrent
nasopharyngeal carcinoma Efficacy and complications Int J Radiat Oncol Biol
Phys 200356(1)177183 doi101016S03603016(03)000749
10 Edge SB Compton CC The american joint committee on cancer The 7th edition of
the AJCC cancer staging manual and the future of TNM Ann Surg Oncol
201017(6)14711474 doi101245s1043401009854
11 Cox JD Stetz J Pajak TF Toxicity criteria of the Radiation Therapy Oncology
Group (RTOG) and the European organization for research and treatment of cancer
(EORTC) Int J Radiat Oncol Biol Phys 199531(5)13411346 doi1010160360
3016(95)00060C
12 Gebhardt BJ Vargo JA Ling D et al Carotid Dosimetry and the Risk of Carotid
Blowout Syndrome After Reirradiation With Head and Neck Stereotactic Body
Radiation Therapy Int J Radiat Oncol Biol Phys 2018101(1)195200
doi101016jijrobp201711045
13 Cohen J Rad I Contemporary management of carotid blowout Curr Opin
Otolaryngol Head Neck Surg 200412(2)110115 doi10109700020840
20040400000010
14 EINaggar A Chan JK Grandis J Takata T Slootweg P World Health
Organization Classification of Tumours 2017
15 Turner JH Reh DD Incidence and survival in patients with sinonasal cancer A
historical analysis of populationbased data Head Neck 201234(6)877885
doi101002hed21830
16 Petersson F Nasopharyngeal carcinoma A review Semin Diagn Pathol
201532(1)5473 doi101053jsemdp201502021
17 Musy PY Reibel JF Levine PA Sinonasal Undifferentiated Carcinoma The Search
for a Better Outcome Laryngoscope 2002112(8)14501455
doi1010970000553720020800000023
18 Eloy JA Vivero RJ Hoang K et al Comparison of transnasal endoscopic and open
craniofacial resection for malignant tumors of the anterior skull base Laryngoscope
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
13
2009119(5)834840 doi101002lary20186
19 Svider PF Setzen M Baredes S Liu JK Eloy JA Overview of Sinonasal and
Ventral Skull Base Malignancy Management Otolaryngol Clin North Am
201750(2)205219 doi101016jotc201612001
20 Blanco AI Chao KSC Ozyigit G et al Carcinoma of paranasal sinuses Longterm
outcomes with radiotherapy Int J Radiat Oncol Biol Phys 200459(1)5158
doi101016jijrobp200309101
21 Chen AM Daly ME Bucci MK et al Carcinomas of the Paranasal Sinuses and
Nasal Cavity Treated With Radiotherapy at a Single Institution Over Five Decades
Are We Making Improvement Int J Radiat Oncol Biol Phys 200769(1)141147
doi101016jijrobp200702031
22 Duprez F Madani I Morbée L et al IMRT for sinonasal tumors minimizes severe
late ocular toxicity and preserves disease control and survival Int J Radiat Oncol
Biol Phys 201283(1)252259 doi101016jijrobp2011061977
23 Kamran SC Riaz N Lee N Nasopharyngeal Carcinoma Surg Oncol Clin N Am
201524(3)547561 doi101016jsoc201503008
24 Sanguineti G Geara FB Garden AS et al Carcinoma of the nasopharynx treated by
radiotherapy alone Determinants of local and regional control Int J Radiat Oncol
Biol Phys 199737(5)985996 doi101016S03603016(97)001041
25 Johansen LV Mestre M Overgaard J Carcinoma of the nasopharynx Analysis of
treatment results in 167 consecutively admitted patients Head Neck
199214(3)200207 doi101002hed2880140307
26 Lee AWM Poon YF Foo W et al Retrospective analysis of 5037 patients with
nasopharyngeal carcinoma treated during 19761985 overall survival and patterns of
failure Int J Radiat Oncol Biol Phys 199223(2)261270 doi1010160360
3016(92)907409
27 AlSarraf M LeBlanc M Giri PG et al Chemoradiotherapy versus radiotherapy in
patients with advanced nasopharyngeal cancer phase III randomized Intergroup
study 0099 J Clin Oncol 199816(4)13101317 doi101200JCO19981641310
28 Chan ATC Teo PML Leung TWT et al A prospective randomized study of
chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
14
carcinoma Int J Radiat Oncol Biol Phys 199533(3)569577 doi1010160360
3016(95)00218N
29 Lee N Xia P Quivey JM et al Intensitymodulated radiotherapy in the treatment of
nasopharyngeal carcinoma An update of the UCSF experience Int J Radiat Oncol
Biol Phys 200253(1)1222 doi101016S03603016(02)027244
30 Chang JT See LC Tang SG Lee SP Wang CC Hong JH The role of
brachytherapy in earlystage nasopharyngeal carcinoma Int J Radiat Oncol Biol
Phys 199636(5)10191024 doi101016S03603016(96)004166
31 Levendag PC Peters R Meeuwis CA et al A new applicator design for
endocavitary brachytherapy of cancer in the nasopharynx Radiother Oncol
199745(1)9598 doi101016S01678140(97)001059
32 Jiang GL Tucker SL Guttenberger R et al Radiationinduced injury to the visual
pathway Radiother Oncol 199430(1)1725 doi10101601678140(94)900051
33 RibassinMajed L Marguet S Lee AWM et al What is the best treatment of locally
advanced nasopharyngeal carcinoma an individual patient data network meta
analysis J Clin Oncol 201735(5)498505 doi101200JCO2016674119
34 Morris WJ Tyldesley S Rodda S et al Androgen Suppression Combined with
Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDERT Trial)
An Analysis of Survival Endpoints for a Randomized Trial Comparing a LowDose
Rate Brachytherapy Boost to a DoseEscalated External Beam Boost for High and
Intermediaterisk Prostate Cancer Int J Radiat Oncol Biol Phys 201798(2)275
285 doi101016jijrobp201611026
35 Feddock J Arnold SM Shelton BJ et al Stereotactic body radiation therapy can be
used safely to boost residual disease in locally advanced nonsmall cell lung cancer
A prospective study Int J Radiat Oncol Biol Phys 201385(5)13251331
doi101016jijrobp201211011

MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
Characteristics of the Patients
Patient Age Gender Tumor
Location Surgery Pathology
(WHO grade) Chemotherapy Clinical
Stage
IMRT
(GyFractions)
Interval
IMRTG
K
(months)
Number
of
Treated
Targets
Volume
(cm3)
GK
Dose
(Gy)
Number
of
Isocenters
CS
Invasion
Toxicity
(grade)
Followup
(months)
1 39 M Nasal Cavity TNE SNUC
(grade IV) Yes IVB 6030 1 3
795 14
67 Yes II 21 644 12
123 12
2 51 F Ethmoid CFRTNE High grade MEC
(NA) Yes IVA 6030 1 1 794 12 75 Yes I 7
3 36 M Ethmoid TNE ENB
(NA) No Kadish
Morita C NA NA 1 117 20 28 No I 32
4 61 F Maxillary
Sinus TNE
Keratinizing
SCC
(grade I)
Yes IVA 6030 3 1 276 12 60 Yes II 29
5 20 M Nasopharynx CFRTNE
Keratinizing
SCC
(grade I)
Yes IVC 7035 1 1 174 10 82 Yes II 11
6 63 M Nasopharynx Biopsy
Nonkeratinizing
SCC
(grade II)
Yes IVA 7035 4 1 555 12 39 No I 23
7 52 F Nasopharynx TNE SNUC
(grade IV) Yes IVA 7035 2 1 245 12 34 Yes I 13
8 42 M Nasal Cavity CFRTNE
Keratinizing
SCC
(grade I)
Yes IVA 5427 3 2
379 15
110 Yes II 4
822 14
9 59 F Nasopharynx TNE
Keratinizing
SCC
(grade I)
Yes IVC 7035 2 1 48 12 205 Yes I 8
MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
Table 1 Abbreviations CS Cavernous Sinus TNE Transnasal Endoscopy CRF Craniofacial Resection SNUC Sinonasal Undifferentiated Carcinoma SCC Squamous Cell Carcinoma ENB
Esthesioneuroblastoma MEC Mucoepidermoid Carcinoma NA Not Applicable




BED – GK Boost
Tissue BED n d ααααββββ
Tumor – SRS Boost 20 1 10 10
Tumor EBRT 72 30 2 10
Tumor Reference 84 35 10

Optic Neuropathy 21 1 5 16
Optic Neuropathy 102 30 1667 16
Optic Neuropathy Reference 124 35 1714 16
Table 2 Abbreviations GK Gamm Knife BED Biologically Effective Dose SRS Stereotactic Radiosurgery EBRT External Beam
Radiotherapy

MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
• Figure Legend

Figure 1 Prior IMRT Patient No 4 underwent to a right orbital exenteration and
maxillectomy AB Treatment plan showing the composite IMRT and GK dose distribution
in axial and coronal views The cavernous sinus is encompassed by the 70 Gy isodose line
(yellow) and the brainstem surface receives less than 54 Gy (blue isodose line) C
Composite plan DVH shows maximum left optic nerve and chiasm doses of 32Gy and 38 Gy
respectively while the right temporal lobe V70 is less than 1 cc

Figure 2 Treatment planning CT and dose distribution of case No 7 showing a
nasopharyngeal tumor extending through the pterygopalatine fossa into the cavernous sinus
A Axial view showing the IMRT dose distribution with the 54 Gy isodose line (black)
finishing at the inferior rectus muscle (red arrow) B and C display the composite isodose
distribution (IMRT + GK boost) B Axial view demonstrates the 70 Gy isodose line
(yellow) with temporal lobe V70 of 1 cc and steep dose falloff C Coronal view illustrates
the sharp craniocaudal dose falloff with the 54 Gy isodose line (black) just inferior to the
optic nerve

Figure 3 Representing a recently treated patient with squamous cell carcinoma of the orbit
requiring exenteration with invasion of the ipsilateral critical structures the steep dose
gradients achieved with GKRS allows for effective dose escalation with minimal impact on
doses to the adjacent critical structures including the brainstem and contralateral optic nerve
(boost target in light green)






MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT









MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
1
Highlights

• Treatment of both sinonasal malignancies and nasopharyngeal carcinoma is
complex and requires a multimodal approach
• Surgery and conventional radiation approaches provide suboptimal tumor control
for tumors invading intracranial structures (ie cavernous sinus)
• Gamma Knife Radiosurgery boost appears to improve local control selected cases
with acceptable toxicity








MANUSCRIPT
ACCEPTED
ACCEPTED MANUSCRIPT
Abbreviations

SNM Sinonasal malignancies NPC Nasopharyngeal Carcinomas IMRT Intensity
Modulated Radiation Therapy RT Radiotherapy GK Gamma Knife LC Local Control
SRS Stereotactic Radiosurgery IRB Institutional Review Board CT Computerized
Tomography MRI Magnetic Resonance Imaging GTV Gross Tumor Volume CTV
Clinical Target Volume (CTV) PTV Planning Target Volume DFS DiseaseFree
Survival OS Overall Survival WHO World Health Organization BED Biologically
Effective Dose EBRT External Beam Radiotherapy



《香当网》用户分享的内容，不代表《香当网》观点或立场，请自行判断内容的真实性和可靠性！
该内容是文档的文本内容，更好的格式请下载文档